The Neurobiology of Anorexia Nervosa: Insights into Pathophysiology and Novel Drug Targets

**51**

**Chapter 4**

**Abstract**

**1. Introduction**

Nervosa

*Ashley Higgins*

The Neurobiology of Anorexia

Anorexia nervosa is considered the most deadly psychological illness. Individuals with and recovered from anorexia nervosa experience numerous physical and mental health difficulties, and treatment outcomes remain unpromising. Anorexia nervosa is rare in the general population, but common among individuals with a first-degree relative with the disorder. In addition, the onset of anorexia nervosa is developmentally specific, which suggests a partly biological etiology. A better understanding of the biological and neurobiological etiology of anorexia nervosa is direly needed to inform new therapies and to identify individuals at risk for the disorder. This paper summarizes the research related to neurotransmitter abnormalities, aberrant brain activity, and genetic and epigenetic mechanisms that

**Keywords:** anorexia nervosa, neurobiology, neurotransmitters, genetics, etiology

Anorexia nervosa (AN) is a serious psychological disorder characterized by low body weight, unhealthy weight loss methods, and an extreme focus on weight and body shape [1]. AN is associated with significant mortality risks due to medical complications, as well as the fact that one in five patients with AN die by suicide [2, 3]. The physical sequelae of AN, which are caused by self-starvation, affect nearly every major organ system. For instance, the gastrointestinal complications of AN include dysphagia [4], delayed gastric emptying [5], and risk of gastric dilation or even perforation [6]. Hematological and musculoskeletal complications include osteoporosis, fracture risk [7], and low red and white blood cell counts [8]. The endocrine system is impacted via elevated cortisol and growth hormones, low serum thyroid levels, and hypoglycemia [5, 9]. Dermatological complications include lanugo, acrocyanosis, and thinning hair [10]. Neurological complications, which will be discussed in depth throughout this chapter, are well-documented in terms of the effects of longterms caloric restriction on brain volume and neural activity [11]. Finally, cardiac complications, which are most often linked to mortality in AN, include bradycardia

[12], prolonged QTc interval [13], and left ventricular atrophy [14].

Current medication and psychotherapies have limited success in treating AN. The prognosis is especially poor if treatment begins more than 3 years after the onset of symptoms [15]. AN currently has no viable treatment options [16], as current medications and psychotherapies provide only minor to modest effects, with especially poor outcomes among women with entrenched AN [16–18]. It is estimated that only half of individuals with AN achieve full remission of symptoms,

may contribute to the etiology of this deadly disorder.

#### **Chapter 4**

## The Neurobiology of Anorexia Nervosa

*Ashley Higgins*

#### **Abstract**

Anorexia nervosa is considered the most deadly psychological illness. Individuals with and recovered from anorexia nervosa experience numerous physical and mental health difficulties, and treatment outcomes remain unpromising. Anorexia nervosa is rare in the general population, but common among individuals with a first-degree relative with the disorder. In addition, the onset of anorexia nervosa is developmentally specific, which suggests a partly biological etiology. A better understanding of the biological and neurobiological etiology of anorexia nervosa is direly needed to inform new therapies and to identify individuals at risk for the disorder. This paper summarizes the research related to neurotransmitter abnormalities, aberrant brain activity, and genetic and epigenetic mechanisms that may contribute to the etiology of this deadly disorder.

**Keywords:** anorexia nervosa, neurobiology, neurotransmitters, genetics, etiology

#### **1. Introduction**

Anorexia nervosa (AN) is a serious psychological disorder characterized by low body weight, unhealthy weight loss methods, and an extreme focus on weight and body shape [1]. AN is associated with significant mortality risks due to medical complications, as well as the fact that one in five patients with AN die by suicide [2, 3]. The physical sequelae of AN, which are caused by self-starvation, affect nearly every major organ system. For instance, the gastrointestinal complications of AN include dysphagia [4], delayed gastric emptying [5], and risk of gastric dilation or even perforation [6]. Hematological and musculoskeletal complications include osteoporosis, fracture risk [7], and low red and white blood cell counts [8]. The endocrine system is impacted via elevated cortisol and growth hormones, low serum thyroid levels, and hypoglycemia [5, 9]. Dermatological complications include lanugo, acrocyanosis, and thinning hair [10]. Neurological complications, which will be discussed in depth throughout this chapter, are well-documented in terms of the effects of longterms caloric restriction on brain volume and neural activity [11]. Finally, cardiac complications, which are most often linked to mortality in AN, include bradycardia [12], prolonged QTc interval [13], and left ventricular atrophy [14].

Current medication and psychotherapies have limited success in treating AN. The prognosis is especially poor if treatment begins more than 3 years after the onset of symptoms [15]. AN currently has no viable treatment options [16], as current medications and psychotherapies provide only minor to modest effects, with especially poor outcomes among women with entrenched AN [16–18]. It is estimated that only half of individuals with AN achieve full remission of symptoms, and even recovered patients typically maintain a low weight and experience chronic depressive symptoms [19]. Given the lack of viable treatment options for AN, leading eating disorders researchers are now recommending that future research focus on identification of risk factors and other preventive strategies [20, 21].

Many of the identified risk factors for AN are biological or genetic in nature. AN is a rare disorder, with estimated lifetime prevalence ranging from 0.1 to 3.6%, and a point prevalence rate ranging from 0.1 to 1.2% in the general population [22]. Though the overall prevalence of AN is quite low, AN represents the third most common chronic illness with adolescent onset [23]. In addition, the risk of AN is elevated among individuals with a family history of AN. It is a well-documented finding that AN tends to run in families [24, 25]. Some studies have found a 10-fold risk of AN among first-degree relatives of individuals with the disorder [26–28] or an overall heritability of 0.56 [25]. Furthermore, AN has a developmentally specific age of onset. Taken together, these findings suggest the presence of biological and/ or genetic risk factors in the etiology of AN [29].

Individuals with AN often display a relentless pursuit of further weight loss and believe themselves to be overweight even when they are emaciated. In addition to pathological eating patterns, individuals with EDs also experience a host of unusual symptoms, such as "(1) extremes of behavioral inhibition and dysinhibition; (2) anxiety, depression, and obsessionality; and (3) puzzling symptoms such as body image distortion, perfectionism, and anhedonia" ([30], p. 38) as well as "intense body-focused anxiety, self-disgust, compulsive behavior and altered information processing—i.e. raised pain threshold, reduced sense of taste, anosognosia, inability to integrate thoughts and feelings, poor visuospatial memory, cognitive rigidity and weak central coherence" ([31], p. 580). Any biological mechanisms accounting for the inherent eating pathology of AN should also modulate these emotional and cognitive phenomena.

Identifying true risk factors for AN presents a complicated methodological problem. By definition, a risk factor must be present prior to the onset of illness, and identifying these factors prior to the symptom onset requires a prospective design [32]. However, given the low prevalence rate of AN, prospective studies are often too complicated to perform; thus, the research literature on AN risk factors is often limited to retrospective studies, with their inherent bias in retrospective recall [33].

Another methodological approach samples from individuals who have recovered from AN (RECAN). While recovery from AN is a long and ill-defined process, more than half of individuals with AN are able to completely or partly achieve remission [34]. Individuals RECAN are assumed to no longer be experiencing the sequelae of the starvation state. However, the use of individuals RECAN is limited as a methodological approach in that "scar" effects from a period of illness could be misidentified as premorbid risk factors [35]. In order to circumvent the possibility of "scar" effects, studies must identify endophenotypes that are present among individuals with active AN, individuals RECAN, and among unaffected family members [36, 37]. Utilizing this approach, several potential endophenotypes have been identified, by eliminating any neurobiological findings that improve with refeeding and identifying abnormalities that are shared by individuals with AN and their unaffected family members [16].

Many of the neurobiological phenomena to be discussed in this paper are present premorbidly, exaggerated by malnutrition, and return to premorbid levels after recovery [38]. There are currently promising lines of research on dopaminergic [29], serotonergic [39], and noradrenergic pathways [31], as well as dysregulations in appetitive functioning [30], genetic and epigenetic contributions [40, 41], contributions from gonadal hormones [42], and aberrations in brain activity [43].

**53**

*The Neurobiology of Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.82751*

Dopaminergic functioning modulates reward and affect, and an aberration in dopaminergic functioning has been implicated in obsessive or ritualistic behaviors, such as the food rituals observed in individuals with AN [29]. It seems intuitive that reward functioning is impaired in AN, as individuals with AN often present as abstemious, anhedonic, and temperate in a multitude of behaviors even in childhood, long before the onset of symptoms [44]. Dopamine is central in processing reward in both primary and secondary reinforcers, including food [45–47]. Several research studies have revealed altered striatal dopamine function in individuals with and RECAN [29, 48, 49]. Ingestion of highly palatable foods, such as high-sugar foods, may trigger dopamine release in individuals without AN; this release of dopamine in response to food is similar to the release of dopamine elicited by amphetamine use, which is often associated with feelings of euphoria [50]. However, among individuals RECAN, amphetamine use triggers the expected endogenous dopamine release, but this release of dopamine is experienced as highly unpleasant and anxiogenic [51]. If similar processes take effect during exposure to highly palatable food, which would be experienced as highly anxiogenic to individuals with AN, this could partially account for the persistence that individuals with AN display in their pursuit of self-starvation; if food is anxiogenic, self-starvation downregulates this anxiety. Whereas individuals without AN experience pleasure from foods, individuals with AN find it aversive. Thus, the reinforcing aspects of food are not experienced by individuals with active AN or individuals RECAN.

Reward processing in general appears to be altered in individuals with AN, even in situations that do not involve food- or weight-related cues. In fMRI research, individuals RECAN failed to differentiate between winning and losing money in a gambling task [52]. Therefore, individuals with AN may have a diminished ability to identify the positive or negative value of a stimulus. Individuals with AN fail to show appropriate appetitive motivational system activation to a variety of cues [49]. Thus, altered dopaminergic function reflects high conditioning of reward for disease-salient stimuli, but a failure to respond appropriately to other positive and

Among individuals RECAN, dopamine metabolite concentrations in the cerebral

spinal fluid remain depleted years after the disorder [53]. Perhaps to correct for this depletion, dopamine 2 and 3 (D2/D3) receptor binding in the ventral striatum is elevated among individuals RECAN [44]. At this time there are no publications on dopamine aberrations in unaffected family members. However, animal models of anorexia strongly suggest a dopaminergic endophenotype, as administering dopamine antagonists in activity-based anorexia in rats facilitates increased food intake [54]. This hints at a dopaminergic role in promoting weight loss, which can

be reversed with psychopharmacology that acts on the dopamine system.

Additionally, serotonergic (5-HT) dysfunction may be a biological marker for AN. Serotonin has seemed a likely candidate for some time, given this neurotransmitter's active influence in modulating mood and appetite [29]. A recent meta-analysis has concluded that being a carrier of the S allele of the 5-HTTLPR polymorphism of the serotonin transporter gene is predictive of eating disorders, particularly anorexia [55]. The gene coding of the serotonin transporter (5-HTT) works in the presynaptic neuron to terminate serotonin activity in the synapse and recycle serotonin back into the presynaptic neuron. 5-HTT is coded by a gene on

**2. Dopamine**

negative cues [18].

**3. Serotonin**

#### **2. Dopamine**

*Anorexia and Bulimia Nervosa*

cognitive phenomena.

family members [16].

brain activity [43].

and even recovered patients typically maintain a low weight and experience chronic depressive symptoms [19]. Given the lack of viable treatment options for AN, leading eating disorders researchers are now recommending that future research focus

Many of the identified risk factors for AN are biological or genetic in nature. AN is a rare disorder, with estimated lifetime prevalence ranging from 0.1 to 3.6%, and a point prevalence rate ranging from 0.1 to 1.2% in the general population [22]. Though the overall prevalence of AN is quite low, AN represents the third most common chronic illness with adolescent onset [23]. In addition, the risk of AN is elevated among individuals with a family history of AN. It is a well-documented finding that AN tends to run in families [24, 25]. Some studies have found a 10-fold risk of AN among first-degree relatives of individuals with the disorder [26–28] or an overall heritability of 0.56 [25]. Furthermore, AN has a developmentally specific age of onset. Taken together, these findings suggest the presence of biological and/

Individuals with AN often display a relentless pursuit of further weight loss and believe themselves to be overweight even when they are emaciated. In addition to pathological eating patterns, individuals with EDs also experience a host of unusual

(2) anxiety, depression, and obsessionality; and (3) puzzling symptoms such as body image distortion, perfectionism, and anhedonia" ([30], p. 38) as well as "intense body-focused anxiety, self-disgust, compulsive behavior and altered information processing—i.e. raised pain threshold, reduced sense of taste, anosognosia, inability to integrate thoughts and feelings, poor visuospatial memory, cognitive rigidity and weak central coherence" ([31], p. 580). Any biological mechanisms accounting for the inherent eating pathology of AN should also modulate these emotional and

Identifying true risk factors for AN presents a complicated methodological problem. By definition, a risk factor must be present prior to the onset of illness, and identifying these factors prior to the symptom onset requires a prospective design [32]. However, given the low prevalence rate of AN, prospective studies are often too complicated to perform; thus, the research literature on AN risk factors is often limited to retrospective studies, with their inherent bias in retrospective recall [33]. Another methodological approach samples from individuals who have recovered from AN (RECAN). While recovery from AN is a long and ill-defined process, more than half of individuals with AN are able to completely or partly achieve remission [34]. Individuals RECAN are assumed to no longer be experiencing the sequelae of the starvation state. However, the use of individuals RECAN is limited as a methodological approach in that "scar" effects from a period of illness could be misidentified as premorbid risk factors [35]. In order to circumvent the possibility of "scar" effects, studies must identify endophenotypes that are present among individuals with active AN, individuals RECAN, and among unaffected family members [36, 37]. Utilizing this approach, several potential endophenotypes have been identified, by eliminating any neurobiological findings that improve with refeeding and identifying abnormalities that are shared by individuals with AN and their unaffected

Many of the neurobiological phenomena to be discussed in this paper are present premorbidly, exaggerated by malnutrition, and return to premorbid levels after recovery [38]. There are currently promising lines of research on dopaminergic [29], serotonergic [39], and noradrenergic pathways [31], as well as dysregulations in appetitive functioning [30], genetic and epigenetic contributions [40, 41], contributions from gonadal hormones [42], and aberrations in

symptoms, such as "(1) extremes of behavioral inhibition and dysinhibition;

on identification of risk factors and other preventive strategies [20, 21].

or genetic risk factors in the etiology of AN [29].

**52**

Dopaminergic functioning modulates reward and affect, and an aberration in dopaminergic functioning has been implicated in obsessive or ritualistic behaviors, such as the food rituals observed in individuals with AN [29]. It seems intuitive that reward functioning is impaired in AN, as individuals with AN often present as abstemious, anhedonic, and temperate in a multitude of behaviors even in childhood, long before the onset of symptoms [44]. Dopamine is central in processing reward in both primary and secondary reinforcers, including food [45–47]. Several research studies have revealed altered striatal dopamine function in individuals with and RECAN [29, 48, 49]. Ingestion of highly palatable foods, such as high-sugar foods, may trigger dopamine release in individuals without AN; this release of dopamine in response to food is similar to the release of dopamine elicited by amphetamine use, which is often associated with feelings of euphoria [50]. However, among individuals RECAN, amphetamine use triggers the expected endogenous dopamine release, but this release of dopamine is experienced as highly unpleasant and anxiogenic [51]. If similar processes take effect during exposure to highly palatable food, which would be experienced as highly anxiogenic to individuals with AN, this could partially account for the persistence that individuals with AN display in their pursuit of self-starvation; if food is anxiogenic, self-starvation downregulates this anxiety. Whereas individuals without AN experience pleasure from foods, individuals with AN find it aversive. Thus, the reinforcing aspects of food are not experienced by individuals with active AN or individuals RECAN.

Reward processing in general appears to be altered in individuals with AN, even in situations that do not involve food- or weight-related cues. In fMRI research, individuals RECAN failed to differentiate between winning and losing money in a gambling task [52]. Therefore, individuals with AN may have a diminished ability to identify the positive or negative value of a stimulus. Individuals with AN fail to show appropriate appetitive motivational system activation to a variety of cues [49]. Thus, altered dopaminergic function reflects high conditioning of reward for disease-salient stimuli, but a failure to respond appropriately to other positive and negative cues [18].

Among individuals RECAN, dopamine metabolite concentrations in the cerebral spinal fluid remain depleted years after the disorder [53]. Perhaps to correct for this depletion, dopamine 2 and 3 (D2/D3) receptor binding in the ventral striatum is elevated among individuals RECAN [44]. At this time there are no publications on dopamine aberrations in unaffected family members. However, animal models of anorexia strongly suggest a dopaminergic endophenotype, as administering dopamine antagonists in activity-based anorexia in rats facilitates increased food intake [54]. This hints at a dopaminergic role in promoting weight loss, which can be reversed with psychopharmacology that acts on the dopamine system.

#### **3. Serotonin**

Additionally, serotonergic (5-HT) dysfunction may be a biological marker for AN. Serotonin has seemed a likely candidate for some time, given this neurotransmitter's active influence in modulating mood and appetite [29]. A recent meta-analysis has concluded that being a carrier of the S allele of the 5-HTTLPR polymorphism of the serotonin transporter gene is predictive of eating disorders, particularly anorexia [55]. The gene coding of the serotonin transporter (5-HTT) works in the presynaptic neuron to terminate serotonin activity in the synapse and recycle serotonin back into the presynaptic neuron. 5-HTT is coded by a gene on

chromosome 17, and the 5-HTTLPR polymorphism of this gene has the greatest impact on behavior. The S allele is a short variant of this 5-HTTLPR polymorphism, which decreases the availability of 5-HTT and results in dysphoria.

In terms of appetite, any treatment that increases intrasynaptic 5-HT or activates 5-HT receptors will reduce appetite and food consumption, while any treatment that reduces transmission or blocks receptors will promote weight gain [56]. Caloric restriction has an enormous impact on the available serotonin in the brain [29]. Tryptophan is one of 20 essential amino acids and can be absorbed only through caloric intake, especially carbohydrate intake [57]. Tryptophan, through a series of chemical processes, becomes serotonin. A restricted diet limits the amount of tryptophan (and, therefore, the amount of serotonin) that is available to the brain [58]. In addition, a restricted diet decreases the rate of synthesis in serotonin receptors and the density of serotonin transporters, which results in oversensitivity to serotonin in postsynaptic receptors [59]. Not surprisingly, individuals in the acutely ill state have lowered concentrations of the 5-HT metabolite 5-HIAA in the cerebral spinal fluid [56]. However, elevated levels of 5-HIAA were likely present premorbidly. Individuals with AN premorbidly report high levels of anxiety, dysphoria, and obsessionality, which are associated with high levels of 5-HT in the synapse [42]. Dieting actually serves to regulate the 5-HT in the synapse. This reduction of serotonin, in the short term, results in anxiolytic effects for people who restrict calories [29]. These anxiolytic effects could explain why individuals with AN cling so desperately to their restrictive behaviors: these behaviors are inadvertently medicating underlying anxiety.

The serotonin system includes at least 14 different receptors. The 5-HT1A and 5-HT2A receptors appear most influential in the pathogenesis of AN. The 5-HT1A autoreceptor serves to decrease 5-HT transmission [56]. Individuals with AN have 50–70% more binding at these receptors, and retain 20–40% more binding after recovery. In addition, the 5-HT1A receptor may play a role in the efficacy of selective serotonin reuptake inhibitors (SSRIs), which are potently effective at treating depression and anxiety [60, 61]. While starvation decreases 5-HT across the brain, the overactive 5-HT1A receptor continues to inhibit 5-HT transmission. The combination of these forces is so powerful that SSRIs exert minimal impact in increasing intrasynaptic 5-HT, which fails to provide symptom relief for individuals with AN [56]. In AN, SSRIs fail to desensitize 5-HT1A receptors, which inhibits presynaptic 5-HT.

Newer imaging technologies, such as PET imaging with selective neurotransmitter radioligands, allow for viewing in vivo neurotransmitter activity in the brain. Postsynaptic 5-HT2A receptors have been studied in this way. The 5-HT2A receptor has been afforded special attention because activity at this receptor is influential in two of the central, yet most perplexing, symptoms of AN: poor problem-solving abilities and distorted body image [62, 63]. 5-HT2A receptor binding is reduced in several brain areas, especially in the cingulate and temporal regions. The cingulate-temporal dysfunction could be related to inefficient problem-solving behaviors among individuals with AN, who struggle with incorporating affective and social stimuli into tasks [64]. Individuals with AN do not seem to learn from mistakes, but stubbornly and obsessively use the same strategies, despite poor results. This could indicate dysfunction in executive functioning and planning. In terms of distorted body image, which is characterological for individuals with AN, 5-HT2A disturbances in the left parietal region of the brain are thought to be responsible [62]. Lesions in the right parietal region have been associated with neglect, which could be theoretically related to body image distortion, especially if this information is coded in the parietal regions of each hemisphere [56]. The activity at 5-HT2A receptors remains dysregulated even after a year of maintaining normal weight, regular menstruation, and no binge/purging/ restricting. Prolonged dysregulation at these receptors may partially account for the inefficacy of SSRIs in treating AN, regardless of the phase of the disorder [17, 18].

**55**

remain as to:

*The Neurobiology of Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.82751*

pharmacological interventions for AN.

better account for this vast range of deficits.

insula, which will be discussed in the next section.

**5. Brain volume, blood flow, and neural activity**

**4. Norepinephrine**

Additionally, serotonergic dysfunction is common to other psychiatric concerns, especially those that are likely to be comorbid with AN, such as major depression [65] and anxiety disorders [66]. While abnormalities in serotonergic functioning are common to all of these disorders, different patterns of serotonergic functioning emerge on a molecular level [67]. While 5-HT1A receptor binding is often decreased in individuals with or recovered from depression [68, 69] and panic disorder [70], 5-HT1A receptor binding is increased in individuals with AN [29]. This could indicate that serotonergic dysfunction is a common vulnerability for a variety of disorders, with disorder-specific patterns at the neuronal level. This also accounts for higher rates of psychiatric concerns among family members of individuals with AN.

Given etiological research on the separate roles of dopamine and serotonin, it is not surprising that the most recent research suggests that interactions between serotonin and dopamine activity truly elicit and maintain the eating pathology of AN [56]. This interaction is not well understood, but could hold promise for future

Based on previous research on dopaminergic and serotonergic dysfunction in individuals with active AN, individuals RECAN, and unaffected family members, it is safe to conclude that neurotransmitter activity is aberrant both during the premorbid, active, and recovery periods of AN. Dopaminergic and serotonergic pathways could account for some, though not all, of the core symptoms of AN [29, 42]. While these pathways (particularly the serotonergic pathway) partly account for rigidity and perfectionism among individuals with AN, individuals with AN display a variety of perplexing symptoms that seem unrelated to both the starvation state itself or serotonin dysfunction alone; individuals with AN report difficulty with pain perceptual, alexithymia, reduced sense of taste, as well as numerous other perplexing symptoms [31]. Aberrant activity in the noradrenergic pathway could

Norepinephrine is a neurotransmitter which serves multiple functions in the body and brain, including regulation of sympathetic arousal/anxiety and cerebral blood flow [71]. Norepinephrine levels are elevated premorbidly in AN [72], but appear to be decreased in plasma and cerebrospinal fluid during active AN ad RECAN [72–74]. Premorbidly high levels of norepinephrine lead to high sympathetic arousal and anxiety [31]. Among individuals with AN, this anxiety is often focused on food- and weight-related issues, though the inherently high trait levels of perfectionism and neuroticism can manifest in other achievement domains such as schoolwork or sports [75]. Since this anxiety is linked an abundance of norepinephrine, dieting in the early stages of AN counteracts this by depleting the brain of the precursors to norepinephrine that are normally ingested through food [31]. Dieting is then maintained through negative reinforcement, leading to a reduction in body weight and entrenchment of AN symptoms. Furthermore, aberrant activity in the noradrenergic system has been linked to irregular patterns of activation in the

Various neuroimaging studies show substantial structural abnormalities in the brain among individuals with active AN [30, 76, 77]. However, significant questions

#### *The Neurobiology of Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.82751*

*Anorexia and Bulimia Nervosa*

chromosome 17, and the 5-HTTLPR polymorphism of this gene has the greatest impact on behavior. The S allele is a short variant of this 5-HTTLPR polymorphism,

In terms of appetite, any treatment that increases intrasynaptic 5-HT or activates 5-HT receptors will reduce appetite and food consumption, while any treatment that reduces transmission or blocks receptors will promote weight gain [56]. Caloric restriction has an enormous impact on the available serotonin in the brain [29]. Tryptophan is one of 20 essential amino acids and can be absorbed only through caloric intake, especially carbohydrate intake [57]. Tryptophan, through a series of chemical processes, becomes serotonin. A restricted diet limits the amount of tryptophan (and, therefore, the amount of serotonin) that is available to the brain [58]. In addition, a restricted diet decreases the rate of synthesis in serotonin receptors and the density of serotonin transporters, which results in oversensitivity to serotonin in postsynaptic receptors [59]. Not surprisingly, individuals in the acutely ill state have lowered concentrations of the 5-HT metabolite 5-HIAA in the cerebral spinal fluid [56]. However, elevated levels of 5-HIAA were likely present premorbidly. Individuals with AN premorbidly report high levels of anxiety, dysphoria, and obsessionality, which are associated with high levels of 5-HT in the synapse [42]. Dieting actually serves to regulate the 5-HT in the synapse. This reduction of serotonin, in the short term, results in anxiolytic effects for people who restrict calories [29]. These anxiolytic effects could explain why individuals with AN cling so desperately to their restrictive behaviors: these behaviors

The serotonin system includes at least 14 different receptors. The 5-HT1A and 5-HT2A receptors appear most influential in the pathogenesis of AN. The 5-HT1A autoreceptor serves to decrease 5-HT transmission [56]. Individuals with AN have 50–70% more binding at these receptors, and retain 20–40% more binding after recovery. In addition, the 5-HT1A receptor may play a role in the efficacy of selective serotonin reuptake inhibitors (SSRIs), which are potently effective at treating depression and anxiety [60, 61]. While starvation decreases 5-HT across the brain, the overactive 5-HT1A receptor continues to inhibit 5-HT transmission. The combination of these forces is so powerful that SSRIs exert minimal impact in increasing intrasynaptic 5-HT, which fails to provide symptom relief for individuals with AN [56]. In AN,

SSRIs fail to desensitize 5-HT1A receptors, which inhibits presynaptic 5-HT.

Newer imaging technologies, such as PET imaging with selective neurotransmitter radioligands, allow for viewing in vivo neurotransmitter activity in the brain. Postsynaptic 5-HT2A receptors have been studied in this way. The 5-HT2A receptor has been afforded special attention because activity at this receptor is influential in two of the central, yet most perplexing, symptoms of AN: poor problem-solving abilities and distorted body image [62, 63]. 5-HT2A receptor binding is reduced in several brain areas, especially in the cingulate and temporal regions. The cingulate-temporal dysfunction could be related to inefficient problem-solving behaviors among individuals with AN, who struggle with incorporating affective and social stimuli into tasks [64]. Individuals with AN do not seem to learn from mistakes, but stubbornly and obsessively use the same strategies, despite poor results. This could indicate dysfunction in executive functioning and planning. In terms of distorted body image, which is characterological for individuals with AN, 5-HT2A disturbances in the left parietal region of the brain are thought to be responsible [62]. Lesions in the right parietal region have been associated with neglect, which could be theoretically related to body image distortion, especially if this information is coded in the parietal regions of each hemisphere [56]. The activity at 5-HT2A receptors remains dysregulated even after a year of maintaining normal weight, regular menstruation, and no binge/purging/ restricting. Prolonged dysregulation at these receptors may partially account for the inefficacy of SSRIs in treating AN, regardless of the phase of the disorder [17, 18].

which decreases the availability of 5-HTT and results in dysphoria.

are inadvertently medicating underlying anxiety.

**54**

Additionally, serotonergic dysfunction is common to other psychiatric concerns, especially those that are likely to be comorbid with AN, such as major depression [65] and anxiety disorders [66]. While abnormalities in serotonergic functioning are common to all of these disorders, different patterns of serotonergic functioning emerge on a molecular level [67]. While 5-HT1A receptor binding is often decreased in individuals with or recovered from depression [68, 69] and panic disorder [70], 5-HT1A receptor binding is increased in individuals with AN [29]. This could indicate that serotonergic dysfunction is a common vulnerability for a variety of disorders, with disorder-specific patterns at the neuronal level. This also accounts for higher rates of psychiatric concerns among family members of individuals with AN.

Given etiological research on the separate roles of dopamine and serotonin, it is not surprising that the most recent research suggests that interactions between serotonin and dopamine activity truly elicit and maintain the eating pathology of AN [56]. This interaction is not well understood, but could hold promise for future pharmacological interventions for AN.

#### **4. Norepinephrine**

Based on previous research on dopaminergic and serotonergic dysfunction in individuals with active AN, individuals RECAN, and unaffected family members, it is safe to conclude that neurotransmitter activity is aberrant both during the premorbid, active, and recovery periods of AN. Dopaminergic and serotonergic pathways could account for some, though not all, of the core symptoms of AN [29, 42]. While these pathways (particularly the serotonergic pathway) partly account for rigidity and perfectionism among individuals with AN, individuals with AN display a variety of perplexing symptoms that seem unrelated to both the starvation state itself or serotonin dysfunction alone; individuals with AN report difficulty with pain perceptual, alexithymia, reduced sense of taste, as well as numerous other perplexing symptoms [31]. Aberrant activity in the noradrenergic pathway could better account for this vast range of deficits.

Norepinephrine is a neurotransmitter which serves multiple functions in the body and brain, including regulation of sympathetic arousal/anxiety and cerebral blood flow [71]. Norepinephrine levels are elevated premorbidly in AN [72], but appear to be decreased in plasma and cerebrospinal fluid during active AN ad RECAN [72–74]. Premorbidly high levels of norepinephrine lead to high sympathetic arousal and anxiety [31]. Among individuals with AN, this anxiety is often focused on food- and weight-related issues, though the inherently high trait levels of perfectionism and neuroticism can manifest in other achievement domains such as schoolwork or sports [75]. Since this anxiety is linked an abundance of norepinephrine, dieting in the early stages of AN counteracts this by depleting the brain of the precursors to norepinephrine that are normally ingested through food [31]. Dieting is then maintained through negative reinforcement, leading to a reduction in body weight and entrenchment of AN symptoms. Furthermore, aberrant activity in the noradrenergic system has been linked to irregular patterns of activation in the insula, which will be discussed in the next section.

#### **5. Brain volume, blood flow, and neural activity**

Various neuroimaging studies show substantial structural abnormalities in the brain among individuals with active AN [30, 76, 77]. However, significant questions remain as to:

*whether such anomalies reflect regionally specific disturbances that might help explain disorder-defining psychopathology or merely generic, global consequences of malnutrition. Similarly, it remains unclear whether structural alterations in AN constitute premorbid traits or persisting "scars," as might be the case if they would still be evident following weight restoration ([76], p. 214).*

Decreased volumes of white and gray brain matter have been documented throughout the brain during the acute phases of illness [77, 78]. More specifically, gray matter atrophy has been noted in the cerebellum, hypothalamus, caudate nucleus and frontal, parietal and temporal areas [77, 79, 80], as well as in the cingulate cortex [81] and the precuneus [82]. The rate of gray matter atrophy is not uniform across the brain during active AN; atrophy in the hypothalamus may appear early in AN, whereas atrophy in the cerebellum is a late consequence of AN among patients with longer durations of illness [77].

However, these gray and white matter findings appear to be specific to the acute phase of illness and caused by malnutrition and cerebral dehydration [77]. A metaanalysis revealed that gray matter is reduced by 5.6% during the acute phases of AN, whereas white matter is reduced by 3.8% [83]. A few months of treatment and results in approximately 50% of gray matter regain and nearly all of the white matter being regained. A few years following remission of AN, gray matter and white matter depletions are no longer statistically significant. It is possible that hormone levels impact how much gray matter is recovered, as high levels of cortisol at the time of hospitalization are negatively correlated with gray matter restoration following weight gain [84]. All told, the decreased volume of white and gray matter in individuals with AN normalizes with proper nutrition [38, 85]. Thus, these gray and white matter findings are not likely to be a contributing factor to the neurobiological etiology of AN.

In contrast, abnormal patterns of blood flow to the brain and brain activity persist after recovery. For instance, individuals who have recovered from AN often have hypoperfusion in the frontal, parietal, temporal and occipital areas of the brain [86]. In addition, overactivation of the frontal and anterior cingulate cortex (ACC) and insula following exposure to pictures of food or the taste of food is present both during active AN and after recovery [87, 88]. Hyperactivity in these regions could be an endophenotype for AN and be related to more global difficulties with appetitive mechanisms.

The complex eating pathology inherent in AN may indicate atypical functioning in appetitive mechanisms. Despite the unique and stereotypic presentation of altered eating patterns in the eating disorder diagnoses, it is still unknown whether individuals with AN have disordered appetitive functioning. The neural and limbic circuits are more likely candidates for deregulating appetitive functioning in AN than peripheral signs (such as hormonal imbalances or abnormalities in the gastrointestinal tract), because these neural and limbic circuits also regulate reward processing and emotionality, which are known to be disordered in AN [89]. Individuals with AN display an almost phobic avoidance of high-fat foods, which persists after recovery. Individuals who have recovered from AN fail to connect hunger cues with positive ratings of food [88]. Particularly promising research has focused specifically on the anterior insula, which is positioned in the primary gustatory cortex [90]. While this is still debated, researchers posit that the anterior insula codes a representation of food and its hedonic value, and projects to other parts of the brain [91, 92]. The anterior insula resides next to the orbito-frontal cortex, which interprets information from the anterior insula and is responsible for flexible decision-making with ever-changing stimuli [93]. Put another way, the anterior insula represents the food and its hedonic value, while the orbito-frontal cortex weighs those representation against hunger and other variables. Critically, the

**57**

*The Neurobiology of Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.82751*

become emaciated" ([30], p. 45).

**6. Genetics**

abnormal patterns of activity in the insula [98].

specific and shared with these other conditions.

both obsessionality and drive-for-thinness [105].

controversial and many fail to replicate genetic association.

orbito-frontal cortex is very sensitive to changes in serotonin, which could account for the inflexibility in eating pathology in individuals with AN [94]. Even though research in this area is still in its infancy, the aforementioned processing abnormalities in the anterior insula and orbito-frontal cortex shed some light as to how "AN individuals fail to become appropriately hungry when starved, and thus are able to

Though disturbances related to the gustatory modulation of the anterior insula certainly appear to be a key part of a biological risk factor in AN, the anterior insula influences many processes unrelated to gustatory mechanisms [30]. Disturbances in the anterior insula could be related to a more general deficit in interoceptive awareness [95, 96]. Altered activity in the insula "supports the idea that they might suffer from a fundamentally and physiologically altered sense of self" ([97], p. 111). Some of the more mysterious symptoms of AN, such as a denial of signs of malnutrition and lack of motivation to change pathological eating behaviors, could be linked to

There is clear and compelling evidence that having a first-degree relative with AN significantly elevates one's risk for developing AN; in fact, relatives of individuals with AN are 11.3 times more likely to develop AN [27]. There is likely some genetic contribution to the etiology of AN. Current heritability estimates range between 50 and 80% [99, 100], though specific genetic mechanisms have been difficult to identify. A noteworthy paradox was pointed out regarding the high heritability of AN and the likelihood of reduced reproductive fitness from prolonged periods of malnutrition [101]. Thus, one can conclude that genes that contribute to the etiology of AN must be rare and of recent origin. In addition, high rates of diagnostic crossover between eating disorder categories (see [102]) and high rates of comorbidity with mood and anxiety disorders (see [103]) also complicate the genetic etiology of AN, since any genetic predispositions for AN should be non-

One method of identifying genes relevant to the pathophysiology of AN is the candidate gene approach. The candidate gene approach is defined as an examination of genes that could be involved in a particular disease or syndrome because the function of those genes is related to the sequelae of the illness [104]. The candidate gene approach could be likened to finding "a needle in the haystack" of 27,000 human genes. Thus, it is not surprising that candidate gene studies for AN are

Family-based linkage analyses, or the process of detecting the location of disease genes on the chromosome, have identified three chromosomal regions of interest for AN; one resides on chromosome 13 (specifically, 13q13.3) and is related to drive-for-thinness, another resides on chromosome 2 (2p11.2) and is related to obsessionality, and a third on chromosome 1 (specifically, 1q1.3) which is related to

Genes related to dopamine transfer (DAT1) and dopamine receptors (DRD2) have been examined among patients with AN. Individuals with AN show elevated expression of DAT1 and reduced expression of DRD2 [106]; while the implications of these expression are not fully understood, a genetic contribution to the etiology of AN related to dopamine expression is consistent with previously mentioned research on altered reward processing in AN. Other genetic research has also identified an interaction of three genes that clear serotonin and norepinephrine from the synapse; these genes (a serotonin transporter gene, a norepinephrine

#### *The Neurobiology of Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.82751*

orbito-frontal cortex is very sensitive to changes in serotonin, which could account for the inflexibility in eating pathology in individuals with AN [94]. Even though research in this area is still in its infancy, the aforementioned processing abnormalities in the anterior insula and orbito-frontal cortex shed some light as to how "AN individuals fail to become appropriately hungry when starved, and thus are able to become emaciated" ([30], p. 45).

Though disturbances related to the gustatory modulation of the anterior insula certainly appear to be a key part of a biological risk factor in AN, the anterior insula influences many processes unrelated to gustatory mechanisms [30]. Disturbances in the anterior insula could be related to a more general deficit in interoceptive awareness [95, 96]. Altered activity in the insula "supports the idea that they might suffer from a fundamentally and physiologically altered sense of self" ([97], p. 111). Some of the more mysterious symptoms of AN, such as a denial of signs of malnutrition and lack of motivation to change pathological eating behaviors, could be linked to abnormal patterns of activity in the insula [98].

#### **6. Genetics**

*Anorexia and Bulimia Nervosa*

with appetitive mechanisms.

*whether such anomalies reflect regionally specific disturbances that might help explain disorder-defining psychopathology or merely generic, global consequences of malnutrition. Similarly, it remains unclear whether structural alterations in AN constitute premorbid traits or persisting "scars," as might be the case if they would* 

Decreased volumes of white and gray brain matter have been documented throughout the brain during the acute phases of illness [77, 78]. More specifically, gray matter atrophy has been noted in the cerebellum, hypothalamus, caudate nucleus and frontal, parietal and temporal areas [77, 79, 80], as well as in the cingulate cortex [81] and the precuneus [82]. The rate of gray matter atrophy is not uniform across the brain during active AN; atrophy in the hypothalamus may appear early in AN, whereas atrophy in the cerebellum is a late consequence of AN

However, these gray and white matter findings appear to be specific to the acute phase of illness and caused by malnutrition and cerebral dehydration [77]. A metaanalysis revealed that gray matter is reduced by 5.6% during the acute phases of AN, whereas white matter is reduced by 3.8% [83]. A few months of treatment and results in approximately 50% of gray matter regain and nearly all of the white matter being regained. A few years following remission of AN, gray matter and white matter depletions are no longer statistically significant. It is possible that hormone levels impact how much gray matter is recovered, as high levels of cortisol at the time of hospitalization are negatively correlated with gray matter restoration following weight gain [84]. All told, the decreased volume of white and gray matter in individuals with AN normalizes with proper nutrition [38, 85]. Thus, these gray and white matter findings

are not likely to be a contributing factor to the neurobiological etiology of AN. In contrast, abnormal patterns of blood flow to the brain and brain activity persist after recovery. For instance, individuals who have recovered from AN often have hypoperfusion in the frontal, parietal, temporal and occipital areas of the brain [86]. In addition, overactivation of the frontal and anterior cingulate cortex (ACC) and insula following exposure to pictures of food or the taste of food is present both during active AN and after recovery [87, 88]. Hyperactivity in these regions could be an endophenotype for AN and be related to more global difficulties

The complex eating pathology inherent in AN may indicate atypical functioning in appetitive mechanisms. Despite the unique and stereotypic presentation of altered eating patterns in the eating disorder diagnoses, it is still unknown whether individuals with AN have disordered appetitive functioning. The neural and limbic circuits are more likely candidates for deregulating appetitive functioning in AN than peripheral signs (such as hormonal imbalances or abnormalities in the gastrointestinal tract), because these neural and limbic circuits also regulate reward processing and emotionality, which are known to be disordered in AN [89]. Individuals with AN display an almost phobic avoidance of high-fat foods, which persists after recovery. Individuals who have recovered from AN fail to connect hunger cues with positive ratings of food [88]. Particularly promising research has focused specifically on the anterior insula, which is positioned in the primary gustatory cortex [90]. While this is still debated, researchers posit that the anterior insula codes a representation of food and its hedonic value, and projects to other parts of the brain [91, 92]. The anterior insula resides next to the orbito-frontal cortex, which interprets information from the anterior insula and is responsible for flexible decision-making with ever-changing stimuli [93]. Put another way, the anterior insula represents the food and its hedonic value, while the orbito-frontal cortex weighs those representation against hunger and other variables. Critically, the

*still be evident following weight restoration ([76], p. 214).*

among patients with longer durations of illness [77].

**56**

There is clear and compelling evidence that having a first-degree relative with AN significantly elevates one's risk for developing AN; in fact, relatives of individuals with AN are 11.3 times more likely to develop AN [27]. There is likely some genetic contribution to the etiology of AN. Current heritability estimates range between 50 and 80% [99, 100], though specific genetic mechanisms have been difficult to identify. A noteworthy paradox was pointed out regarding the high heritability of AN and the likelihood of reduced reproductive fitness from prolonged periods of malnutrition [101]. Thus, one can conclude that genes that contribute to the etiology of AN must be rare and of recent origin. In addition, high rates of diagnostic crossover between eating disorder categories (see [102]) and high rates of comorbidity with mood and anxiety disorders (see [103]) also complicate the genetic etiology of AN, since any genetic predispositions for AN should be nonspecific and shared with these other conditions.

One method of identifying genes relevant to the pathophysiology of AN is the candidate gene approach. The candidate gene approach is defined as an examination of genes that could be involved in a particular disease or syndrome because the function of those genes is related to the sequelae of the illness [104]. The candidate gene approach could be likened to finding "a needle in the haystack" of 27,000 human genes. Thus, it is not surprising that candidate gene studies for AN are controversial and many fail to replicate genetic association.

Family-based linkage analyses, or the process of detecting the location of disease genes on the chromosome, have identified three chromosomal regions of interest for AN; one resides on chromosome 13 (specifically, 13q13.3) and is related to drive-for-thinness, another resides on chromosome 2 (2p11.2) and is related to obsessionality, and a third on chromosome 1 (specifically, 1q1.3) which is related to both obsessionality and drive-for-thinness [105].

Genes related to dopamine transfer (DAT1) and dopamine receptors (DRD2) have been examined among patients with AN. Individuals with AN show elevated expression of DAT1 and reduced expression of DRD2 [106]; while the implications of these expression are not fully understood, a genetic contribution to the etiology of AN related to dopamine expression is consistent with previously mentioned research on altered reward processing in AN. Other genetic research has also identified an interaction of three genes that clear serotonin and norepinephrine from the synapse; these genes (a serotonin transporter gene, a norepinephrine

transporter gene, and a monoamine oxidase A gene) appear to contribute to the risk of restricting AN [41]. While the presence of each gene variant alone is associated with a somewhat increased risk of restricting AN, the combination of all three gene variants leads to a risk that is up to eight times greater than the risk associated with one gene variant alone.

Finally, there are epigenetic factors to consider. Perhaps the most important epigenetic mechanism to consider is the role of estradiol in triggering genetic risk for AN, which is discussed below. All told, the genetic and epigenetic contributions to AN remain largely unknown. Genetic studies are limited by previously mentioned methodological issues, such as the low prevalence of AN and the near impossibility of recruiting individuals with AN during the premorbid period for genetic research. However, progress in identifying genes or patterns of gene expression could lead to pharmacological advances that are direly needed for this population given the poor response to common psychotropics such as selective serotonin reuptake inhibitors, tricyclic antidepressants, and antipsychotics [17, 18].

#### **7. Pubertal hormones**

The vast majority of individuals with AN are biologically female and begin experiencing symptoms of AN during the pubertal and pre-pubertal periods of development [1]. These findings suggest that gonadal hormones specific to females may play a role in the epigenesis of AN. It is possible that genetic factors may be more impactful for females than males with regards to drive for thinness and body dissatisfaction [107] as well as for concerns about body shape and weight [108]. In addition to gender differences in genetic factors, genetic risk for eating disorders appears to be moderated by age, as there is almost no genetic effect (5% or less on disordered eating among preadolescent female twins, but by late adolescence there is evidence of substantial genetic effects [109]. Upon closer examination, the genetic effect appears to be due to pubertal status and not age, as 11-year-old twins who had begun puberty showed a higher magnitude of genetic effects compared to same-age twins who had not begun puberty [110]. Pubertal hormones, such as estradiol, which steadily increases during puberty among females, may trigger the genetic risk for disordered eating, as high levels of estradiol are associated with magnitude of genetic effects in a manner independent of age and physical signs of puberty development, such as body hair or breast development [111].

In addition to triggering the genetic risk for AN, low estradiol levels are associated with a number of negative effects during the active phases of AN. Not surprisingly, malnourished individuals show a variety of hormonal imbalances, most of which return to baseline after recovery [42]. Pubertal hormones appear to follow this same pattern of alteration during active illness but return to baseline upon weight regain. In a typically developing adolescent, an increase in pubertal hormones aids in brain maturation, most notably in the limbic system [112, 113]. These hormone levels are altered among individuals diagnosed with AN, who may experience amenorrhea due to low body weight and/or body fat [114]. When individuals achieve weight regain and recommence with menstruation, cognitive functioning improves, suggesting that increasing levels of estradiol during weight regain may assist with neural recovery [115].

#### **8. Conclusions and future directions**

The etiology of AN is multifaceted, with contributions from genetic factors, biological factors, family dynamics, personality characteristics, and sociocultural

**59**

provided the original work is properly cited.

**Conflict of interest**

**Author details**

Ashley Higgins

There are no conflicts of interest to report.

Immaculata University, Malvern, PA, United States of America

\*Address all correspondence to: ahiggins@immaculata.edu

*The Neurobiology of Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.82751*

influences. The development of this disorder and its maintenance remain poorly understood despite a significant increase in rigorous scientific study into risk factors and shared vulnerabilities with other eating disorders and psychological disorders. In recent years, the neurobiological etiology of AN has been examined through a wide variety of imaging studies, genetic studies, and hormonal/biological studies (see [97]). A number of key findings are summarized in this paper. Across these studies, it is clear that the brains of individuals with AN show evidence of altered reward processing and appetitive mechanisms, which are linked to a number of dopaminergic findings (perhaps, most importantly, how the brains of individuals with AN process cues of palatable foods as highly anxiogenic and aversive [50, 51]. Serotonergic functioning has been long-thought to account for behavioral rigidity and trait obsessionality in AN [56], and recent genetic research has identified a number of potential serotonergic genetic candidates or interactions of genetic candidates that represent significant risk factors for AN [44, 74, 104, 107]. Finally, altered noradrenergic functioning and aberrant activity in the insula represent a unique but comprehensive view of the global difficulties individuals with AN have with emotions, insight, and interoceptive awareness [31, 71]. These findings, taken together, can illuminate future pathways for pharmacotherapies that will be more effective for individuals with AN. Other brain-based findings discussed in this paper, such as gray and white matter atrophy, are unlikely to represent

true risk factors, because the vast majority improve with proper nutrition.

In conclusion, the neurobiological etiology of AN in-and-of-itself is complex and complicated by factors such as the low prevalence rate of AN [1], lack of prospective research [32], and the at-times catastrophic impact of malnutrition on the brain and body [38]. AN continues to be considered the most deadly psychological illness, and individuals RECAN may face a lifetime of physical and emotional challenges [1]. Given the ego-syntonic nature of this disorder and that current treatment outcomes are suboptimal for this population, a better understanding of the biological vulnerabilities of this illness and the development of new therapies are direly needed.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

#### *The Neurobiology of Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.82751*

*Anorexia and Bulimia Nervosa*

one gene variant alone.

**7. Pubertal hormones**

tricyclic antidepressants, and antipsychotics [17, 18].

transporter gene, and a monoamine oxidase A gene) appear to contribute to the risk of restricting AN [41]. While the presence of each gene variant alone is associated with a somewhat increased risk of restricting AN, the combination of all three gene variants leads to a risk that is up to eight times greater than the risk associated with

Finally, there are epigenetic factors to consider. Perhaps the most important epigenetic mechanism to consider is the role of estradiol in triggering genetic risk for AN, which is discussed below. All told, the genetic and epigenetic contributions to AN remain largely unknown. Genetic studies are limited by previously mentioned methodological issues, such as the low prevalence of AN and the near impossibility of recruiting individuals with AN during the premorbid period for genetic research. However, progress in identifying genes or patterns of gene expression could lead to pharmacological advances that are direly needed for this population given the poor response to common psychotropics such as selective serotonin reuptake inhibitors,

The vast majority of individuals with AN are biologically female and begin experiencing symptoms of AN during the pubertal and pre-pubertal periods of development [1]. These findings suggest that gonadal hormones specific to females may play a role in the epigenesis of AN. It is possible that genetic factors may be more impactful for females than males with regards to drive for thinness and body dissatisfaction [107] as well as for concerns about body shape and weight [108]. In addition to gender differences in genetic factors, genetic risk for eating disorders appears to be moderated by age, as there is almost no genetic effect (5% or less on disordered eating among preadolescent female twins, but by late adolescence there is evidence of substantial genetic effects [109]. Upon closer examination, the genetic effect appears to be due to pubertal status and not age, as 11-year-old twins who had begun puberty showed a higher magnitude of genetic effects compared to same-age twins who had not begun puberty [110]. Pubertal hormones, such as estradiol, which steadily increases during puberty among females, may trigger the genetic risk for disordered eating, as high levels of estradiol are associated with magnitude of genetic effects in a manner independent of age and physical signs of

puberty development, such as body hair or breast development [111].

estradiol during weight regain may assist with neural recovery [115].

**8. Conclusions and future directions**

In addition to triggering the genetic risk for AN, low estradiol levels are associated with a number of negative effects during the active phases of AN. Not surprisingly, malnourished individuals show a variety of hormonal imbalances, most of which return to baseline after recovery [42]. Pubertal hormones appear to follow this same pattern of alteration during active illness but return to baseline upon weight regain. In a typically developing adolescent, an increase in pubertal hormones aids in brain maturation, most notably in the limbic system [112, 113]. These hormone levels are altered among individuals diagnosed with AN, who may experience amenorrhea due to low body weight and/or body fat [114]. When individuals achieve weight regain and recommence with menstruation, cognitive functioning improves, suggesting that increasing levels of

The etiology of AN is multifaceted, with contributions from genetic factors, biological factors, family dynamics, personality characteristics, and sociocultural

**58**

influences. The development of this disorder and its maintenance remain poorly understood despite a significant increase in rigorous scientific study into risk factors and shared vulnerabilities with other eating disorders and psychological disorders.

In recent years, the neurobiological etiology of AN has been examined through a wide variety of imaging studies, genetic studies, and hormonal/biological studies (see [97]). A number of key findings are summarized in this paper. Across these studies, it is clear that the brains of individuals with AN show evidence of altered reward processing and appetitive mechanisms, which are linked to a number of dopaminergic findings (perhaps, most importantly, how the brains of individuals with AN process cues of palatable foods as highly anxiogenic and aversive [50, 51]. Serotonergic functioning has been long-thought to account for behavioral rigidity and trait obsessionality in AN [56], and recent genetic research has identified a number of potential serotonergic genetic candidates or interactions of genetic candidates that represent significant risk factors for AN [44, 74, 104, 107]. Finally, altered noradrenergic functioning and aberrant activity in the insula represent a unique but comprehensive view of the global difficulties individuals with AN have with emotions, insight, and interoceptive awareness [31, 71]. These findings, taken together, can illuminate future pathways for pharmacotherapies that will be more effective for individuals with AN. Other brain-based findings discussed in this paper, such as gray and white matter atrophy, are unlikely to represent true risk factors, because the vast majority improve with proper nutrition.

In conclusion, the neurobiological etiology of AN in-and-of-itself is complex and complicated by factors such as the low prevalence rate of AN [1], lack of prospective research [32], and the at-times catastrophic impact of malnutrition on the brain and body [38]. AN continues to be considered the most deadly psychological illness, and individuals RECAN may face a lifetime of physical and emotional challenges [1]. Given the ego-syntonic nature of this disorder and that current treatment outcomes are suboptimal for this population, a better understanding of the biological vulnerabilities of this illness and the development of new therapies are direly needed.

#### **Conflict of interest**

There are no conflicts of interest to report.

#### **Author details**

Ashley Higgins Immaculata University, Malvern, PA, United States of America

\*Address all correspondence to: ahiggins@immaculata.edu

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[106] Frieling H, Römer KD, Scholz S, Mittelbach F, Wilhelm J, De Zwaan M, et al. Epigenetic dysregulation of dopaminergic genes in eating disorders. International Journal of Eating Disorders. 2010;**43**:577-583. DOI:

[107] Baker JH, Maes HH, Lissner L, Aggen SH, Lichtenstein P, Kendler KS. Genetic risk factors for disordered eating in adolescent males and females. Journal of Abnormal Psychology. 2009;**118**:576-586. DOI: 10.1037/

[108] Sloft-Op 't Landt MCT, Bartels M, Van Furth EF, Van Beijsterveldt CEM, Meulenbelt I, Slagboom PE, et al. Genetic influences on disordered eating behaviour are largely independent of body mass index. Acta Psychiatrica Scandinavica. 2008;**117**:348-356. DOI: 10.1111/j.1600-0447.2007.01132.x

[109] Klump KL, Burt SA, McGue M, Iacono WG. Changes in genetic and environmental influences on disordered eating across adolescence: A longitudinal twin study. Archives of General Psychiatry. 2007;**64**:1409-1415. DOI: 10.1001/archpsyc.64.12.1409

[110] Klump KL, Perkins PS, Burt SA, McGue MATT, Iacono WG. Puberty moderates genetic influences on disordered eating. Psychological Medicine. 2007;**37**:627-634. DOI: 10.1017/S0033291707000189

pp. 157-175

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a0016314

[97] Kaye WH, Wierenga CE, Bailer UF, Simmons AN, Bischoff-Grethe A. Nothing tastes as good as skinny feels: The neurobiology of anorexia nervosa. Trends in Neuroscience. 2013;**36**:110-120. DOI: 10.1016/j.

[98] Nunn K, Frampton I, Gordon I, Lask B. The fault is not in her parents but in her insula—A neurobiological hypothesis of anorexia nervosa. European Eating Disorders Review. 2008;**16**:355-360. DOI: 10.1002/erv.890

[99] Bulik CM, Thornton LM, Root TL, Pisetsky EM, Lichtenstein P, Pedersen NL. Understanding the relation between anorexia nervosa and bulimia nervosa in a Swedish national twin sample. Biological Psychiatry. 2010;**67**:71-77. DOI: 10.1016/j.biopsych.2009.08.010

[100] Thornton LM, Mazzeo SE, Bulik CM. The heritability of eating disorders: Methods and current findings. In: Adan RA, Kaye WH, editors. Behavioral Neurobiology of Eating Disorders. New York, NY: Springer; 2011. pp. 141-156

[101] Uher R. The role of genetic variation in the causation of mental illness: An evolution-informed framework. Molecular Psychiatry. 2009;**14**:1072-1082. DOI: 10.1038/

[102] Schaumberg K, Jangmo A, Thornton LM, Birgegård A, Almqvist C, Norring C, et al. Patterns of diagnostic transition in eating disorders: A longitudinal population study in Sweden. Psychological Medicine. 2018:1-9. DOI: 10.1017/

[103] Bühren K, Schwarte R, Fluck F, Timmesfeld N, Krei M, Egberts K, et al. Comorbid psychiatric disorders in female adolescents with first-onset anorexia nervosa. European Eating Disorders Review. 2014;**22**:39-44. DOI:

mp.2009.85

S0033291718001472

10.1002/erv.2254

tins.2013.01.003

*DOI: http://dx.doi.org/10.5772/intechopen.82751 The Neurobiology of Anorexia Nervosa*

*Anorexia and Bulimia Nervosa*

a000265

Konrad K. Morphological changes in the brain of acutely ill and weightrecovered patients with anorexia

nervosa. A meta-analysis and qualitative review. Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie. 2014;**42**:7-17. DOI: 10.1024/1422-4917/

in humans. European Journal of

[90] Schoenfeld M, Neuer G,

physbeh.2005.04.012

Neuroscience. 2004;**20**:1411-1418. DOI: 10.1111/j.1460-9568.2004.03589.x

Tempelmann C, Schussler K, Noesselt T, Hopf J, et al. Functional magnetic resonance tomography correlates of taste perception in the human primary taste cortex. Neuroscience. 2004;**127**:347-353. DOI: 10.1016/j. neuroscience.2004.05.024

[91] Rolls ET. Taste, olfactory, and food texture processing in the brain, and the control of food intake. Physiology & Behavior. 2005;**85**:45-56. DOI: 10.1016/j.

[92] Small D. Toward an understanding of the brain substrates of reward in humans. Neuron. 2002;**22**:668-671. DOI: 10.1016/S0896-6273(02)00620-7

[93] Kazama A, Bachevalier J. Selection aspiration of neurotoxic lesions of the orbitofrontal areas 11 and 13 spared monkey's performance on the object reversal discrimination task. Journal of Neuroscience. 2006;**29**:2794-2804. DOI: 10.1523/JNEUROSCI.4655-08.2009

[94] Clarke H, Walker SD, Robbins T, Roberts A. Cognitive inflexibility after prefrontal serotonin depletion is behaviorally and neurochemically specific. Cerebral Cortex. 2007;**17**:18-27.

[95] Fassino S, Pierò A, Gramaglia C, Abbate-Daga G. Clinical,

psychopathological and personality correlates of interoceptive awareness in anorexia nervosa, bulimia nervosa and obesity. Psychopathology. 2004;**37**: 168-174. DOI: 10.1159/000079420

[96] Lilenfeld LR, Wonderlich S, Riso LP, Crosby R, Mitchell J. Eating disorders and personality: A methodological and empirical review. Clinical Psychology Review. 2006;**26**:299-320. DOI: 10.1016/j.cpr.2005.10.003

DOI: 10.1093/cercor/bhj120

[84] Mainz V, Schulte-Rüther M, Fink GR, Herpertz-Dahlmann B, Konrad K. Structural brain abnormalities in adolescent anorexia nervosa before and after weight recovery and associated hormonal changes. Psychosomatic Medicine. 2012;**74**:574-582. DOI: 10.1097/PSY.0b013e31824ef10e

[85] Roberto CA, Mayer LE, Brickman AM, Barnes A, Muraskin J, Yeung LK, et al. Brain tissue volume changes following weight gain in adults with anorexia nervosa. International Journal of Eating Disorders. 2011;**44**:406-411.

DOI: 10.1002/eat.20840

8749.2001.tb00196.x

[86] Rastam M, Bjure J, Vestergren E, Uvebrant P, Gillberg IC, Wentz E, et al. Regional cerebral blood flow in weight-restored anorexia nervosa: A preliminary study. Developmental Medicine & Child Neurology.

2001;**43**:239-242. DOI: 10.1111/j.1469-

[87] Cowdrey FA, Park RJ, Harmer CJ, McCabe C. Increased neural processing

[88] Santel S, Baving L, Krauel K, Munte T, Rotte M. Hunger and satiety in anorexia nervosa: fMRI during cognitive processing of food pictures. Brain Research. 2006;**1114**:138-148. DOI: 10.1016/j.brainres.2006.07.045

of rewarding and aversive food stimuli in recovered anorexia nervosa. Biological Psychiatry. 2011;**70**:736-743. DOI: 10.1016/j.biopsych.2011.05.028

[89] Hinton E, Parkinson JA, Holland A, Arana F, Roberts A, Owen A. Neural contributions to the motivational control of appetite

**66**

[97] Kaye WH, Wierenga CE, Bailer UF, Simmons AN, Bischoff-Grethe A. Nothing tastes as good as skinny feels: The neurobiology of anorexia nervosa. Trends in Neuroscience. 2013;**36**:110-120. DOI: 10.1016/j. tins.2013.01.003

[98] Nunn K, Frampton I, Gordon I, Lask B. The fault is not in her parents but in her insula—A neurobiological hypothesis of anorexia nervosa. European Eating Disorders Review. 2008;**16**:355-360. DOI: 10.1002/erv.890

[99] Bulik CM, Thornton LM, Root TL, Pisetsky EM, Lichtenstein P, Pedersen NL. Understanding the relation between anorexia nervosa and bulimia nervosa in a Swedish national twin sample. Biological Psychiatry. 2010;**67**:71-77. DOI: 10.1016/j.biopsych.2009.08.010

[100] Thornton LM, Mazzeo SE, Bulik CM. The heritability of eating disorders: Methods and current findings. In: Adan RA, Kaye WH, editors. Behavioral Neurobiology of Eating Disorders. New York, NY: Springer; 2011. pp. 141-156

[101] Uher R. The role of genetic variation in the causation of mental illness: An evolution-informed framework. Molecular Psychiatry. 2009;**14**:1072-1082. DOI: 10.1038/ mp.2009.85

[102] Schaumberg K, Jangmo A, Thornton LM, Birgegård A, Almqvist C, Norring C, et al. Patterns of diagnostic transition in eating disorders: A longitudinal population study in Sweden. Psychological Medicine. 2018:1-9. DOI: 10.1017/ S0033291718001472

[103] Bühren K, Schwarte R, Fluck F, Timmesfeld N, Krei M, Egberts K, et al. Comorbid psychiatric disorders in female adolescents with first-onset anorexia nervosa. European Eating Disorders Review. 2014;**22**:39-44. DOI: 10.1002/erv.2254

[104] Helder SG, Collier DA. The genetics of eating disorders. In: Adan RA, Kaye WH, editors. Behavioral Neurobiology of Eating Disorders. New York, NY: Springer; 2011. pp. 157-175

[105] Devlin B, Bacanu SA, Klump KL, Bulik CM, Fichter MM, Halmi KA, et al. Linkage analysis of anorexia nervosa incorporating behavioral covariates. Human Molecular Genetics. 2002;**11**: 689-696. DOI: 10.1093/hmg/11.6.689

[106] Frieling H, Römer KD, Scholz S, Mittelbach F, Wilhelm J, De Zwaan M, et al. Epigenetic dysregulation of dopaminergic genes in eating disorders. International Journal of Eating Disorders. 2010;**43**:577-583. DOI: 10.1002/eat.20745

[107] Baker JH, Maes HH, Lissner L, Aggen SH, Lichtenstein P, Kendler KS. Genetic risk factors for disordered eating in adolescent males and females. Journal of Abnormal Psychology. 2009;**118**:576-586. DOI: 10.1037/ a0016314

[108] Sloft-Op 't Landt MCT, Bartels M, Van Furth EF, Van Beijsterveldt CEM, Meulenbelt I, Slagboom PE, et al. Genetic influences on disordered eating behaviour are largely independent of body mass index. Acta Psychiatrica Scandinavica. 2008;**117**:348-356. DOI: 10.1111/j.1600-0447.2007.01132.x

[109] Klump KL, Burt SA, McGue M, Iacono WG. Changes in genetic and environmental influences on disordered eating across adolescence: A longitudinal twin study. Archives of General Psychiatry. 2007;**64**:1409-1415. DOI: 10.1001/archpsyc.64.12.1409

[110] Klump KL, Perkins PS, Burt SA, McGue MATT, Iacono WG. Puberty moderates genetic influences on disordered eating. Psychological Medicine. 2007;**37**:627-634. DOI: 10.1017/S0033291707000189

[111] Klump KL, Keel PK, Sisk C, Burt SA. Preliminary evidence that estradiol moderates genetic influences on disordered eating attitudes and behaviors during puberty. Psychological Medicine. 2010;**40**:1745-1753. DOI: 10.1017/S0033291709992236

[112] Bramen JE, Hranilovich JA, Dahl RE, Forbes EE, Chen J, Toga AW, et al. Puberty influences medial temporal lobe and cortical gray matter maturation differently in boys than girls matched for sexual maturity. Cerebral Cortex. 2011;**21**:636-646. DOI: 10.1093/cercor/ bhq137

[113] Peper JS, Hulshoff Pol HE, Crone EA, van Honk J. Sex steroids and brain structure in pubertal boys and girls: A mini-review of neuroimaging studies. Neuroscience. 2011;**191**:28-37. DOI: 10.1016/j.neuroscience.2011.02.014

[114] Golden N, Carlson J. The pathophysiology of amenorrhea in the adolescent. Annals of the New York Academy of Sciences. 2008;1135: 163-178. DOI: 10.1196/annals.1429.014

[115] Chui HT, Christensen BK, Zipursky RB, Richards BA, Hanratty MK, Kabani NJ, et al. Cognitive function and brain structure in females with a history of adolescent-onset anorexia nervosa. Pediatrics. 2008;**122**:426-437. DOI: 10.1542/peds.2008-0170

**69**

**Chapter 5**

**Abstract**

Possible Dysregulation of Orexin

Anorexia nervosa (AN) is a psychiatric illness characterized by a lack of motivation and a taste for rewarding food consumption. Mood disorders such as depression and stress are frequently associated with this condition. Abnormalities in several neural systems have been identified in patients with AN, including serotonin, dopamine (DA), appetite-related neuropeptides, and other neurochemical systems. Moreover, the changes that occur between the mesolimbic dopaminergic pathway and the orexin neurons in the lateral hypothalamus (LH) in response to the reduction in food consumption are key in the development of AN. Several studies suggest a functional relationship between orexin and dopaminergic circuits. LH orexin neurons project dense fibers on dopaminergic neurons, potently activating these neurons. DA and orexin neurons regulate negative and positive motivational states, such as drug and food seeking behavior. For this reason, it is important to extend the study of the functional and emotional interactions that exist between both neuronal systems to design new drugs that act at a behavioral and molecular level to treat AN. This chapter provides an overview of the evidence from literature implicating dopamine-orexin systems in AN and discusses recent advances that have contributed to our current

and Dopamine Systems in

*Marcela Morales-Mulia and Sandra Morales-Mulia*

understanding of the mechanisms underlying the molecular bases of AN.

orexin neurons, motivation, anxiety disorders

**1. Introduction**

general population [2].

**Keywords:** mesocorticolimbic system, dopamine receptors, reward, mental illness,

Anorexia nervosa (AN) has been classified as a chronic psychiatric disease since this condition has a strong emotional component. AN belongs to a group of eating disorders and is characterized by extreme body weight loss. AN patients show combination of physical, psychological, and behavioral disturbances that usually have their onset during adolescence. AN is associated with high levels of psychiatric comorbidity including psychosis, hyperactivity, depression, and anxiety. In consequence, this illness has become a major focus of attention in terms of both the research community and the general public. The prevalence of AN is approximately 1% in women and less than 0.5% in men [1]. Patients with AN show a high degree of anhedonia (the reduced capacity to experience reward or pleasure) and have a disturbed body image and an intense fear of weight gain. Standardized mortality ratios show that the rate of death in AN is at least five times greater than that in the

Anorexia Nervosa

#### **Chapter 5**

*Anorexia and Bulimia Nervosa*

[111] Klump KL, Keel PK, Sisk C, Burt SA. Preliminary evidence that estradiol moderates genetic influences on disordered eating attitudes and behaviors during puberty. Psychological Medicine. 2010;**40**:1745-1753. DOI: 10.1017/S0033291709992236

[112] Bramen JE, Hranilovich JA, Dahl RE, Forbes EE, Chen J, Toga AW, et al. Puberty influences medial temporal lobe and cortical gray matter maturation differently in boys than girls matched for sexual maturity. Cerebral Cortex. 2011;**21**:636-646. DOI: 10.1093/cercor/

[113] Peper JS, Hulshoff Pol HE, Crone EA, van Honk J. Sex steroids and brain structure in pubertal boys and girls: A mini-review of neuroimaging studies. Neuroscience. 2011;**191**:28-37. DOI: 10.1016/j.neuroscience.2011.02.014

pathophysiology of amenorrhea in the adolescent. Annals of the New York Academy of Sciences. 2008;1135: 163-178. DOI: 10.1196/annals.1429.014

[115] Chui HT, Christensen BK, Zipursky RB, Richards BA, Hanratty MK, Kabani NJ, et al. Cognitive function and brain structure in females with a history of adolescent-onset anorexia nervosa. Pediatrics. 2008;**122**:426-437. DOI:

[114] Golden N, Carlson J. The

10.1542/peds.2008-0170

bhq137

**68**

## Possible Dysregulation of Orexin and Dopamine Systems in Anorexia Nervosa

*Marcela Morales-Mulia and Sandra Morales-Mulia*

#### **Abstract**

Anorexia nervosa (AN) is a psychiatric illness characterized by a lack of motivation and a taste for rewarding food consumption. Mood disorders such as depression and stress are frequently associated with this condition. Abnormalities in several neural systems have been identified in patients with AN, including serotonin, dopamine (DA), appetite-related neuropeptides, and other neurochemical systems. Moreover, the changes that occur between the mesolimbic dopaminergic pathway and the orexin neurons in the lateral hypothalamus (LH) in response to the reduction in food consumption are key in the development of AN. Several studies suggest a functional relationship between orexin and dopaminergic circuits. LH orexin neurons project dense fibers on dopaminergic neurons, potently activating these neurons. DA and orexin neurons regulate negative and positive motivational states, such as drug and food seeking behavior. For this reason, it is important to extend the study of the functional and emotional interactions that exist between both neuronal systems to design new drugs that act at a behavioral and molecular level to treat AN. This chapter provides an overview of the evidence from literature implicating dopamine-orexin systems in AN and discusses recent advances that have contributed to our current understanding of the mechanisms underlying the molecular bases of AN.

**Keywords:** mesocorticolimbic system, dopamine receptors, reward, mental illness, orexin neurons, motivation, anxiety disorders

#### **1. Introduction**

Anorexia nervosa (AN) has been classified as a chronic psychiatric disease since this condition has a strong emotional component. AN belongs to a group of eating disorders and is characterized by extreme body weight loss. AN patients show combination of physical, psychological, and behavioral disturbances that usually have their onset during adolescence. AN is associated with high levels of psychiatric comorbidity including psychosis, hyperactivity, depression, and anxiety. In consequence, this illness has become a major focus of attention in terms of both the research community and the general public. The prevalence of AN is approximately 1% in women and less than 0.5% in men [1]. Patients with AN show a high degree of anhedonia (the reduced capacity to experience reward or pleasure) and have a disturbed body image and an intense fear of weight gain. Standardized mortality ratios show that the rate of death in AN is at least five times greater than that in the general population [2].

Little is known about the etiology and the intrinsic biological alterations of anorexia, but it appears to be the result of different factors, for example, low self-esteem, certain personality traits such as perfectionism, mental illnesses such as depression, anxiety, self-harm, difficulty to manage stress and cope with life. Feelings of obsession and compulsion are also related with AN. Society and communication media play a key role in this pathology, since through them we are constantly told that the image of the body is very important because it reflects our value, as people. While culture, society, and the media exert pressure on women to remain thin, now it is widely accepted that there is a biological basis for this psychiatric disorder. Henceforth, the complexity of AN has limited the development of neuroscience-based treatments, and no medication or other biological treatment has been approved for the disorder. Then, to understand the biology of pathological eating behavior is an important step in the development of appropriate pharmacotherapies that can be used to treat AN patients.

To date abnormalities in several neural systems have been identified in patients with AN, including serotonin and DA, appetite-related neuropeptides, and other neurochemical systems. This chapter will focus especially on the dopaminergic neurons of the ventral tegmental area (VTA) that project the nucleus accumbens (NAc) to form the mesocorticolimbic circuit; and in the orexin neurons localized exclusively in two subregions of the hypothalamus; the perifornical area (PFA) and the LH, where orexin peptide is expressing [3].

Previously, it was thought that the serotonin system was the only or most important neurotransmitter involved in AN, and all research was carried out around its neurotransmission. Subsequently, preclinic and clinic evidence propose that the dopaminergic system could be a key factor in the pathophysiology of eating disorders. The AN is characterized by a reduction in food intake (diet restriction) and hyperactivity. In this sense, decrease in DA content has been observed in hypothalamus, hippocampus, and the dorsal striatum after a restricted diet. Moreover, the motor activity is modulated mainly by dopaminergic circuits. These first data point out for the first time the possible contribution of dopaminergic transmission in anorexia.

The signals to eat or to stop eating are very complex and extend beyond the control of the homeostatic system that responds to metabolic and satiety signals from the gut. Recently, it has been proposed that mesocorticolimbic dopaminergic system also responds to features of food such as the sight, smell, and taste in addition to cues that predict food intake and override the ingestive behavior [4]. The motivation to eat is key in eating behavior and is regulated by several intrinsic and extrinsic factors. Neuronal and circulating peptides are released in response of internal states, such as hunger or satiety, to stimulate or repress food intake, respectively. Accumulating evidence has pointing out the orexin-containing neurons as central regulators of feeding behavior, energy balance modulation, and metabolic homeostasis.

#### **2. Dopamine neurons**

DA is a catecholamine and is a key neuromodulator involved in motivated behaviors. DA-containing neurons are characterized by the presence of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines, and are found throughout the mammalian central nervous system (CNS), including the ventral midbrain (VM) [5]. Midbrain DA-containing neurons are arranged principally in two nucleus: the substantia nigra pars compacta (SNc, also known as the A9 group) and the VTA, or A10 group [5, 6]. Different populations of DA-containing

**71**

declared.

*Possible Dysregulation of Orexin and Dopamine Systems in Anorexia Nervosa*

neurons project to distinct areas and control or modulate specific functions, according to their targets. We will emphasize in the VTA nucleus, which project to ventromedial striatum (NAc) and PFC, forming the mesocorticolimbic system. These DA-containing neurons regulate emotional behavior, natural motivation, reward and cognitive function, and are largely implicated in a range of psychiatric

DA acts primly through of two G protein-coupled DA D1 (D1R) and D2 (D2R) receptors [10]. D1R is a postsynaptic receptor that mediates more directly behavior, and the D2R is a presynaptic autoreceptor that regulates DA release in a negative feedback fashion; D1R increases, whereas D2R decreases adenylyl-cyclase activity, and both receptor types are distributed throughout the CNS [11]. A variety of studies indicate that an altered DA function in AN could be implicated. Patients with AN have shown low levels of homovanillic acid in their cerebrospinal fluid (CSF), the major DA metabolite [12]; in addition, a positron emission tomography (PET) study revealed an increase in D2R binding in the anteroventral striatum (NAc in rodents), in a mixed group of women recovered from both restricted-type anorexia nervosa and binge-eating/purging-type [13]. These data suggest that neuronal or synaptic DA may be reduced, but that DA receptors could be increased in number or sensitivity in a compensatory or negative feedback fashion [14]. Thus, a downregulation of receptor sensitivity might be an important therapeutic goal in AN, to

Several hypotheses have been raised about the contribution of DA in AN. On one side, Bergh and Södersten [15] suggest that normal DA responses to hunger and exercise facilitate a progression into AN; in addition, O'Hara et al. [16] proposed that an anomaly in the reward system mediated by the DA leads to the development,

**2.1 Mesocorticolimbic dopamine neurons may facilitate the development of** 

According to Bergh and Södersten [15], dieting, along with high levels of exercise, leads to a stress response that increases cortisol and corticotrophin-releasing factor (CRF) [17–22], which in turn promotes an increase in DA levels in the NAc [23, 24]. In such a way, DA facilitates rewarding behaviors such as diet and exercise to become habits similar to those associated with drug dependency or self-starvation by conditioning this type of reward to initially neutral stimuli [15, 25–28]. In addition, the high CRF levels induced by diet restriction and exercise also facilitate to seek for food, while simultaneously suppressing food intake [29]. However, until now there is no clinical study that compares the DA levels in anorexic subjects before and after developing anorexia that shows chronically high levels of DA before the disease was

The mentalistic concept of AN assumes that it results from a mental illness. This concept describes this illness as a set of chronic and serious mental disorders with debilitating physical, cognitive, and socioemotional impairments such as anxiety, depression, obsessional traits, and pathological cognitions. Therefore, when the initial care of a patient with anorexia is focused only on cognitive therapies to treat psychological disorders do not usually give good long-time results. Moreover, symptoms such as anxiety and depression also emerge in healthy people during a starvation period [30]. There are many arguments against the hypothesis that an underlying mental disorder causes AN [31]. Recently, it was discovered that AN

*DOI: http://dx.doi.org/10.5772/intechopen.83843*

compensate the low levels of DA.

**anorexia nervosa**

maintenance, and resistance to the treatment of the AN.

**2.2 Aberrant concept of starvation in anorexia nervosa**

disorders [7–9].

#### *Possible Dysregulation of Orexin and Dopamine Systems in Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.83843*

neurons project to distinct areas and control or modulate specific functions, according to their targets. We will emphasize in the VTA nucleus, which project to ventromedial striatum (NAc) and PFC, forming the mesocorticolimbic system. These DA-containing neurons regulate emotional behavior, natural motivation, reward and cognitive function, and are largely implicated in a range of psychiatric disorders [7–9].

DA acts primly through of two G protein-coupled DA D1 (D1R) and D2 (D2R) receptors [10]. D1R is a postsynaptic receptor that mediates more directly behavior, and the D2R is a presynaptic autoreceptor that regulates DA release in a negative feedback fashion; D1R increases, whereas D2R decreases adenylyl-cyclase activity, and both receptor types are distributed throughout the CNS [11]. A variety of studies indicate that an altered DA function in AN could be implicated. Patients with AN have shown low levels of homovanillic acid in their cerebrospinal fluid (CSF), the major DA metabolite [12]; in addition, a positron emission tomography (PET) study revealed an increase in D2R binding in the anteroventral striatum (NAc in rodents), in a mixed group of women recovered from both restricted-type anorexia nervosa and binge-eating/purging-type [13]. These data suggest that neuronal or synaptic DA may be reduced, but that DA receptors could be increased in number or sensitivity in a compensatory or negative feedback fashion [14]. Thus, a downregulation of receptor sensitivity might be an important therapeutic goal in AN, to compensate the low levels of DA.

Several hypotheses have been raised about the contribution of DA in AN. On one side, Bergh and Södersten [15] suggest that normal DA responses to hunger and exercise facilitate a progression into AN; in addition, O'Hara et al. [16] proposed that an anomaly in the reward system mediated by the DA leads to the development, maintenance, and resistance to the treatment of the AN.

#### **2.1 Mesocorticolimbic dopamine neurons may facilitate the development of anorexia nervosa**

According to Bergh and Södersten [15], dieting, along with high levels of exercise, leads to a stress response that increases cortisol and corticotrophin-releasing factor (CRF) [17–22], which in turn promotes an increase in DA levels in the NAc [23, 24]. In such a way, DA facilitates rewarding behaviors such as diet and exercise to become habits similar to those associated with drug dependency or self-starvation by conditioning this type of reward to initially neutral stimuli [15, 25–28]. In addition, the high CRF levels induced by diet restriction and exercise also facilitate to seek for food, while simultaneously suppressing food intake [29]. However, until now there is no clinical study that compares the DA levels in anorexic subjects before and after developing anorexia that shows chronically high levels of DA before the disease was declared.

#### **2.2 Aberrant concept of starvation in anorexia nervosa**

The mentalistic concept of AN assumes that it results from a mental illness. This concept describes this illness as a set of chronic and serious mental disorders with debilitating physical, cognitive, and socioemotional impairments such as anxiety, depression, obsessional traits, and pathological cognitions. Therefore, when the initial care of a patient with anorexia is focused only on cognitive therapies to treat psychological disorders do not usually give good long-time results. Moreover, symptoms such as anxiety and depression also emerge in healthy people during a starvation period [30]. There are many arguments against the hypothesis that an underlying mental disorder causes AN [31]. Recently, it was discovered that AN

*Anorexia and Bulimia Nervosa*

therapies that can be used to treat AN patients.

the LH, where orexin peptide is expressing [3].

Little is known about the etiology and the intrinsic biological alterations of anorexia, but it appears to be the result of different factors, for example, low self-esteem, certain personality traits such as perfectionism, mental illnesses such as depression, anxiety, self-harm, difficulty to manage stress and cope with life. Feelings of obsession and compulsion are also related with AN. Society and communication media play a key role in this pathology, since through them we are constantly told that the image of the body is very important because it reflects our value, as people. While culture, society, and the media exert pressure on women to remain thin, now it is widely accepted that there is a biological basis for this psychiatric disorder. Henceforth, the complexity of AN has limited the development of neuroscience-based treatments, and no medication or other biological treatment has been approved for the disorder. Then, to understand the biology of pathological eating behavior is an important step in the development of appropriate pharmaco-

To date abnormalities in several neural systems have been identified in patients with AN, including serotonin and DA, appetite-related neuropeptides, and other neurochemical systems. This chapter will focus especially on the dopaminergic neurons of the ventral tegmental area (VTA) that project the nucleus accumbens (NAc) to form the mesocorticolimbic circuit; and in the orexin neurons localized exclusively in two subregions of the hypothalamus; the perifornical area (PFA) and

Previously, it was thought that the serotonin system was the only or most important neurotransmitter involved in AN, and all research was carried out around its neurotransmission. Subsequently, preclinic and clinic evidence propose that the dopaminergic system could be a key factor in the pathophysiology of eating disorders. The AN is characterized by a reduction in food intake (diet restriction) and hyperactivity. In this sense, decrease in DA content has been observed in hypothalamus, hippocampus, and the dorsal striatum after a restricted diet. Moreover, the motor activity is modulated mainly by dopaminergic circuits. These first data point out for the first time the possible contribution of dopaminergic transmission

The signals to eat or to stop eating are very complex and extend beyond the control of the homeostatic system that responds to metabolic and satiety signals from the gut. Recently, it has been proposed that mesocorticolimbic dopaminergic system also responds to features of food such as the sight, smell, and taste in addition to cues that predict food intake and override the ingestive behavior [4]. The motivation to eat is key in eating behavior and is regulated by several intrinsic and extrinsic factors. Neuronal and circulating peptides are released in response of internal states, such as hunger or satiety, to stimulate or repress food intake, respectively. Accumulating evidence has pointing out the orexin-containing neurons as central regulators of feeding behavior, energy balance modulation, and metabolic

DA is a catecholamine and is a key neuromodulator involved in motivated behaviors. DA-containing neurons are characterized by the presence of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines, and are found throughout the mammalian central nervous system (CNS), including the ventral midbrain (VM) [5]. Midbrain DA-containing neurons are arranged principally in two nucleus: the substantia nigra pars compacta (SNc, also known as the A9 group) and the VTA, or A10 group [5, 6]. Different populations of DA-containing

**70**

in anorexia.

homeostasis.

**2. Dopamine neurons**

and anxiety have different genetic risk factors. Also, almost all mental disorder symptoms observed in anorexics disappear after normalization of eating behavior [31, 32].

O'Hara et al. [16] do not agree with the mentalist concept because this does not assume the normal functions of the neuroendocrine system, which is responsible for regulating the release of peptides that regulate food consumption. The mentalist concept does not take into account the physiological aspects in eating disorders, and this may be the reason why this approach to treating anorexia as a consequence of a mental illness has not led to an effective treatment. O'Hara et al. [16] proposed that an abnormality in the reward system mediated by DA leads to the development, maintenance, and resistance to treatment in the AN.

They suggest that the decrease in dopaminergic activity and the rejection of food intake are key in the development of anorexia. Therefore, they propose increasing DA levels to normalize the consumption of food to reduce the stress generated by starvation, which in turn reduces the release of CRF to gradually increase the consumption of food. However, recent studies suggest that changes in DA found in anorexic patients are due more to a normal characteristic of starvation than to a disease marker.

#### **3. Hypothalamic orexin neurons modulate dopaminergic neurons**

Orexin-A and orexin-B neuropeptides were initially identified as endogenous ligands for two orphan G protein-coupled receptors; the OX1R is coupled entirely to Gq, whereas OX2R is coupled to both Gi/o and Gq [33]. Both orexins are derived from proteolytic cleavage, of a precursor peptide (pre-pro-orexin), and are produced by a group of neurons in the LH and PFA, a region known as the feeding center (**Figure 1**). OX-A has the same affinity with both receptors, while OX-B has a greater affinity for OX2R than OX1R [33, 34]. These receptors are highly expressed throughout the brain including the "dopaminergic reward pathways" (**Figure 1**) [35–39]. Moreover, these

#### **Figure 1.**

*Schematic representation of the brain areas related to motivated and emotional behaviors. (A) Coronal section of the rat brain showing the lateral (LH) and perifornical area (PEA) of hypothalamus. (B) Representation of the main orexin projections and the expression of orexin receptors 1 and 2 (OX1R and OX2R) in these brain regions. The fear circuit comprising the hippocampus (Hypp), medial prefrontal cortex (mPFC), and amygdala (AMY). Areas implicated in anxiety: bed of the stria terminals (BNST), paraventricular thalamus (PVT), and septum. The paraventricular nucleus of the hypothalamus (PVN) regulates stress responses and the hypothalamic-pituitary-adrenal axis hormone cascade. The mesocorticolimbic system modulates the rewarding properties of food and drugs of abuse and comprising the ventral tegmental area (VTA) and nucleus accumbens (NAc). The locus coeruleus (LC) also has dense orexin innervations in concordance with its involvement in arousal and emotional memory. Abbreviation: LH, lateral hypothalamus.*

**73**

*Possible Dysregulation of Orexin and Dopamine Systems in Anorexia Nervosa*

behaviors, such as exercise, sex, and, of course food intake.

related to drug, alcohol, and food seeking.

peptides are also regarded as an important factor that regulates feeding behavior, owing to their localization within the lateral hypothalamic area, the classic "feeding

Orexins were recognized as positive regulators of energy expenditure, thanks to the development of the orexin neuron-deficient mice. Studies conducted in these animals led to propose that orexins promote acute food consumption on one hand and on the other hand prevent the progress of obesity [40]. Since then, numerous pharmacological and genetic studies have supported that these peptides together with their receptors are key regulators of energy expenditure, thus influencing the

The activation of the orexin system by means of the microinjection of orexin-A in the hypothalamus has shown that these peptides act as protectors in the development of obesity, by increasing energy expenditure. Also, orexin neurons increase energy expenditure by increasing thermogenesis in brown adipose tissue [40]. On the other hand, it has been observed that overexoression of pre-pro-orexin gene in an animal model promotes resistance to obesity induced by consumption of a high-fat diet [41] The available anatomical, genetic, and pharmacological evidence supports that the behavioral consequences of the activity of the orexin system are due to parallel signaling to multiple brain regions and neurotransmitter systems such as DA. For example, the NAc is involved in hedonic and motivational aspects of feeding [42] and is an important brain region because endogenous orexin peptides act to modulate DA release [43], which act over hedonic processes associated with food evaluation and consumption. In addition, NAc is involved in the reward of natural

Orexins in the VTA, the major dopaminergic nucleus, have been implicated in drug and alcohol seeking and reinstatement. as well as food seeking, in highly salient circumstances, food seeking in highly salient circumstances, for example, during hunger, presentation of palatable foods or with exposure to food-related cues, but not in the consumption of regular food [44, 45]. An alternative mechanism by which orexins can stimulate the consumption of highly palatable food is via the paraventricular thalamic nucleus (PVT) because orexin neurons in the hypothalamus also send dense projections to the PVT [37], which in turn regulates DA efflux to the NAc via its glutamatergic projections [46, 47]. It has been reported that orexin actions in PVT promote DA efflux in the NAc, while the inhibition of its receptor OX1R in this region decreases hedonic intake of palatable foods [48]. Therefore, orexins not only can act directly in the VTA to increase DA [45, 49] but they also increase DA via action in the PVT to promote hedonic food intake [48]. In summary, the control that orexins exert over VTA-NAc circuit is key to modulate motivational behaviors and reward processes

Functional studies show the relationship between LH orexins and VTA-NAc circuit where orexins exert their actions on the dopaminergic neurons by increasing the firing frequency in VTA neurons in vitro and in vivo [50, 51]. These peptides induce an increase in DA release and its metabolites in both NAc and PFC [4, 49, 52, 53]. Electrical stimulation of the LH nucleus can increase both food intake and accumbal DA turnover [54–56]. In contrast, the inhibition of OX1R reduces DA cells firing [57], as well as significantly decrease in amphetamine, and cocaine-induced DA release in the NAc [57, 58]. On the other hand, the intracerebroventricular administration of OX-A leads to stress-related behavior like grooming, stereotypy, and hyperlocomotion [59], actions that were inhibited by DA D1 receptor (D1R) or DA D2 receptor (D2R) antagonists in rodents [59]. These data provide strong evidence that the orexin system contributes to DAergic neurons regulation in the

*DOI: http://dx.doi.org/10.5772/intechopen.83843*

center."

energy balance.

#### *Possible Dysregulation of Orexin and Dopamine Systems in Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.83843*

peptides are also regarded as an important factor that regulates feeding behavior, owing to their localization within the lateral hypothalamic area, the classic "feeding center."

Orexins were recognized as positive regulators of energy expenditure, thanks to the development of the orexin neuron-deficient mice. Studies conducted in these animals led to propose that orexins promote acute food consumption on one hand and on the other hand prevent the progress of obesity [40]. Since then, numerous pharmacological and genetic studies have supported that these peptides together with their receptors are key regulators of energy expenditure, thus influencing the energy balance.

The activation of the orexin system by means of the microinjection of orexin-A in the hypothalamus has shown that these peptides act as protectors in the development of obesity, by increasing energy expenditure. Also, orexin neurons increase energy expenditure by increasing thermogenesis in brown adipose tissue [40]. On the other hand, it has been observed that overexoression of pre-pro-orexin gene in an animal model promotes resistance to obesity induced by consumption of a high-fat diet [41]

The available anatomical, genetic, and pharmacological evidence supports that the behavioral consequences of the activity of the orexin system are due to parallel signaling to multiple brain regions and neurotransmitter systems such as DA. For example, the NAc is involved in hedonic and motivational aspects of feeding [42] and is an important brain region because endogenous orexin peptides act to modulate DA release [43], which act over hedonic processes associated with food evaluation and consumption. In addition, NAc is involved in the reward of natural behaviors, such as exercise, sex, and, of course food intake.

Orexins in the VTA, the major dopaminergic nucleus, have been implicated in drug and alcohol seeking and reinstatement. as well as food seeking, in highly salient circumstances, food seeking in highly salient circumstances, for example, during hunger, presentation of palatable foods or with exposure to food-related cues, but not in the consumption of regular food [44, 45]. An alternative mechanism by which orexins can stimulate the consumption of highly palatable food is via the paraventricular thalamic nucleus (PVT) because orexin neurons in the hypothalamus also send dense projections to the PVT [37], which in turn regulates DA efflux to the NAc via its glutamatergic projections [46, 47]. It has been reported that orexin actions in PVT promote DA efflux in the NAc, while the inhibition of its receptor OX1R in this region decreases hedonic intake of palatable foods [48]. Therefore, orexins not only can act directly in the VTA to increase DA [45, 49] but they also increase DA via action in the PVT to promote hedonic food intake [48]. In summary, the control that orexins exert over VTA-NAc circuit is key to modulate motivational behaviors and reward processes related to drug, alcohol, and food seeking.

Functional studies show the relationship between LH orexins and VTA-NAc circuit where orexins exert their actions on the dopaminergic neurons by increasing the firing frequency in VTA neurons in vitro and in vivo [50, 51]. These peptides induce an increase in DA release and its metabolites in both NAc and PFC [4, 49, 52, 53]. Electrical stimulation of the LH nucleus can increase both food intake and accumbal DA turnover [54–56]. In contrast, the inhibition of OX1R reduces DA cells firing [57], as well as significantly decrease in amphetamine, and cocaine-induced DA release in the NAc [57, 58]. On the other hand, the intracerebroventricular administration of OX-A leads to stress-related behavior like grooming, stereotypy, and hyperlocomotion [59], actions that were inhibited by DA D1 receptor (D1R) or DA D2 receptor (D2R) antagonists in rodents [59]. These data provide strong evidence that the orexin system contributes to DAergic neurons regulation in the

*Anorexia and Bulimia Nervosa*

[31, 32].

disease marker.

and anxiety have different genetic risk factors. Also, almost all mental disorder symptoms observed in anorexics disappear after normalization of eating behavior

maintenance, and resistance to treatment in the AN.

O'Hara et al. [16] do not agree with the mentalist concept because this does not assume the normal functions of the neuroendocrine system, which is responsible for regulating the release of peptides that regulate food consumption. The mentalist concept does not take into account the physiological aspects in eating disorders, and this may be the reason why this approach to treating anorexia as a consequence of a mental illness has not led to an effective treatment. O'Hara et al. [16] proposed that an abnormality in the reward system mediated by DA leads to the development,

They suggest that the decrease in dopaminergic activity and the rejection of food

intake are key in the development of anorexia. Therefore, they propose increasing DA levels to normalize the consumption of food to reduce the stress generated by starvation, which in turn reduces the release of CRF to gradually increase the consumption of food. However, recent studies suggest that changes in DA found in anorexic patients are due more to a normal characteristic of starvation than to a

**3. Hypothalamic orexin neurons modulate dopaminergic neurons**

Orexin-A and orexin-B neuropeptides were initially identified as endogenous ligands for two orphan G protein-coupled receptors; the OX1R is coupled entirely to Gq, whereas OX2R is coupled to both Gi/o and Gq [33]. Both orexins are derived from proteolytic cleavage, of a precursor peptide (pre-pro-orexin), and are produced by a group of neurons in the LH and PFA, a region known as the feeding center (**Figure 1**). OX-A has the same affinity with both receptors, while OX-B has a greater affinity for OX2R than OX1R [33, 34]. These receptors are highly expressed throughout the brain including the "dopaminergic reward pathways" (**Figure 1**) [35–39]. Moreover, these

*Schematic representation of the brain areas related to motivated and emotional behaviors. (A) Coronal section of the rat brain showing the lateral (LH) and perifornical area (PEA) of hypothalamus. (B) Representation of the main orexin projections and the expression of orexin receptors 1 and 2 (OX1R and OX2R) in these brain regions. The fear circuit comprising the hippocampus (Hypp), medial prefrontal cortex (mPFC), and amygdala (AMY). Areas implicated in anxiety: bed of the stria terminals (BNST), paraventricular thalamus (PVT), and septum. The paraventricular nucleus of the hypothalamus (PVN) regulates stress responses and the hypothalamic-pituitary-adrenal axis hormone cascade. The mesocorticolimbic system modulates the rewarding properties of food and drugs of abuse and comprising the ventral tegmental area (VTA) and nucleus accumbens (NAc). The locus coeruleus (LC) also has dense orexin innervations in concordance with its* 

*involvement in arousal and emotional memory. Abbreviation: LH, lateral hypothalamus.*

**72**

**Figure 1.**

mesocorticolimbic pathway and that the action of orexins in these neurons could involve a variety of behaviors that are known to be regulated by DA.

This framework suggests that understanding the function of the orexin requires studying them in a brain region-specific basis, as well as understanding the interactions between different brain regions that receive orexinergic input [40]

#### **4. Anorexia nervosa and anxiety disorders: role of orexin and dopamine**

#### **4.1 Anorexia nervosa and anxiety disorders**

AN is a very complex disease, characterized by a profound dysregulation in neurocircuits related to control eating behavior, anxiety, fear, and reward positive/ negative reinforcers. AN is a serious motivated behavioral condition with high morbidity and mortality. Anorexic patients usually have a high comorbidity with severe anxiety disorders, such as obsessive-compulsive disorder (OCD) and social anxiety disorder (SAD) [60]. One characteristic that anorexics share with people suffering from SAD is their fear and concern about how other people perceive them. Elevated neuroticism and perfectionism as well as decreased novelty seeking are anxious personality traits observed in these disorders [60]. Therefore, anxiety disorders and AN are strongly correlated; in both disorders, the fear is organized around an irrational belief associated with heightened vigilance and pronounced anxiety. Another characteristic shared between AN and OCD is compulsivity: to engage in repetitive and stereotyped acts that have unwanted outcomes [61] and arises from a reduced ability to control inflexible yet maladaptive behavior as the starvation, which persists in the face of negative consequences, for example, interfering with academic/occupational/social interests in longer term and the behaviors promoting further, and potentially dangerous, weight loss.

Recently, Lloyd et al. [62] have proposed a central role for anxiety in the development of compulsive starvation; they suggest a dual mechanism by which anxiety could be motivating the initiation of AN and propose that the reinforcement effects of starvation cause excessive repetition of behaviors leading to the buildout of psychological symptoms of AN. They also suggest that starvation becomes compulsive until it has adverse implications for anxiety, which generates the symptoms of AN and which encourages the formation of a vicious circle that guarantees the persistence of an extreme dietary restriction. Stress and distress tolerance have been suggested as important factors in determining the onset and course of AN [61]. Stressful and traumatic events often precede eating diseases. Notably, high levels of anxiety tend to also precede the onset of addiction and OCD.

Dietary restriction has an anxiolytic effect, because women recovered from AN show elevated levels of serotonin (5-HT) metabolites [63], and gene variants linked to more active 5-HT and noradrenaline (NA) systems are implicated in AN [64, 65], supporting the involvement of these neurotransmitter systems in the heightened anxiety that precedes AN. Thus, dietary restriction relieves the anxiety (or negative reinforcement) provided by the dietary restriction that increases with anxiety.

Starvation is a compulsive behavior that over time becomes a habit with a dominant influence in individuals with AN. Surprisingly, in anorexics, there is an imperative need to keep starving [62]. However, this behavior puts your life at risk.

Subjects with AN show an extreme aversive state characterized by high levels of anxiety when eating, that is, when they do not carry out their compulsive behavior of starvation [61, 66]. This is also observed in addiction and OCD, where the execution of compulsions serves to temporarily relieve the negative effects [61, 67–69].

**75**

*Possible Dysregulation of Orexin and Dopamine Systems in Anorexia Nervosa*

reduced consumption of tryptophan and tyrosine, respectively [70, 71].

Several studies indicate that the levels of anxiety in anorexics are even higher than before the restriction of food and that this anxious behavior is partially mediated by an increased sensitivity of the 5-HT and NA systems, which results from the

When starvation becomes necessary to avoid an extremely anxious state, the desire to starve is enhanced given the poor emotion regulation abilities of individuals with AN, which limits the use of alternative strategies to overcome

Anxiety precedes and coincides with restrictive eating in AN [75–78], which is not the case for individuals without the disorder [77]. Repeatedly engaging in dietary restriction in an anxious state facilitates anxiety to evoke restrictive eating

Thus, several mechanisms likely explain how anxiety promotes engagement in maladaptive dietary restriction habits that have developed during a compulsive

**4.2 Dopamine and orexins systems: evidence for an interconnection in anorexia**

Stress and distress tolerance have been suggested as important factors in determining the onset and course of AN. Stressful and traumatic events often precede eating diseases. AN comprises a hyperactivation of the HPA axis [79]. Patients with AN present significantly elevated concentration of plasma cortisol, increased central CRF, and significantly less cortisol suppression after dexamethasone administration than controls [80, 81]. Moreover, hormonal changes also do not seem to be specific for AN and are found in other diseases or in healthy subjects as a consequence of malnutrition and starvation [82]. In general, these data show the need to study other molecules as possible indicators of HPA-axis hyperactivity on the one hand and that regulate emotional states on the other hand. DA and orexins share diverse characteristics at the physiological, psychological, and psychiatric levels, such as the ability to modulate the HPA axis activity, induce drug and food seeking behavior, increase the motivation to obtain food, and regulate emotional

At first it was thought that orexins participated in the consumption of food because orexin central administration produces food seeking, and food deprivation increases orexin mRNA [83, 84]. In addition, orexin neurons are excited by peripheral signals of nutrient needs (e.g., ghrelin), inhibited by satiety signals (e.g., glucose) and interact with feeding peptides to promote food consumption and seeking [85–89]. Notably, orexin neurons are active during hunger and help to translate peripheral hunger signals into increased appetitive responding for food and cues associated to consumption of food. Thus, orexins facilitate food seeking especially

Orexins orchestrate various aspects of stress responses. For example, acute (but

In the case of DA, it is involved in motivational but not consummatory aspects of feeding. The blocking of mesocorticolimbic dopaminergic system decreases the response for motivational tasks associated with obtaining food [91]. DA depletion

not chronic and predictable) stress is associated with orexin neuron activation [90]. The orexins help to organize the response to stress, but only when it assumes a motivated and adaptable behavior to cope with stress, that is, when you can escape the stressor. In contrast, when a stressor is chronic, predictable, and impossible to escape, the activity of orexin system decreases, and this hypoactivity can produce

*DOI: http://dx.doi.org/10.5772/intechopen.83843*

habits, due to a pairing of emotion and behavior.

states, such as depression and anxiety.

in motivationally charged circumstances.

motivational symptoms similar to depression.

dysphoria [72–74].

illness.

**nervosa**

*Possible Dysregulation of Orexin and Dopamine Systems in Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.83843*

Several studies indicate that the levels of anxiety in anorexics are even higher than before the restriction of food and that this anxious behavior is partially mediated by an increased sensitivity of the 5-HT and NA systems, which results from the reduced consumption of tryptophan and tyrosine, respectively [70, 71].

When starvation becomes necessary to avoid an extremely anxious state, the desire to starve is enhanced given the poor emotion regulation abilities of individuals with AN, which limits the use of alternative strategies to overcome dysphoria [72–74].

Anxiety precedes and coincides with restrictive eating in AN [75–78], which is not the case for individuals without the disorder [77]. Repeatedly engaging in dietary restriction in an anxious state facilitates anxiety to evoke restrictive eating habits, due to a pairing of emotion and behavior.

Thus, several mechanisms likely explain how anxiety promotes engagement in maladaptive dietary restriction habits that have developed during a compulsive illness.

#### **4.2 Dopamine and orexins systems: evidence for an interconnection in anorexia nervosa**

Stress and distress tolerance have been suggested as important factors in determining the onset and course of AN. Stressful and traumatic events often precede eating diseases. AN comprises a hyperactivation of the HPA axis [79]. Patients with AN present significantly elevated concentration of plasma cortisol, increased central CRF, and significantly less cortisol suppression after dexamethasone administration than controls [80, 81]. Moreover, hormonal changes also do not seem to be specific for AN and are found in other diseases or in healthy subjects as a consequence of malnutrition and starvation [82]. In general, these data show the need to study other molecules as possible indicators of HPA-axis hyperactivity on the one hand and that regulate emotional states on the other hand. DA and orexins share diverse characteristics at the physiological, psychological, and psychiatric levels, such as the ability to modulate the HPA axis activity, induce drug and food seeking behavior, increase the motivation to obtain food, and regulate emotional states, such as depression and anxiety.

At first it was thought that orexins participated in the consumption of food because orexin central administration produces food seeking, and food deprivation increases orexin mRNA [83, 84]. In addition, orexin neurons are excited by peripheral signals of nutrient needs (e.g., ghrelin), inhibited by satiety signals (e.g., glucose) and interact with feeding peptides to promote food consumption and seeking [85–89]. Notably, orexin neurons are active during hunger and help to translate peripheral hunger signals into increased appetitive responding for food and cues associated to consumption of food. Thus, orexins facilitate food seeking especially in motivationally charged circumstances.

Orexins orchestrate various aspects of stress responses. For example, acute (but not chronic and predictable) stress is associated with orexin neuron activation [90]. The orexins help to organize the response to stress, but only when it assumes a motivated and adaptable behavior to cope with stress, that is, when you can escape the stressor. In contrast, when a stressor is chronic, predictable, and impossible to escape, the activity of orexin system decreases, and this hypoactivity can produce motivational symptoms similar to depression.

In the case of DA, it is involved in motivational but not consummatory aspects of feeding. The blocking of mesocorticolimbic dopaminergic system decreases the response for motivational tasks associated with obtaining food [91]. DA depletion

*Anorexia and Bulimia Nervosa*

mesocorticolimbic pathway and that the action of orexins in these neurons could

This framework suggests that understanding the function of the orexin requires studying them in a brain region-specific basis, as well as understanding the interac-

**4. Anorexia nervosa and anxiety disorders: role of orexin and dopamine**

AN is a very complex disease, characterized by a profound dysregulation in neurocircuits related to control eating behavior, anxiety, fear, and reward positive/ negative reinforcers. AN is a serious motivated behavioral condition with high morbidity and mortality. Anorexic patients usually have a high comorbidity with severe anxiety disorders, such as obsessive-compulsive disorder (OCD) and social anxiety disorder (SAD) [60]. One characteristic that anorexics share with people suffering from SAD is their fear and concern about how other people perceive them. Elevated neuroticism and perfectionism as well as decreased novelty seeking are anxious personality traits observed in these disorders [60]. Therefore, anxiety disorders and AN are strongly correlated; in both disorders, the fear is organized around an irrational belief associated with heightened vigilance and pronounced anxiety. Another characteristic shared between AN and OCD is compulsivity: to engage in repetitive and stereotyped acts that have unwanted outcomes [61] and arises from a reduced ability to control inflexible yet maladaptive behavior as the starvation, which persists in the face of negative consequences, for example, interfering with academic/occupational/social interests in longer term and the behaviors promoting

Recently, Lloyd et al. [62] have proposed a central role for anxiety in the development of compulsive starvation; they suggest a dual mechanism by which anxiety could be motivating the initiation of AN and propose that the reinforcement effects of starvation cause excessive repetition of behaviors leading to the buildout of psychological symptoms of AN. They also suggest that starvation becomes compulsive until it has adverse implications for anxiety, which generates the symptoms of AN and which encourages the formation of a vicious circle that guarantees the persistence of an extreme dietary restriction. Stress and distress tolerance have been suggested as important factors in determining the onset and course of AN [61]. Stressful and traumatic events often precede eating diseases. Notably, high levels of

Dietary restriction has an anxiolytic effect, because women recovered from AN show elevated levels of serotonin (5-HT) metabolites [63], and gene variants linked to more active 5-HT and noradrenaline (NA) systems are implicated in AN [64, 65], supporting the involvement of these neurotransmitter systems in the heightened anxiety that precedes AN. Thus, dietary restriction relieves the anxiety (or negative reinforcement) provided by the dietary restriction that increases with anxiety. Starvation is a compulsive behavior that over time becomes a habit with a dominant influence in individuals with AN. Surprisingly, in anorexics, there is an imperative need to keep starving [62]. However, this behavior puts your life at risk. Subjects with AN show an extreme aversive state characterized by high levels of anxiety when eating, that is, when they do not carry out their compulsive behavior of starvation [61, 66]. This is also observed in addiction and OCD, where the execution of compulsions serves to temporarily relieve the negative effects [61, 67–69].

involve a variety of behaviors that are known to be regulated by DA.

**4.1 Anorexia nervosa and anxiety disorders**

further, and potentially dangerous, weight loss.

anxiety tend to also precede the onset of addiction and OCD.

tions between different brain regions that receive orexinergic input [40]

**74**

or administration of DA receptor antagonists in NAc reduces the motivation to consumption high palatable food [92–95]. The motivation to eat is a key factor to maintain a normal feeding behavior.

Dysfunction of the OXs and DA systems may contribute to the pathology of anxiety and addiction to food and drugs of abuse, which is commonly associated with anxiety and/or defective fear processing, depression, and cognitive impairment as well as other comorbid conditions. Increase in orexin mRNA levels has been observed in animals exposed to different stressors such as immobilization [96], cold stress [96], or hypoglycemia [84], while that both acute and chronic stress promote major changes in DA signaling in the mesocorticolimbic pathway such as increases in DA release in the striatum, NAc, and PFC [97–99]. D2R receptor knockout mice display anxiety and depression-like behaviors upon chronic stress [100]. Repeated restrain stress produces increases and decreases in DA receptor densities within the mesoaccumbens and nigrostriatal systems in two different strains of mice [101]. So, these results suggested that stressful conditions could be augmented the vulnerability to develop psychiatric illnesses as AN. So, any decline in the transmission of DA and orexins can generate a lack of motivation to consume food. However, there are few studies about the participation of DA receptors in the PFA/HL areas on the control of food drinking. Studies suggest that ethanol intake and excessive food consumption could be similarly affected by DA in the PFA/HL areas, with increases in both ethanol and food intake after D1 receptor activation and decrease in both consumptions after the activation of D2 [100].

Considering that the anxiety induces specific reduction of the D2R in the NAc and that DA attenuates several addictive behaviors in animals [100], it is difficult not to think that DA may act as an anxiolytic agent through the D2R activation. On the other hand, the decreased release of orexins could promote low food consumption, that is, the dysfunction of the orexin system could be accentuating the lack of motivation for the search and consumption of food in anorexics. In this way, the stimulation of orexin receptors together with DA could reduce the stress generated by starvation and, at the same time, increase the motivation for food consumption.

#### **5. Conclusion**

Considering on the one hand that AN is a compulsive disorder, and on the other hand that starvation is the result of a negative reinforcement, it is suggested that the dysfunction of DA and orexins in the mesocorticolimbic system is key to the successful treatment of AN. The model can justify the use of existing and planned prevention and treatment programs but may also guide the development of novel interventions to favorably affect the incidence and recovery rates of a lifethreatening condition.

#### **Acknowledgements**

To the Consejo Nacional de Ciencia y Tecnología (CONACyT 241216) and Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz (IC16033.0).

**77**

**Author details**

Marcela Morales-Mulia1

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Science Faculty, Autonomous University of Mexico, UNAM, Mexico City, Mexico

\* and Sandra Morales-Mulia<sup>2</sup>

1 National Institute of Psychiatry RFM, Mexico City, Mexico

\*Address all correspondence to: mmulia@imp.edu.mx

*Possible Dysregulation of Orexin and Dopamine Systems in Anorexia Nervosa*

*DOI: http://dx.doi.org/10.5772/intechopen.83843*

CNS central nervous system

D1R dopamine D1 receptor D2R dopamine D2 receptor LH lateral hypothalamus mRNA messenger ribonucleic acid

HPA axis hypothalamic-pituitary-adrenal axis

CRF corticotrophin-releasing factor

OCD obsessive-compulsive disorder

PVT paraventricular thalamic nucleus

SNc substantia nigra pars compacta

AN anorexia nervosa

DA dopamine

NA noradrenaline NAc nucleus accumbens

OX1R orexin 1 receptor OX2R orexin 2 receptor

PFA perifornical area 5-HT serotonin

SAD social anxiety disorder

TH tyrosine hydroxylase VM ventral midbrain VTA ventral tegmental area

**Nomenclature**

#### **Conflict of interest**

The authors declare that they have no conflict of interest.

*Possible Dysregulation of Orexin and Dopamine Systems in Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.83843*

#### **Nomenclature**

*Anorexia and Bulimia Nervosa*

maintain a normal feeding behavior.

consumptions after the activation of D2 [100].

or administration of DA receptor antagonists in NAc reduces the motivation to consumption high palatable food [92–95]. The motivation to eat is a key factor to

Dysfunction of the OXs and DA systems may contribute to the pathology of anxiety and addiction to food and drugs of abuse, which is commonly associated with anxiety and/or defective fear processing, depression, and cognitive impairment as well as other comorbid conditions. Increase in orexin mRNA levels has been observed in animals exposed to different stressors such as immobilization [96], cold stress [96], or hypoglycemia [84], while that both acute and chronic stress promote major changes in DA signaling in the mesocorticolimbic pathway such as increases in DA release in the striatum, NAc, and PFC [97–99]. D2R receptor knockout mice display anxiety and depression-like behaviors upon chronic stress [100]. Repeated restrain stress produces increases and decreases in DA receptor densities within the mesoaccumbens and nigrostriatal systems in two different strains of mice [101]. So, these results suggested that stressful conditions could be augmented the vulnerability to develop psychiatric illnesses as AN. So, any decline in the transmission of DA and orexins can generate a lack of motivation to consume food. However, there are few studies about the participation of DA receptors in the PFA/HL areas on the control of food drinking. Studies suggest that ethanol intake and excessive food consumption could be similarly affected by DA in the PFA/HL areas, with increases in both ethanol and food intake after D1 receptor activation and decrease in both

Considering that the anxiety induces specific reduction of the D2R in the NAc and that DA attenuates several addictive behaviors in animals [100], it is difficult not to think that DA may act as an anxiolytic agent through the D2R activation. On the other hand, the decreased release of orexins could promote low food consumption, that is, the dysfunction of the orexin system could be accentuating the lack of motivation for the search and consumption of food in anorexics. In this way, the stimulation of orexin receptors together with DA could reduce the stress generated by starvation and, at the same time, increase the motivation for food

Considering on the one hand that AN is a compulsive disorder, and on the other hand that starvation is the result of a negative reinforcement, it is suggested that the dysfunction of DA and orexins in the mesocorticolimbic system is key to the successful treatment of AN. The model can justify the use of existing and planned prevention and treatment programs but may also guide the development of novel interventions to favorably affect the incidence and recovery rates of a life-

To the Consejo Nacional de Ciencia y Tecnología (CONACyT 241216) and Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz (IC16033.0).

The authors declare that they have no conflict of interest.

**76**

consumption.

**5. Conclusion**

threatening condition.

**Acknowledgements**

**Conflict of interest**


### **Author details**

Marcela Morales-Mulia1 \* and Sandra Morales-Mulia<sup>2</sup>

1 National Institute of Psychiatry RFM, Mexico City, Mexico

2 Science Faculty, Autonomous University of Mexico, UNAM, Mexico City, Mexico

\*Address all correspondence to: mmulia@imp.edu.mx

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[14] Karson CN. Spontaneous eye-blink rates and dopaminergic systems. Brain. 1983;**106**:643-653

[15] Bergh C, Södersten P. Anorexia nervosa, self-starvation and the reward of stress. Nature Medicine. 1996;**2**:21-22

[16] O'Hara CB, Campbell IC, Schmidt U. A reward-centred model of anorexia nervosa: A focussed narrative review of the neurological and psychophysiological literature. Neuroscience & Biobehavioral. Reviews.

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[28] Södersten P, Nergårdh R, Bergh C, Zandian M, Scheurink A. Behavioral neuroendocrinology and treatment of anorexia nervosa. Frontiers in Neuroendocrinology. 2008;**29**:445-462. DOI: 10.1016/j.yfrne.2008.06.001

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10.1210/JC.2015-2078

[21] Schorr M, Lawson EA, Dichtel LE, Klibanski A, Miller KK. Cortisol measures across the weight spectrum. Journal of Clinical Endocrinology & Metabolism. 2015;**100**:3313-3321. DOI:

[22] Shibuya I, Nagamitsu S, Okamura H, Komatsu H, Ozono S, Yamashita Y, et al. Changes in salivary cortisol levels as a prognostic predictor in children with anorexia nervosa. International Journal of Psychophysiology. Nov

neubiorev.2015.02.012

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psy.0000227749.58726.41

jc.2009-2608

*Possible Dysregulation of Orexin and Dopamine Systems in Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.83843*

2015;**52**:131-152. DOI: 10.1016/j. neubiorev.2015.02.012

[17] Hotta M, Shibasaki T, Masuda A, Imaki T, Demura H, Ling N, et al. The responses of plasma adrenocorticotropin and cortisol to corticotropin-releasing hormone (CRH) and cerebrospinal fluid immunoreactive CRH in anorexia nervosa patients. Journal of Clinical Endocrinology and Metabolism. 1986;**62**:319-324. DOI: 10.1210/jcem-62-2-319

[18] Rojo L, Conesa L, Bermudez O, Livianos L. Influence of stress in the onset of eating disorders: Data from a two-stage epidemiologic controlled study. Psychosomatic Medicine. 2006;**68**:628-635. DOI: 10.1097/01. psy.0000227749.58726.41

[19] Estour B, Germain N, Diconne E, Frere D, Cottet-Emard J-M, Carrot G, et al. Hormonal profile heterogeneity and short-term physical risk in restrictive anorexia nervosa. Journal of Clinical Endocrinology & Metabolism. 2010;**95**:2203-2210. DOI: 10.1210/ jc.2009-2608

[20] Gwirtsman HE, Kaye WH, George DT, Jimerson DC, Ebert MH, Gold PW. Central and peripheral ACTH and cortisol levels in anorexia nervosa and bulimia. Archives of General Psychiatry. 1989;**46**:61-69. DOI: 10.1001/ archpsyc.1989.01810010063009

[21] Schorr M, Lawson EA, Dichtel LE, Klibanski A, Miller KK. Cortisol measures across the weight spectrum. Journal of Clinical Endocrinology & Metabolism. 2015;**100**:3313-3321. DOI: 10.1210/JC.2015-2078

[22] Shibuya I, Nagamitsu S, Okamura H, Komatsu H, Ozono S, Yamashita Y, et al. Changes in salivary cortisol levels as a prognostic predictor in children with anorexia nervosa. International Journal of Psychophysiology. Nov

2011;**82**(2):196-201. DOI: 10.1016/j. ijpsycho.2011.08.008

[23] Holly EN, DeBold JF, Miczek KA. Increased mesocorticolimbic dopamine during acute and repeated social defeat stress: Modulation by corticotropin releasing factor receptors in the ventral tegmental area. Psychopharmacology. 2015;**232**:4469-4479. DOI: 10.1007/ s00213-015-4082-z

[24] Wanat MJ, Hopf FW, Stuber GD, Phillips PE, Bonci A. Corticotropinreleasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of Ih. Journal of Physiology. 2008;**586**(8):2157-2170. DOI: 10.1113/jphysiol.2007

[25] Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: From actions to habits to compulsion. Nature Neuroscience. 2005;**8**:1481-1489. DOI: 10.1038/nn1579

[26] Jansen A. A learning model of binge eating: Cue reactivity and cue exposure. Behaviour Research and Therapy. 1998;**36**:257-272. DOI: 10.1016/ S0005-7967(98)00055-2

[27] Méquinion M, Chauveau C, Viltart O. The use of animal models to decipher physiological and neurobiological alterations of anorexia nervosa patients. Frontiers in Endocrinology (Lausanne). 2015;**6**:68. DOI: 10.3389/ fendo.2015.00068

[28] Södersten P, Nergårdh R, Bergh C, Zandian M, Scheurink A. Behavioral neuroendocrinology and treatment of anorexia nervosa. Frontiers in Neuroendocrinology. 2008;**29**:445-462. DOI: 10.1016/j.yfrne.2008.06.001

[29] Stengel A, Taché Y. CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress. Frontiers in

**78**

*Anorexia and Bulimia Nervosa*

**References**

[1] Zipfel S, Giel KE, Bulik CM, Hay P, Schmidt U. Anorexia nervosa: Aetiology, assessment, and treatment. Lancet Psychiatry. Dec 2015;**2**(12):1099-1111. DOI: 10.1016/S2215-0366(15)00356-9

[9] Hornykiewicz O.

Psychopharmacological implications of dopamine and dopamine antagonists: A critical evaluation of current evidence. Neuroscience. 1978;**3**:773-783. DOI: 10.1016/0306-4522(78)90030-1

[10] Asakawa A, Inui A, Momose K, Ueno N, Fujino MA, Kasuga M. Endomorphins have orexigenic and anxiolytic activities in mice. Neuroreport. 1998;**9**:2265-2267

[11] Cooper JR, Bloom FE, Roth RH. The Biochemical Basis of Neuropharmacology. 8th ed. Oxford: Oxford University Press; 2003. 518 p.

DOI: 10.1093/ageing/afw180

[12] Kaye WH, Ebert MH, Raleigh M, Lake R. Abnormalities in CNS monoamine metabolism in anorexia nervosa. Archives of General Psychiatry.

1984;**41**:350-355. DOI: 10.1176/

[13] Frank GK, Bailer UF, Henry SE, Drevets W, Meltzer CC, Price JC, et al. Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomographyand [11c]raclopride. Biological Psychiatry. 2005;**58**:908-912. DOI: 10.1016/j.biopsych.2005.05.003

[14] Karson CN. Spontaneous eye-blink rates and dopaminergic systems. Brain.

[15] Bergh C, Södersten P. Anorexia nervosa, self-starvation and the reward of stress. Nature Medicine.

[16] O'Hara CB, Campbell IC, Schmidt U. A reward-centred model of anorexia nervosa: A focussed narrative review of the neurological and psychophysiological literature. Neuroscience & Biobehavioral. Reviews.

ajp.141.12.1598

1983;**106**:643-653

1996;**2**:21-22

[2] Arcelus J, Mitchell AJ, Wales J, Nielsen S. Mortality rates in patients with anorexia nervosa and other eating disorders. A meta-analysis of 36 studies. Archives of General Psychiatry. Jul 2011;**68**(7):724-731. DOI: 10.1001/

[3] Yoshida K, McCormack S, España RA, Crocker A, Scammell TE. Afferents to the orexin neurons of the rat brain. Journal of Comparative Neurology. 2006;**494**:845-861. DOI: 10.1002/

[4] Palmiter RD. Is dopamine a physiologically relevant mediator of feeding behavior? Trends in

10.1016/j.tins.2007.06.004

Amsterdam; New York; 1983

Experientia. 1964;**20**:398-399

of obsessive compulsive disorder and attention deficit hyperactivity disorder. Progress in Neuropsychopharmacology & Biological Psychiatry. 2001;**25**:5-26. DOI: 10.1016/S0278-5846(00)00146-9

[7] Carlsson ML. On the role of prefrontal cortex glutamate for the antithetical phenomenology

[8] Chao J, Nestler EJ. Molecular neurobiology of drug addiction. Annual Review of Medicine.

med.55.091902.103730

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[79] Gazendam FJ, Kamphuis JH, Kindt M. Deficient safety learning characterizes high trait anxious individuals. Biological Psychology. 2013;**92**:342-352. DOI: 10.1016/j. biopsycho.2012.11.006

[80] Licinio J, Wong ML, Gold PW. The hypothalamic-pituitary-adrenal axis in anorexia nervosa. Psychiatry Research. 1996;**62**:75-83. DOI: 10.1016/0165-1781(96)02991-5

[81] Walsh BT, Roose SP, Katz JL, Dyrenfurth I, Wright L, Vande Wiele R, et al. Hypothalamic-pituitary-adrenalcortical activity in anorexia nervosa and bulimia. Psychoneuroendocrinology. 1987;**12**:131-140

[82] Fichter MM, Doerr P, Pirke KM, Lund R. Behavior, attitude, nutrition and endocrinology in anorexia nervosa. Acta Psychiatrica Scandinavica. 1982;**66**:429-444. DOI: 10.1111/j.1600- 0447.1982.tb04500.x

[83] Jászberényi M, Bujdosó E, Pataki I, Telegdy G. Effect of orexins on the hypothalamic-pituitary-adrenal system. Journal of Neuroendocrinology. 2000;**12**:1174-1178

[84] Griffond B, Risold PY, Jacquemard C, Colard C, Fellmann D. Insulininduced hypoglycemia increases preprohypocretin (orexin) mRNA in the rat lateral hypothalamic area. Neuroscience Letters. 1999;**262**:77-80. DOI: 10.1016/S0304-3940(98)00976-8

[85] Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: A family of hypothalamic neuropéptidos and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;**92**:573-585. DOI: 10.1016/ S0092-8674(02)09256-5

[86] Berthoud HR, Munzberg H. The lateral hypothalamus as integrator of metabolic and environmental needs: From electrical self-stimulation to opto-genetics. Physiology & Behavior. 2011;**104**:29-39. DOI: 10.1016/j. physbeh.2011.04.051

[87] Burdakov D, Karnani MM, Gonzalez A. Lateral hypothalamus as a sensor-regulator in respiratory and metabolic control. Physiology & Behavior. 2013;**121**:117-124. DOI: 10.1016/j.physbeh.2013.03.023

[88] Cason AM, Smith RJ, Tahsili-Fahadan P, Moorman DE, Sartor GC, Aston-Jones G. Role of orexin/ hypocretin in reward-seeking and addiction: Implications for obesity. Physiology & Behavior. 2010;**100**:419-428. DOI: 10.1016/j. physbeh.2010.03.009

[89] Sheng Z, Santiago AM, Thomas MP, Routh VH. Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry. Molecular and Cellular Neuroscience. 2014;**62**:30-41. DOI: 10.1016/j.mcn.2014.08.001

[90] Yeoh JW, Campbell EJ, James MH, Graham BA, Dayas CV. Orexin antagonists for neuropsychiatric disease: Progress and potential pitfalls. Frontiers in Neuroscience. 2014;**8**:36. DOI: 10.3389/fnins.2014.00036

[91] Salamone JD, Cousins MS, Snyder BJ. Behavioral functions of nucleus accumbens dopamine: Empirical and conceptual problems with the anhedonia hypothesis.

Neuroscience and Biobehavioural Review. 1997;**21**:341-359. DOI: 10.1016/ S0149-7634(96)00017-6

[92] Cousins MS, Salamone JD. Nucleus accumbens dopamine depletions in rats affect relative response allocation in a novel cost/benefit procedure. Pharmacology Biochemistry and Behavior. 1994;**49**:85-91. DOI: 10.1016/0091-3057(94)90460-X

[93] Nowend KL, Arizzi M, Carlson BB, Salamone JD. D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption. Pharmacology Biochemistry and Behavior. 2001;**69**:373-382. DOI: 10.1016/ S0091-3057(01)00524-X

[94] Salamone JD, Arizzi MN, Sandoval MD, Cervone KM, Aberman JE. Dopamine antagonists alter response allocation but do not suppress appetite for food in rats: Contrast between the effects of SKF 83566, raclopride, and fenfluramine on a concurrent choice task. Psychopharmacology. 2002;**160**:371-380. DOI: 10.1007/ s00213-001-0994-x

[95] Salamone JD, Steinpreis RE, McCullough LD, Smith P, Grebel D, Mahan K. Haloperidol and nucleus accumbens dopamine depletion suppress lever pressing for food but increase free food consumption in a novel food choice procedure. Psychopharmacology. 1991;**104**:515-521

[96] Ida T, Nakahara K, Murakami T, Hanada R, Nakazato M, Murakami N. Possible involvement of orexin in the stress reaction in rats. Biochemical and Biophysical Research Communications. 2000;**270**:318-323. DOI: 10.1006/ bbrc.2000.2412

[97] Abercrombie ED, Keefe KA, DiFrischia DS, Zigmond MJ. Differential effect of stress on in vivo dopamine

**85**

*Possible Dysregulation of Orexin and Dopamine Systems in Anorexia Nervosa*

*DOI: http://dx.doi.org/10.5772/intechopen.83843*

release in striatum, nucleus accumbens, and medial frontal cortex. Journal of Neurochemistry. 1989;**52**:1655-1658. DOI: 10.1111/j.1471-4159.1989.tb09224.x

[98] Imperato A, Angelucci L, Casoloni P, Zocchi A, Puglisi-Allegra S. Repeated stressful experiences differently affect limbic dopamine release during and following stress. Brain Research. 1992;**577**:194-199. DOI:

10.1016/0006-8993(92)90274-D

2004;**74**:301-320. DOI: 10.1016/j.

pneurobio.2004.09.004

DOI: 10.1038/ncomms2598

1998;**84**:193-200. DOI: 10.1016/ S0306-4522(97)00468-5

[99] Pezze MA, Feldon J. Mesolimbic dopaminergic pathways in fear

conditioning. Progress in Neurobiology.

[100] Sim H, Choi T-Y, Lee HJ, Kang EY, Yoon S, Han P-L, et al. Role of dopamine D2 receptors in plasticity of stressinduced addictive behaviours. Nature Communications. 2013;**4**:1579-1589.

[101] Cabib S, Giardino L, Calzá L, Zanni M, Mele A, Puglisi-Allegra S. Stress promotes major changes in dopamine densities within the mesoaccumbens and nigrostriatal systems. Neuroscience. *Possible Dysregulation of Orexin and Dopamine Systems in Anorexia Nervosa DOI: http://dx.doi.org/10.5772/intechopen.83843*

release in striatum, nucleus accumbens, and medial frontal cortex. Journal of Neurochemistry. 1989;**52**:1655-1658. DOI: 10.1111/j.1471-4159.1989.tb09224.x

*Anorexia and Bulimia Nervosa*

[85] Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: A family of hypothalamic neuropéptidos and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;**92**:573-585. DOI: 10.1016/ S0092-8674(02)09256-5

Neuroscience and Biobehavioural Review. 1997;**21**:341-359. DOI: 10.1016/

[92] Cousins MS, Salamone JD. Nucleus accumbens dopamine depletions in rats affect relative response allocation in a novel cost/benefit procedure. Pharmacology Biochemistry and Behavior. 1994;**49**:85-91. DOI: 10.1016/0091-3057(94)90460-X

[93] Nowend KL, Arizzi M, Carlson BB, Salamone JD. D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption. Pharmacology

Biochemistry and Behavior. 2001;**69**:373-382. DOI: 10.1016/ S0091-3057(01)00524-X

[94] Salamone JD, Arizzi MN,

[95] Salamone JD, Steinpreis RE, McCullough LD, Smith P, Grebel D, Mahan K. Haloperidol and nucleus accumbens dopamine depletion suppress lever pressing for food but increase free food consumption in a novel food choice procedure. Psychopharmacology. 1991;**104**:515-521

[96] Ida T, Nakahara K, Murakami T, Hanada R, Nakazato M, Murakami N. Possible involvement of orexin in the stress reaction in rats. Biochemical and Biophysical Research Communications. 2000;**270**:318-323. DOI: 10.1006/

[97] Abercrombie ED, Keefe KA,

DiFrischia DS, Zigmond MJ. Differential effect of stress on in vivo dopamine

s00213-001-0994-x

bbrc.2000.2412

Sandoval MD, Cervone KM, Aberman JE. Dopamine antagonists alter response allocation but do not suppress appetite for food in rats: Contrast between the effects of SKF 83566, raclopride, and fenfluramine on a concurrent choice task. Psychopharmacology. 2002;**160**:371-380. DOI: 10.1007/

S0149-7634(96)00017-6

[86] Berthoud HR, Munzberg H. The lateral hypothalamus as integrator of metabolic and environmental needs: From electrical self-stimulation to opto-genetics. Physiology & Behavior.

2011;**104**:29-39. DOI: 10.1016/j.

[87] Burdakov D, Karnani MM, Gonzalez A. Lateral hypothalamus as a sensor-regulator in respiratory and metabolic control. Physiology & Behavior. 2013;**121**:117-124. DOI: 10.1016/j.physbeh.2013.03.023

[88] Cason AM, Smith RJ, Tahsili-Fahadan P, Moorman DE, Sartor GC, Aston-Jones G. Role of orexin/ hypocretin in reward-seeking and addiction: Implications for obesity. Physiology & Behavior. 2010;**100**:419-428. DOI: 10.1016/j.

[89] Sheng Z, Santiago AM, Thomas MP, Routh VH. Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry. Molecular and Cellular Neuroscience. 2014;**62**:30-41. DOI: 10.1016/j.mcn.2014.08.001

[90] Yeoh JW, Campbell EJ, James MH, Graham BA, Dayas CV. Orexin antagonists for neuropsychiatric disease: Progress and potential pitfalls. Frontiers in Neuroscience. 2014;**8**:36. DOI: 10.3389/fnins.2014.00036

[91] Salamone JD, Cousins MS, Snyder BJ. Behavioral functions of nucleus accumbens dopamine: Empirical and conceptual problems with the anhedonia hypothesis.

physbeh.2011.04.051

physbeh.2010.03.009

**84**

[98] Imperato A, Angelucci L, Casoloni P, Zocchi A, Puglisi-Allegra S. Repeated stressful experiences differently affect limbic dopamine release during and following stress. Brain Research. 1992;**577**:194-199. DOI: 10.1016/0006-8993(92)90274-D

[99] Pezze MA, Feldon J. Mesolimbic dopaminergic pathways in fear conditioning. Progress in Neurobiology. 2004;**74**:301-320. DOI: 10.1016/j. pneurobio.2004.09.004

[100] Sim H, Choi T-Y, Lee HJ, Kang EY, Yoon S, Han P-L, et al. Role of dopamine D2 receptors in plasticity of stressinduced addictive behaviours. Nature Communications. 2013;**4**:1579-1589. DOI: 10.1038/ncomms2598

[101] Cabib S, Giardino L, Calzá L, Zanni M, Mele A, Puglisi-Allegra S. Stress promotes major changes in dopamine densities within the mesoaccumbens and nigrostriatal systems. Neuroscience. 1998;**84**:193-200. DOI: 10.1016/ S0306-4522(97)00468-5

**87**

**Chapter 6**

**Abstract**

Dysbiosis of the Microbiota

Pathophysiological Implications

Anorexia nervosa (AN) is a severe and often enduring condition of which the etiology is unknown. Studies on the gut microbiota in AN have found deviations from that of healthy individuals, which may imply a relation to pathophysiology, development and maintenance of the disorder via the gut-brain axis, which has been shown in other disorders. A narrative review of the gut microbiota studies in AN is presented. Several studies point to a dysbiosis in AN which may have implications for maintenance of a low body weight, immunological changes and a severely reduced food intake. An association may be found to clinical symptoms in AN. A pathophysiological model for disease is presented implying a role of the microbiota in maintenance of AN. Dysbiosis in AN may play an important role in the develop-

Anorexia nervosa (AN) is a serious and often enduring psychiatric condition. The hallmark features of AN are a phobia for weight gain, and for intake of fattening food, disturbance in body image, and often compensatory behaviors such as excessive exercise and purging, which overall leads to a reduction of energy intake relative to energy expenditure leading to low body weight. An increased risk of suicide and frequent potential life-threatening medical complications of several body organs contribute to AN having a high standardized mortality ratio of 5.2 [3.7**–**7.5]

The weight loss is in some patients preceded by a depression, a trauma, gastrointestinal symptoms or an infection. But in a majority of patients there is no detectable psychiatric or somatic disorder preceding the weight loss. In children and adolescents with AN, family-based treatment as described by Lock and LeGrange is recommended [3] and if treatment is started shortly after debut of the disorder, the prognosis is fairly good. However, if treatment is delayed, the prognosis becomes worse [4]**.** In adults, individual eating-disorder-focused therapy (CBT-ED) is recommended [5]. With this treatment, drop-out rates are high and even with optimal treatment by well-trained therapists only 50% of the patients who start CBT-ED

**Keywords:** anorexia nervosa, feces, microbiota, species, biomarkers

[1]. This is coupled with a high risk of enduring disease [2].

have good effect of the therapy [6, 7].

in Anorexia Nervosa:

*Magnus Sjögren, Stein Frostad* 

ment and maintenance of AN.

**1. Introduction**

*and Kenneth Klingenberg Barfod*

#### **Chapter 6**

## Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications

*Magnus Sjögren, Stein Frostad and Kenneth Klingenberg Barfod*

#### **Abstract**

Anorexia nervosa (AN) is a severe and often enduring condition of which the etiology is unknown. Studies on the gut microbiota in AN have found deviations from that of healthy individuals, which may imply a relation to pathophysiology, development and maintenance of the disorder via the gut-brain axis, which has been shown in other disorders. A narrative review of the gut microbiota studies in AN is presented. Several studies point to a dysbiosis in AN which may have implications for maintenance of a low body weight, immunological changes and a severely reduced food intake. An association may be found to clinical symptoms in AN. A pathophysiological model for disease is presented implying a role of the microbiota in maintenance of AN. Dysbiosis in AN may play an important role in the development and maintenance of AN.

**Keywords:** anorexia nervosa, feces, microbiota, species, biomarkers

#### **1. Introduction**

Anorexia nervosa (AN) is a serious and often enduring psychiatric condition. The hallmark features of AN are a phobia for weight gain, and for intake of fattening food, disturbance in body image, and often compensatory behaviors such as excessive exercise and purging, which overall leads to a reduction of energy intake relative to energy expenditure leading to low body weight. An increased risk of suicide and frequent potential life-threatening medical complications of several body organs contribute to AN having a high standardized mortality ratio of 5.2 [3.7**–**7.5] [1]. This is coupled with a high risk of enduring disease [2].

The weight loss is in some patients preceded by a depression, a trauma, gastrointestinal symptoms or an infection. But in a majority of patients there is no detectable psychiatric or somatic disorder preceding the weight loss. In children and adolescents with AN, family-based treatment as described by Lock and LeGrange is recommended [3] and if treatment is started shortly after debut of the disorder, the prognosis is fairly good. However, if treatment is delayed, the prognosis becomes worse [4]**.** In adults, individual eating-disorder-focused therapy (CBT-ED) is recommended [5]. With this treatment, drop-out rates are high and even with optimal treatment by well-trained therapists only 50% of the patients who start CBT-ED have good effect of the therapy [6, 7].

Considering the high mortality, high chronicity and lack of knowledge on the etiology of AN, there is an immense need for an improved understanding of the etiology and pathophysiology of the disease in order to find ways to better treatments. This knowledge would preferably explain both the routes into developing the disorder and mechanisms that serve to maintain it, and proposedly involve both biological and psychological factors, such that measures and biomarkers to follow the development and recovery from of the disease could be identified. Potential further benefits with biomarkers for AN may be guidance for risk stratification, treatment and target identification for novel treatments. The last few years have seen an increase in studies on the gut microbiota and its associated microbiome which might harbor trait biomarkers for AN.

The "microbiota" refers to the cumulative microorganisms, including Bacteria, Viruses, Archaea, Protists and Fungi, which populate a number of human tissues and biofluids including the skin, lungs, roal mucosa, saliva, and gastrointestinal tract, and the "microbiome" refers to the collective genomes of the present microorganisms [8]. There are more than 1000 'species-level' phylotypes that coexist in a human [9], and the majority of these phylotypes are Bacteria, with *Faecalibacterium prausnitzii*, *Roseburia intestinalis*, and *Bacteroides uniformis* dominating in the adult microbiota found in feces samples [10]. The composition of the phylotypes is mostly consistent across individuals, albeit there may be a large variability with regard to relative composition and diversity of the included microorganisms, intra-individually depending on anatomical site and inter-individually at the same anatomical location. In addition, there are inter-individual variations at the same anatomical site.

The gut microbiota is critical for the development of the gut mucosal immunity [11, 12], and it is also involved in the regulation of the hypothalamic**-**pituitaryadrenal (HPA) axis [13], serotonergic neurotransmission [14], and signaling mechanisms affecting neuronal circuits involved in motor control and anxiety in mice [15]. This pathway has been named the gut-brain axis [16].

#### **2. The gut-brain axis**

The existence of the gut-brain axis is exemplified by irritable bowel syndrome (IBS) where more than half of the patients also suffer from mood disorders and for which antidepressants is one of the more common pharmaceutical treatments [17]. In IBS and other potential gut-brain axis disorders, cognitive alterations seem to be key features of the disorders [18]. These cognitive alterations might be induced by signal transduction from gut to the brain [18]. In addition, the existence is also shown by the effects of antibiotic exposure, which may lead to altered brain function such as anxiety, panic disorder, major depression, psychosis, and delirium which are usually described as side effects of antibiotic treatment [19]. Support for the latter comes also from studies in mice which have shown that an altered composition of the gut microbiota in adult mice, and an increased exploratory behavioral including hippocampal expression of Brain Derived Nerve growth Factor (BDNF) has been found after oral administration of non-absorbable antimicrobials [20], in contrast to intraperitoneal administration, which had no effect on behavior or BDNF levels.

Another area of evidence for the gut-brain-axis stems from dietary induction of changes in gut microbiota and linked psychopathological outcomes. For example, a high fat diet has been found associated with an altered microbial diversity and diminished synaptic plasticity [21, 22] but also increased vulnerability and anxietylike behavior in the mice [23]. In addition, a diet high in sucrose also led to an altered microbial diversity associated with impaired development of spatial bias for

**89**

*Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications*

rhythm all have been shown to affect the microbiota composition.

seemed to attenuate these physiological effects [28].

feedback loop between depressive states and dysbiosis.

**3. How is the effects in the gut-brain axis mediated?**

AN and schizophrenia [39].

long term memory, short term memory, and reversal trainings [24]. Another strong evidence for the gut-brain axis comes from a study in mice exposed to a microbiome depletion and/or transplantation paradigm where microbiota, in a first step, was isolated from donors who were provided with either in high fat diet or a controlled diet, and thereafter in a second step, transfused to mice who developed significant and selective disruptions in exploratory, cognitive, and also developed the stereotypical behavior following the high fat diet [25]. However, there are also evidence from studies where alcohol exposure, smoking habits, and disruptions in diurnal

There are also other evidence pointing to a reciprocal interaction from a study where a second generation antipsychotics, olanzapine, was exposed to rats and found to affect the composition of the microbiota, which also triggered an inflammatory response and weight gain [26, 27]. Furthermore, the exposure to antibiotics

The microbiome has also been found to have been altered in various psychiatric conditions, or to affect its clinical expression, as well altered in rodent models for these disorders [29]. One example is major depressive disorder (MDD) where, for example, in germ-free mice (mice completely void of bacterial microbiota or derived molecules), there are both changes from comparable normal mice in the hypothalamic, pituitary, adrenal stress response, as well as altered levels of monoamines concentrations or their receptors [13–15, 20, 30]. Indirect evidence in MDD also comes from an increased serum antibody level to lipopolysaccharides that stems from Gram-negative enterobacteria, which are higher in MDD compared to controls [31], and which is associated with stress associated increased gut permeability and bacterial translocation in animal models [32, 33]. In addition, depression also altered the gut microbiota in a mouse model, in which chronic depression and anxiety-like behaviors were induced by olfactory bulbectomy [34], suggesting a

Furthermore, a similar type of relation between dysbiosis and psychopathogenesis is found in schizophrenia [35, 36]. For example, elevated levels of serological markers of bacterial translocation have been found to be highly correlated with systemic inflammatory markers in schizophrenia [37], and, cytokine levels in schizophrenia are correlated with the severity of symptomatology [38]. From a genetic point of view, several of the strongest associations identified between genetic risk and schizophrenia stems from genes that are linked to immunological function [57, 58]. This is particularly interesting in view of the genetic association between

The mechanism behind the gut brain axis may be multifaceted involving neural signal transduction in nervus vagus, neurotransmitters, immunological mechanisms, and mechanisms related to metabolism and energy utilization [40]. One of the strongest links from a mechanistic point of view, stems from research on serotonin and the microbiota. Enterochromaffin (EC) cells provides approximately 95% of the total body content of serotonin [41] of which the majority exists in plasma. Multiple levels of evidence links disturbances in the serotonergic system and several psychiatric disorder such as depression, anxiety, and borderline personality disorder. For example, the metabolism of tryptophan, a precursor of serotonin, is potentially regulated by the gut microbiota thereby enabling it to influence brain function [42]. Tryptophan is an essential amino acid derived from the diet [43], and tryptophan that is absorbed from the gut into the bloodstream passes the

*DOI: http://dx.doi.org/10.5772/intechopen.85253*

#### *Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications DOI: http://dx.doi.org/10.5772/intechopen.85253*

long term memory, short term memory, and reversal trainings [24]. Another strong evidence for the gut-brain axis comes from a study in mice exposed to a microbiome depletion and/or transplantation paradigm where microbiota, in a first step, was isolated from donors who were provided with either in high fat diet or a controlled diet, and thereafter in a second step, transfused to mice who developed significant and selective disruptions in exploratory, cognitive, and also developed the stereotypical behavior following the high fat diet [25]. However, there are also evidence from studies where alcohol exposure, smoking habits, and disruptions in diurnal rhythm all have been shown to affect the microbiota composition.

There are also other evidence pointing to a reciprocal interaction from a study where a second generation antipsychotics, olanzapine, was exposed to rats and found to affect the composition of the microbiota, which also triggered an inflammatory response and weight gain [26, 27]. Furthermore, the exposure to antibiotics seemed to attenuate these physiological effects [28].

The microbiome has also been found to have been altered in various psychiatric conditions, or to affect its clinical expression, as well altered in rodent models for these disorders [29]. One example is major depressive disorder (MDD) where, for example, in germ-free mice (mice completely void of bacterial microbiota or derived molecules), there are both changes from comparable normal mice in the hypothalamic, pituitary, adrenal stress response, as well as altered levels of monoamines concentrations or their receptors [13–15, 20, 30]. Indirect evidence in MDD also comes from an increased serum antibody level to lipopolysaccharides that stems from Gram-negative enterobacteria, which are higher in MDD compared to controls [31], and which is associated with stress associated increased gut permeability and bacterial translocation in animal models [32, 33]. In addition, depression also altered the gut microbiota in a mouse model, in which chronic depression and anxiety-like behaviors were induced by olfactory bulbectomy [34], suggesting a feedback loop between depressive states and dysbiosis.

Furthermore, a similar type of relation between dysbiosis and psychopathogenesis is found in schizophrenia [35, 36]. For example, elevated levels of serological markers of bacterial translocation have been found to be highly correlated with systemic inflammatory markers in schizophrenia [37], and, cytokine levels in schizophrenia are correlated with the severity of symptomatology [38]. From a genetic point of view, several of the strongest associations identified between genetic risk and schizophrenia stems from genes that are linked to immunological function [57, 58]. This is particularly interesting in view of the genetic association between AN and schizophrenia [39].

#### **3. How is the effects in the gut-brain axis mediated?**

The mechanism behind the gut brain axis may be multifaceted involving neural signal transduction in nervus vagus, neurotransmitters, immunological mechanisms, and mechanisms related to metabolism and energy utilization [40]. One of the strongest links from a mechanistic point of view, stems from research on serotonin and the microbiota. Enterochromaffin (EC) cells provides approximately 95% of the total body content of serotonin [41] of which the majority exists in plasma. Multiple levels of evidence links disturbances in the serotonergic system and several psychiatric disorder such as depression, anxiety, and borderline personality disorder. For example, the metabolism of tryptophan, a precursor of serotonin, is potentially regulated by the gut microbiota thereby enabling it to influence brain function [42]. Tryptophan is an essential amino acid derived from the diet [43], and tryptophan that is absorbed from the gut into the bloodstream passes the

*Anorexia and Bulimia Nervosa*

anatomical site.

**2. The gut-brain axis**

which might harbor trait biomarkers for AN.

Considering the high mortality, high chronicity and lack of knowledge on the etiology of AN, there is an immense need for an improved understanding of the etiology and pathophysiology of the disease in order to find ways to better treatments. This knowledge would preferably explain both the routes into developing the disorder and mechanisms that serve to maintain it, and proposedly involve both biological and psychological factors, such that measures and biomarkers to follow the development and recovery from of the disease could be identified. Potential further benefits with biomarkers for AN may be guidance for risk stratification, treatment and target identification for novel treatments. The last few years have seen an increase in studies on the gut microbiota and its associated microbiome

The "microbiota" refers to the cumulative microorganisms, including Bacteria, Viruses, Archaea, Protists and Fungi, which populate a number of human tissues and biofluids including the skin, lungs, roal mucosa, saliva, and gastrointestinal tract, and the "microbiome" refers to the collective genomes of the present microorganisms [8]. There are more than 1000 'species-level' phylotypes that coexist in a human [9], and the majority of these phylotypes are Bacteria, with *Faecalibacterium prausnitzii*, *Roseburia intestinalis*, and *Bacteroides uniformis* dominating in the adult microbiota found in feces samples [10]. The composition of the phylotypes is mostly consistent across individuals, albeit there may be a large variability with regard to relative composition and diversity of the included microorganisms, intra-individually depending on anatomical site and inter-individually at the same anatomical location. In addition, there are inter-individual variations at the same

The gut microbiota is critical for the development of the gut mucosal immunity

The existence of the gut-brain axis is exemplified by irritable bowel syndrome (IBS) where more than half of the patients also suffer from mood disorders and for which antidepressants is one of the more common pharmaceutical treatments [17]. In IBS and other potential gut-brain axis disorders, cognitive alterations seem to be key features of the disorders [18]. These cognitive alterations might be induced by signal transduction from gut to the brain [18]. In addition, the existence is also shown by the effects of antibiotic exposure, which may lead to altered brain function such as anxiety, panic disorder, major depression, psychosis, and delirium which are usually described as side effects of antibiotic treatment [19]. Support for the latter comes also from studies in mice which have shown that an altered composition of the gut microbiota in adult mice, and an increased exploratory behavioral including hippocampal expression of Brain Derived Nerve growth Factor (BDNF) has been found after oral administration of non-absorbable antimicrobials [20], in contrast to intraperitoneal administration, which had no effect on behavior or BDNF levels. Another area of evidence for the gut-brain-axis stems from dietary induction of changes in gut microbiota and linked psychopathological outcomes. For example, a high fat diet has been found associated with an altered microbial diversity and diminished synaptic plasticity [21, 22] but also increased vulnerability and anxietylike behavior in the mice [23]. In addition, a diet high in sucrose also led to an altered microbial diversity associated with impaired development of spatial bias for

[11, 12], and it is also involved in the regulation of the hypothalamic**-**pituitaryadrenal (HPA) axis [13], serotonergic neurotransmission [14], and signaling mechanisms affecting neuronal circuits involved in motor control and anxiety in

mice [15]. This pathway has been named the gut-brain axis [16].

**88**

blood-brain barrier to contribute to serotonin synthesis in situ [43]. The availability of tryptophan is strongly affected by the gut microbiota, and several studies have indicated that bacteria such as streptococcus, Escherichia, enterococcus species and *Bifidobacterium infantis*, and especially indigenous spore-forming bacteria may modulate serotonin levels by increasing plasma tryptophan [44]. An example of this is studies in germ free mice that have found that they exhibit an increased plasma tryptophan concentration [14, 15], which after post weaning colonization can be normalized [14]. The serotonergic neurotransmission may thereby be influenced by the availability of tryptophan for serotonin production [45]. There are studies have found that a depletion of tryptophan influences mood, anxiety and borderline personality traits, for example, in AN and bulimia nervosa [46–49].

There are also other evidences that link the gut microbiota with psychiatric conditions such as MDD. For examples, a recent publication by Seng et al. [50] provides three additional levels of evidences: (a) that germ free mice lacks gut microbiota and display depression like features in forced swimming test compared to conventionally raised healthy control mice; (b) that the gut microbiota composition of MDD patients differ from that of healthy controls; and (c) and that transplantation of MDD microbiota to germ free mice led to the development of depression like behaviors. In addition, Seng et al. found that mice that were harboring the microbiota from MDD patients primarily exhibited disturbances of microbiome genes and host metabolism which thereby suggests that the depression-like behavior was mediated through the host metabolism [50].

Another neurotransmitter that is produced by the microbiota and that may influence host behavior is gamma aminobutyric acid (GABA) which is the main inhibitory neurotransmitter in the CNS. GABA produced by the probiotic *Lactobacillus rhamnosus* was administered to mice and led to an alteration in the expression of GABA receptors in different CNS regions, associated with reduced anxiety and depression-like behaviors [51].

Another mechanism for interaction between the microbiome and the CNS is at the level of the blood-brain barrier (BBB). The vascular BBB is comprised of specialized brain endothelial cells acts as a regulatory interface between brain and blood that prevent the unrestricted transfer of molecules into the CNS. Disruption of the tight junctions of the BBB can expose the CNS, and has also been linked to CNS disorders [52]. A dysbiotic microbiome could possibly interact with the BBB in several ways: bacterial factors and immune-active molecules released from peripheral sites influenced by the microbiome can cross the BBB, alter BBB integrity or change BBB transport [53]. In germ-free mice, it has been shown that the BBB has increased permeability compared to pathogen-free mice with a normal gut flora. The increased permeability was associated with reduced expression of the tight junction proteins. Exposure of germ-free adult mice to a normal gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins [54]. Metabolic products such as short-chain fatty acids (SCFAs) are produced through the fermentation of dietary fibers by the gut microbiota [55] and can cross the BBB to affect brain function. A low production of SCFAs could lead to increased BBB permeability and SCFAs has been shown to be able to improve a dysfunctional BBB in germ-free mice [54]. Another example is that antibiotics are able to modify barrier integrity and alter behavior in mice [56] and alterations to the microbiome composition in mice in favor of, for example, probiotic bifidobacteria spp. through food supplement with prebiotics showed impact on neuroinflammation and were accompanied with changes in the expression of tight junction proteins [57]. Furthermore, leptin, a key hormone for the control of appetite and weight gain, is normally restricted by the BBB but has been shown in mice with a deficit in leptin transport to the brain to enhance the sense of food reward [58].

**91**

*Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications*

Dysbiosis has been proposed in AN and through the long periods of starvation associated with the core psychopathology of AN, a considerable adaptation in gut microbiota could occur in individuals with AN. A systematic review by Schwennsen et al. [59] found some evidence of dysbiosis in AN, such as the abundance of the gut

[62] or altered in AN [63]. In addition, the diversity of the gut microbiota in AN was described as normal [61, 63], or reduced (alpha, i.e., within-sample diversity)

Common microbiota findings in the acute stages of AN were low levels of phylum Bacteroidetes [61, 64], while the phylum Firmicutes was increased in AN in three studies [61, 64, 65] however decreased in a fourth [63]. Furthermore, the genus *Methanobrevibacter* and specifically, the species *M. smithii*, has been found increased in AN patients in several studies [60, 61, 63, 65]. It is important to remember the presence or lack of a specific bacterial spp. identified by their 16rRNA gene is not the same as the presences or lack of certain metabolic functions or microbiota steady-state dynamic. The state of knowledge of the microbiota in AN

This systematic review [59] identified two studies describing an association between the microbiota and clinical symptoms in AN. In one study, ClpB protein concentrations were significantly correlated with several subscales on the Eating Disorder Inventory-2 (EDI-2) for patients with eating disorders and the Montgomery-Åsberg Depression Rating Scale (MADRS) total score and specifically the anhedonia score for AN patients (p < 0.05) [66]. In another study, an association between alpha diversity and depression and eating disorder psychopathology was found in AN [64]. Should further studies find further support for that the microbiota drives the symptoms of AN, this would strengthen targeting the micro-

**5. How is the gut-brain axis involved in AN? Breakdown of organic** 

A potential mechanism through which the microbiota indirectly influences the pathophysiology and symptoms of AN is through the breakdown of organic material in the gut and the transfer of metabolites into the blood stream. One of the microbiota that has been described in AN is *M. smithii,* which is involved in the breakdown of polysaccharides from vegetable sources and the finding of this specific Archaeon could illustrate an adaptation to a typical diet rich in vegetables and fruits in persons with AN. In addition, methanogenic Archaea, such as *M. smithii*, have also been linked to constipation, a common complaint in patients with AN, which statins have been shown to alleviate by suppressing the growth of methanogens [65, 67–69]. The evidence of *M. smithii* in feces from constipated patients necessitate further investigation of whether this finding in AN patients is only related to constipation or also

The gut microbiota is involved in both weight gain and weight loss as well as with energy extraction from the diet in both humans and animals [70, 71]. Differences in the composition of the gut microbiota between obese and lean individuals have been consistently described, potentially illustrating differences in energy extraction

microbiota in AN, which was described as either normal [60, 61], reduced

[64] both in the acute stage and after weight restoration.

**4.1 The microbiota and relation to clinical symptoms in AN**

is in its infancy and more studies are needed.

biota as a primary level of treatment of AN.

**material in the gut and its exposure in plasma**

related to AN psychopathology as a potential biomarker.

*DOI: http://dx.doi.org/10.5772/intechopen.85253*

**4. Microbiota findings in AN studies**

*Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications DOI: http://dx.doi.org/10.5772/intechopen.85253*

#### **4. Microbiota findings in AN studies**

*Anorexia and Bulimia Nervosa*

blood-brain barrier to contribute to serotonin synthesis in situ [43]. The availability of tryptophan is strongly affected by the gut microbiota, and several studies have indicated that bacteria such as streptococcus, Escherichia, enterococcus species and *Bifidobacterium infantis*, and especially indigenous spore-forming bacteria may modulate serotonin levels by increasing plasma tryptophan [44]. An example of this is studies in germ free mice that have found that they exhibit an increased plasma tryptophan concentration [14, 15], which after post weaning colonization can be normalized [14]. The serotonergic neurotransmission may thereby be influenced by the availability of tryptophan for serotonin production [45]. There are studies have found that a depletion of tryptophan influences mood, anxiety and borderline

There are also other evidences that link the gut microbiota with psychiatric conditions such as MDD. For examples, a recent publication by Seng et al. [50] provides three additional levels of evidences: (a) that germ free mice lacks gut microbiota and display depression like features in forced swimming test compared to conventionally raised healthy control mice; (b) that the gut microbiota composition of MDD patients differ from that of healthy controls; and (c) and that transplantation of MDD microbiota to germ free mice led to the development of depression like behaviors. In addition, Seng et al. found that mice that were harboring the microbiota from MDD patients primarily exhibited disturbances of microbiome genes and host metabolism which thereby suggests that the depression-like behavior was

Another neurotransmitter that is produced by the microbiota and that may

Another mechanism for interaction between the microbiome and the CNS is at the level of the blood-brain barrier (BBB). The vascular BBB is comprised of specialized brain endothelial cells acts as a regulatory interface between brain and blood that prevent the unrestricted transfer of molecules into the CNS. Disruption of the tight junctions of the BBB can expose the CNS, and has also been linked to CNS disorders [52]. A dysbiotic microbiome could possibly interact with the BBB in several ways: bacterial factors and immune-active molecules released from peripheral sites influenced by the microbiome can cross the BBB, alter BBB integrity or change BBB transport [53]. In germ-free mice, it has been shown that the BBB has increased permeability compared to pathogen-free mice with a normal gut flora. The increased permeability was associated with reduced expression of the tight junction proteins. Exposure of germ-free adult mice to a normal gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins [54]. Metabolic products such as short-chain fatty acids (SCFAs) are produced through the fermentation of dietary fibers by the gut microbiota [55] and can cross the BBB to affect brain function. A low production of SCFAs could lead to increased BBB permeability and SCFAs has been shown to be able to improve a dysfunctional BBB in germ-free mice [54]. Another example is that antibiotics are able to modify barrier integrity and alter behavior in mice [56] and alterations to the microbiome composition in mice in favor of, for example, probiotic bifidobacteria spp. through food supplement with prebiotics showed impact on neuroinflammation and were accompanied with changes in the expression of tight junction proteins [57]. Furthermore, leptin, a key hormone for the control of appetite and weight gain, is normally restricted by the BBB but has been shown in mice with a deficit in leptin

influence host behavior is gamma aminobutyric acid (GABA) which is the main inhibitory neurotransmitter in the CNS. GABA produced by the probiotic *Lactobacillus rhamnosus* was administered to mice and led to an alteration in the expression of GABA receptors in different CNS regions, associated with reduced

transport to the brain to enhance the sense of food reward [58].

personality traits, for example, in AN and bulimia nervosa [46–49].

mediated through the host metabolism [50].

anxiety and depression-like behaviors [51].

**90**

Dysbiosis has been proposed in AN and through the long periods of starvation associated with the core psychopathology of AN, a considerable adaptation in gut microbiota could occur in individuals with AN. A systematic review by Schwennsen et al. [59] found some evidence of dysbiosis in AN, such as the abundance of the gut microbiota in AN, which was described as either normal [60, 61], reduced [62] or altered in AN [63]. In addition, the diversity of the gut microbiota in AN was described as normal [61, 63], or reduced (alpha, i.e., within-sample diversity) [64] both in the acute stage and after weight restoration.

Common microbiota findings in the acute stages of AN were low levels of phylum Bacteroidetes [61, 64], while the phylum Firmicutes was increased in AN in three studies [61, 64, 65] however decreased in a fourth [63]. Furthermore, the genus *Methanobrevibacter* and specifically, the species *M. smithii*, has been found increased in AN patients in several studies [60, 61, 63, 65]. It is important to remember the presence or lack of a specific bacterial spp. identified by their 16rRNA gene is not the same as the presences or lack of certain metabolic functions or microbiota steady-state dynamic. The state of knowledge of the microbiota in AN is in its infancy and more studies are needed.

#### **4.1 The microbiota and relation to clinical symptoms in AN**

This systematic review [59] identified two studies describing an association between the microbiota and clinical symptoms in AN. In one study, ClpB protein concentrations were significantly correlated with several subscales on the Eating Disorder Inventory-2 (EDI-2) for patients with eating disorders and the Montgomery-Åsberg Depression Rating Scale (MADRS) total score and specifically the anhedonia score for AN patients (p < 0.05) [66]. In another study, an association between alpha diversity and depression and eating disorder psychopathology was found in AN [64]. Should further studies find further support for that the microbiota drives the symptoms of AN, this would strengthen targeting the microbiota as a primary level of treatment of AN.

#### **5. How is the gut-brain axis involved in AN? Breakdown of organic material in the gut and its exposure in plasma**

A potential mechanism through which the microbiota indirectly influences the pathophysiology and symptoms of AN is through the breakdown of organic material in the gut and the transfer of metabolites into the blood stream. One of the microbiota that has been described in AN is *M. smithii,* which is involved in the breakdown of polysaccharides from vegetable sources and the finding of this specific Archaeon could illustrate an adaptation to a typical diet rich in vegetables and fruits in persons with AN. In addition, methanogenic Archaea, such as *M. smithii*, have also been linked to constipation, a common complaint in patients with AN, which statins have been shown to alleviate by suppressing the growth of methanogens [65, 67–69]. The evidence of *M. smithii* in feces from constipated patients necessitate further investigation of whether this finding in AN patients is only related to constipation or also related to AN psychopathology as a potential biomarker.

The gut microbiota is involved in both weight gain and weight loss as well as with energy extraction from the diet in both humans and animals [70, 71]. Differences in the composition of the gut microbiota between obese and lean individuals have been consistently described, potentially illustrating differences in energy extraction

efficiency between obese and lean individuals [72, 73], and specific gut dysbiosis could predispose to the drive toward negative energy balance in AN. With regard to the effect of weight gain on the fecal microbiota, Firmicutes has been found increased after weight restoration in two studies in AN [61, 64].

#### **6. AN comorbid disorder as evidence of microbiota influence**

Intestinal dysbiosis has previously been associated with psychological function and mental health including depression and anxiety, both of which are commonly comorbid with AN [40]. AN patients often present with comorbid anxiety (75% lifetime prevalence of anxiety disorder) [74] and depression (more than 34% lifetime prevalence of depression) [75, 76]. These findings provide further support for a role of dysbiosis in the pathophysiology of AN.

#### **7. A leaking gut in AN?**

During starvation, some of the gut bacteria will have insufficient nutrient supply for survival. Slowly growing bacteria or bacteria able to feed on the mucus lining the gut wall will survive for a longer period of time [77]. The competition between bacteria with different growth capacities to survive and proliferate in the gut has probably taken place for millions of years. Thus, it is reasonable to expect that various mechanisms for survival and proliferation have emerged among gut bacteria including the capacity to release of substances inhibiting food intake of the host. Alterations in gut permeability has been linked to a number of intestinal diseases, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), but also to extraintestinal disease as depression, anxiety and autism specter disorders [78, 79]. Increased gut permeability may also facilitate signal transduction from the gut to the brain via the vagus nerve and blood [80], possibly in synergy with interaction with increased BBB permeability. In addition, in animal and human studies, the experience of stress is also linked to an increase in permeability of the intestinal barrier. This increase in permeability seems to be mediated through, among other factors, hypothalamic hormones, especially corticotropi-releasing hormone (CRH) [77]. Increased mucin degrading bacteria has been demonstrated in AN [81] indicating that decreased food intake induce overgrowth of bacteria able to feed on the mucus layer and thereby increase gut permeability.

An example of a possible biomarker species is the bacterium *Akkermansia muciniphila* which is abundant in humans and rodents and has been inversely correlates with body weight and is associated with metabolic syndromes and auto-immune diseases [82]. *A. municiphilia* is a symbiotic bacterium of the mucus layer, can utilize mucin as its sole carbon, nitrogen, and energy source and is able to produce certain SCFAs [83, 84]. In mice, it has been shown that the abundance of *A. muciniphila* decreased in obese and type 2 diabetic mice and that administration of the bacterium increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion [82]. In a single AN patient case story, it has been shown that one treatment with a fecal matter transplant from a healthy donor led to weight gain and an increase in *A. municiphilia* and SCFAs blood levels [85]*. A. municiphilia* is an example of a complex interaction where the bacterium simultaneously degrade the mucin for energy, but also at the same time induces higher mucus production from the host. This could in turn improve protection of the gut wall from interaction with harmful molecules from other gut bacteria and leakage into the blood.

Furthermore, in an activity based mouse model of AN Jésus et al. demonstrated increased permeability in the colon, that is, "gut leakiness", in anorexic mice,

**93**

**Figure 1.**

*Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications*

gut and its impact on the brain and psychopathology in eating disorders.

however the authors also found that the gut leakiness was more related to malnutrition than exercise [86]. Although there may be conflicting studies [87], yet another study examining the role of exercise on gut permeability, found that exercise increases intestinal permeability measured with the lactulose and rhamnose dif-

Another support for a leaking gut wall in AN comes from a study by Breton et al. [66], who found an increase in ClpB protein concentrations in plasma in eating disorder patients compared to plasma of controls, and furthermore, that ClpB protein concentrations correlated positively with alpha-Melanocyte Stimulating Hormone-(alpha-MSH)-reactive IgG for all patients with eating disorders. ClpB protein is produced by *Enterobacteriae* such as *Escherichia coli* and has been found as a conformational mimetic of alpha-MSH, which is thought to be involved in satiety and anxiety [89]. The study adds evidence to the potential role of ClpB protein produced by *Enterobacteriae* in the

The potentially altered gut permeability in AN may underlie the low-grade inflammation and increased risk of autoimmune diseases found in eating disorders [90]. Moreover, starvation has a significant impact on the gut microbiota, and a diet based on animal products used for re-nutrition, may stimulate the growth of

The initial reduction of food intake induces alterations in the gut microbiota. These alterations in gut microbiota induce increased gut permeability. Due to this

*The initial reduction of food intake induces alterations in the gut microbiota. These alterations in gut microbiota induce increased gut permeability. Due to this altered microbiota and increased gut and in addition, increased blood-brain barrier permeability, neurohormonal signals interfering with food intake are transferred to the brain, influencing brain functions, for example, cognition. This contributes in creating a vicious circle* 

*which subserves maintaining in the mechanisms associated with AN.*

*DOI: http://dx.doi.org/10.5772/intechopen.85253*

ferential urinary excretion test [88].

bacteria that trigger inflammation [91].

**8. A model for the pathophysiology of AN**

*Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications DOI: http://dx.doi.org/10.5772/intechopen.85253*

however the authors also found that the gut leakiness was more related to malnutrition than exercise [86]. Although there may be conflicting studies [87], yet another study examining the role of exercise on gut permeability, found that exercise increases intestinal permeability measured with the lactulose and rhamnose differential urinary excretion test [88].

Another support for a leaking gut wall in AN comes from a study by Breton et al. [66], who found an increase in ClpB protein concentrations in plasma in eating disorder patients compared to plasma of controls, and furthermore, that ClpB protein concentrations correlated positively with alpha-Melanocyte Stimulating Hormone-(alpha-MSH)-reactive IgG for all patients with eating disorders. ClpB protein is produced by *Enterobacteriae* such as *Escherichia coli* and has been found as a conformational mimetic of alpha-MSH, which is thought to be involved in satiety and anxiety [89]. The study adds evidence to the potential role of ClpB protein produced by *Enterobacteriae* in the gut and its impact on the brain and psychopathology in eating disorders.

The potentially altered gut permeability in AN may underlie the low-grade inflammation and increased risk of autoimmune diseases found in eating disorders [90]. Moreover, starvation has a significant impact on the gut microbiota, and a diet based on animal products used for re-nutrition, may stimulate the growth of bacteria that trigger inflammation [91].

#### **8. A model for the pathophysiology of AN**

The initial reduction of food intake induces alterations in the gut microbiota. These alterations in gut microbiota induce increased gut permeability. Due to this

#### **Figure 1.**

*Anorexia and Bulimia Nervosa*

**7. A leaking gut in AN?**

efficiency between obese and lean individuals [72, 73], and specific gut dysbiosis could predispose to the drive toward negative energy balance in AN. With regard to the effect of weight gain on the fecal microbiota, Firmicutes has been found

Intestinal dysbiosis has previously been associated with psychological function and mental health including depression and anxiety, both of which are commonly comorbid with AN [40]. AN patients often present with comorbid anxiety (75% lifetime prevalence of anxiety disorder) [74] and depression (more than 34% lifetime prevalence of depression) [75, 76]. These findings provide further support

During starvation, some of the gut bacteria will have insufficient nutrient supply for survival. Slowly growing bacteria or bacteria able to feed on the mucus lining the gut wall will survive for a longer period of time [77]. The competition between bacteria with different growth capacities to survive and proliferate in the gut has probably taken place for millions of years. Thus, it is reasonable to expect that various mechanisms for survival and proliferation have emerged among gut bacteria including the capacity to release of substances inhibiting food intake of the host. Alterations in gut permeability has been linked to a number of intestinal diseases, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), but also to extraintestinal disease as depression, anxiety and autism specter disorders [78, 79]. Increased gut permeability may also facilitate signal transduction from the gut to the brain via the vagus nerve and blood [80], possibly in synergy with interaction with increased BBB permeability. In addition, in animal and human studies, the experience of stress is also linked to an increase in permeability of the intestinal barrier. This increase in permeability seems to be mediated through, among other factors, hypothalamic hormones, especially corticotropi-releasing hormone (CRH) [77]. Increased mucin degrading bacteria has been demonstrated in AN [81] indicating that decreased food intake induce overgrowth of bacteria able to feed on the mucus layer and thereby increase gut permeability.

An example of a possible biomarker species is the bacterium *Akkermansia muciniphila* which is abundant in humans and rodents and has been inversely correlates with body weight and is associated with metabolic syndromes and auto-immune diseases [82]. *A. municiphilia* is a symbiotic bacterium of the mucus layer, can utilize mucin as its sole carbon, nitrogen, and energy source and is able to produce certain SCFAs [83, 84]. In mice, it has been shown that the abundance of *A. muciniphila* decreased in obese and type 2 diabetic mice and that administration of the bacterium increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion [82]. In a single AN patient case story, it has been shown that one treatment with a fecal matter transplant from a healthy donor led to weight gain and an increase in *A. municiphilia* and SCFAs blood levels [85]*. A. municiphilia* is an example of a complex interaction where the bacterium simultaneously degrade the mucin for energy, but also at the same time induces higher mucus production from the host. This could in turn improve protection of the gut wall from interaction with harmful

Furthermore, in an activity based mouse model of AN Jésus et al. demonstrated

increased permeability in the colon, that is, "gut leakiness", in anorexic mice,

molecules from other gut bacteria and leakage into the blood.

increased after weight restoration in two studies in AN [61, 64].

for a role of dysbiosis in the pathophysiology of AN.

**6. AN comorbid disorder as evidence of microbiota influence**

**92**

*The initial reduction of food intake induces alterations in the gut microbiota. These alterations in gut microbiota induce increased gut permeability. Due to this altered microbiota and increased gut and in addition, increased blood-brain barrier permeability, neurohormonal signals interfering with food intake are transferred to the brain, influencing brain functions, for example, cognition. This contributes in creating a vicious circle which subserves maintaining in the mechanisms associated with AN.*

altered microbiota and increased gut and in addition, increased blood-brain barrier permeability, neurohormonal signals interfering with food intake are transferred to the brain, influencing brain functions, for example, cognition. This contributes in creating a vicious circle which subserves in maintaining the mechanisms associated with AN (**Figure 1**).

### **9. Conclusions**

There are a lot of evidence linking dysbiosis and inflammatory and psychiatric disorders and although there are only a few studies that have examined the microbiota in AN, several of these point to a dysbiosis also in AN. The effects of this dysbiosis is mediated through the gut-brain axis, and leakage through the gut and potentially also the BBB, provide pathways for neurohormonal signals to induce and maintain psychiatric disorders such as AN. The evidence in AN will need confirmation and further clarification in larger, randomized and controlled studies. We propose a model for disease development and maintenance in AN where a dysbiosis is a key component. Future studies will need to clarify the pathophysiology of AN.

### **Acknowledgements**

We are thankful to Psychiatric Center Ballerup and the Capitol Region of Denmark, for providing support for this study.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Magnus Sjögren1,2\*, Stein Frostad3 and Kenneth Klingenberg Barfod4

1 Mental Health Center Ballerup, Ballerup, Denmark

2 Institute for Clinical Medicine, University of Copenhagen, Denmark

3 Department of Mental Health Research, Division of Psychiatry, Haukeland University Hospital, Bergen, Norway

4 Department of Veterinary and Animal Sciences, Section of Experimental Animal Models, University of Copenhagen, Denmark

\*Address all correspondence to: jan.magnus.sjoegren@regionh.dk

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**95**

2019]

*Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications*

the human distal intestine. PLoS One.

[10] Qin J et al. A human gut microbial

gene catalogue established by metagenomic sequencing. Nature.

[11] Sudo N et al. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. Journal of Immunology.

[12] Guarner F, Malagelada JR. Gut flora in health and disease. Lancet.

[14] Clarke G et al. The microbiome-

serotonergic system in a sex-dependent

development and behavior. Proceedings of the National Academy of Sciences of the United States of America.

2010;**464**(7285):59-65

1997;**159**(4):1739-1745

2003;**361**(9356):512-519

263-275

[13] Sudo N et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. The Journal of Physiology. 2004;**558**(Pt 1):

gut-brain axis during early life regulates the hippocampal

2013;**18**(6):666-673

2011;**108**(7):3047-3052

manner. Molecular Psychiatry.

[15] Diaz Heijtz R et al. Normal gut microbiota modulates brain

[16] Cryan JF, O'Mahony SM. The microbiome-gut-brain axis: From bowel to behavior. Neurogastroenterology and

[17] Neufeld KA, Foster JA. Effects of gut microbiota on the brain: Implications for psychiatry. Journal of Psychiatry & Neuroscience.

Motility. 2011;**23**(3):187-192

2009;**34**(3):230-231

2009;**4**(8):e6669

*DOI: http://dx.doi.org/10.5772/intechopen.85253*

[1] Keshaviah A et al. Re-examining premature mortality in anorexia nervosa: A meta-analysis redux. Comprehensive Psychiatry. 2014;**55**(8):1773-1784

[2] Steinhausen HC. Outcome of eating disorders. Child and Adolescent Psychiatric Clinics of North America.

[3] Lock J, Le Grange D. Treatment Manual for Anorexia Nervosa: A Family-Based Approach. 2nd ed. New York;

[4] Treasure J, Russell G. The case for early intervention in anorexia nervosa: Theoretical exploration of maintaining factors. The British Journal

of Psychiatry. 2011;**199**(1):5-7

[5] Eating Disorders: Recognition and treatment. Clinical Guideline, National Guideline Alliance (UK). London: National Institute for Health and Care Excellence; 2017. https://www.nice.org. uk/guidance/NG69 [Accessed 1 Mar

[6] Cooper Z, Fairburn CG. The evolution of "enhanced" cognitive behavior therapy for eating disorders: Learning from treatment nonresponse. Cognitive and Behavioral Practice. 2011;**18**(3):394-402

[7] Frostad S et al. Implementation of enhanced cognitive behaviour therapy (CBT-E) for adults with anorexia nervosa in an outpatient eating-disorder unit at a public hospital. Journal of

Eating Disorders. 2018;**6**:12

[8] Quigley EMM. Gut bacteria in health and disease. Gastroenterology &

[9] Claesson MJ et al. Comparative analysis of pyrosequencing and a phylogenetic microarray for exploring microbial community structures in

Hepatology. 2013;**9**(9):560-569

2009;**18**(1):225-242

**References**

London: Guilford; 2013

*Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications DOI: http://dx.doi.org/10.5772/intechopen.85253*

#### **References**

*Anorexia and Bulimia Nervosa*

with AN (**Figure 1**).

**Acknowledgements**

**Conflict of interest**

**Author details**

Magnus Sjögren1,2\*, Stein Frostad3

University Hospital, Bergen, Norway

Models, University of Copenhagen, Denmark

Denmark, for providing support for this study.

The authors declare no conflict of interest.

1 Mental Health Center Ballerup, Ballerup, Denmark

2 Institute for Clinical Medicine, University of Copenhagen, Denmark

\*Address all correspondence to: jan.magnus.sjoegren@regionh.dk

3 Department of Mental Health Research, Division of Psychiatry, Haukeland

**9. Conclusions**

**94**

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

4 Department of Veterinary and Animal Sciences, Section of Experimental Animal

altered microbiota and increased gut and in addition, increased blood-brain barrier permeability, neurohormonal signals interfering with food intake are transferred to the brain, influencing brain functions, for example, cognition. This contributes in creating a vicious circle which subserves in maintaining the mechanisms associated

There are a lot of evidence linking dysbiosis and inflammatory and psychiatric disorders and although there are only a few studies that have examined the microbiota in AN, several of these point to a dysbiosis also in AN. The effects of this dysbiosis is mediated through the gut-brain axis, and leakage through the gut and potentially also the BBB, provide pathways for neurohormonal signals to induce and maintain psychiatric disorders such as AN. The evidence in AN will need confirmation and further clarification in larger, randomized and controlled studies. We propose a model for disease development and maintenance in AN where a dysbiosis is a key component. Future studies will need to clarify the pathophysiology of AN.

We are thankful to Psychiatric Center Ballerup and the Capitol Region of

and Kenneth Klingenberg Barfod4

[1] Keshaviah A et al. Re-examining premature mortality in anorexia nervosa: A meta-analysis redux. Comprehensive Psychiatry. 2014;**55**(8):1773-1784

[2] Steinhausen HC. Outcome of eating disorders. Child and Adolescent Psychiatric Clinics of North America. 2009;**18**(1):225-242

[3] Lock J, Le Grange D. Treatment Manual for Anorexia Nervosa: A Family-Based Approach. 2nd ed. New York; London: Guilford; 2013

[4] Treasure J, Russell G. The case for early intervention in anorexia nervosa: Theoretical exploration of maintaining factors. The British Journal of Psychiatry. 2011;**199**(1):5-7

[5] Eating Disorders: Recognition and treatment. Clinical Guideline, National Guideline Alliance (UK). London: National Institute for Health and Care Excellence; 2017. https://www.nice.org. uk/guidance/NG69 [Accessed 1 Mar 2019]

[6] Cooper Z, Fairburn CG. The evolution of "enhanced" cognitive behavior therapy for eating disorders: Learning from treatment nonresponse. Cognitive and Behavioral Practice. 2011;**18**(3):394-402

[7] Frostad S et al. Implementation of enhanced cognitive behaviour therapy (CBT-E) for adults with anorexia nervosa in an outpatient eating-disorder unit at a public hospital. Journal of Eating Disorders. 2018;**6**:12

[8] Quigley EMM. Gut bacteria in health and disease. Gastroenterology & Hepatology. 2013;**9**(9):560-569

[9] Claesson MJ et al. Comparative analysis of pyrosequencing and a phylogenetic microarray for exploring microbial community structures in

the human distal intestine. PLoS One. 2009;**4**(8):e6669

[10] Qin J et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;**464**(7285):59-65

[11] Sudo N et al. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. Journal of Immunology. 1997;**159**(4):1739-1745

[12] Guarner F, Malagelada JR. Gut flora in health and disease. Lancet. 2003;**361**(9356):512-519

[13] Sudo N et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. The Journal of Physiology. 2004;**558**(Pt 1): 263-275

[14] Clarke G et al. The microbiomegut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Molecular Psychiatry. 2013;**18**(6):666-673

[15] Diaz Heijtz R et al. Normal gut microbiota modulates brain development and behavior. Proceedings of the National Academy of Sciences of the United States of America. 2011;**108**(7):3047-3052

[16] Cryan JF, O'Mahony SM. The microbiome-gut-brain axis: From bowel to behavior. Neurogastroenterology and Motility. 2011;**23**(3):187-192

[17] Neufeld KA, Foster JA. Effects of gut microbiota on the brain: Implications for psychiatry. Journal of Psychiatry & Neuroscience. 2009;**34**(3):230-231

[18] Kennedy PJ et al. Irritable bowel syndrome: A microbiomegut-brain axis disorder? World Journal of Gastroenterology. 2014;**20**(39):14105-14125

[19] Sternbach H, State R. Antibiotics: Neuropsychiatric effects and psychotropic interactions. Harvard Review of Psychiatry. 1997;**5**(4):214-226

[20] Bercik P et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011;**141**(2):599-609, 609 e1-3

[21] Liu Z et al. High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity. PLoS One. 2015;**10**(5):e0128274

[22] Daniel H et al. High-fat diet alters gut microbiota physiology in mice. The ISME Journal. 2014;**8**(2):295-308

[23] Sharma S, Fernandes MF, Fulton S. Adaptations in brain reward circuitry underlie palatable food cravings and anxiety induced by high-fat diet withdrawal. International Journal of Obesity. 2013;**37**(9):1183-1191

[24] Magnusson KR et al. Relationships between diet-related changes in the gut microbiome and cognitive flexibility. Neuroscience. 2015;**300**:128-140

[25] Bruce-Keller AJ et al. Obesetype gut microbiota induce neurobehavioral changes in the absence of obesity. Biological Psychiatry. 2015;**77**(7):607-615

[26] Davey KJ et al. Gender-dependent consequences of chronic olanzapine in the rat: Effects on body weight, inflammatory, metabolic and microbiota parameters. Psychopharmacology. 2012;**221**(1):155-169

[27] Ley RE et al. Microbial ecology: Human gut microbes associated with obesity. Nature. 2006;**444**(7122):1022-1023

[28] Davey KJ et al. Antipsychotics and the gut microbiome: Olanzapine-induced metabolic dysfunction is attenuated by antibiotic administration in the rat. Translational Psychiatry. 2013;**3**:e309

[29] Hansen AK et al. A review of applied aspects of dealing with gut microbiota impact on rodent models. ILAR Journal. 2015;**56**(2):250-264

[30] Neufeld KM et al. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterology and Motility. 2011;**23**(3):255-264, e119

[31] Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: Intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinology Letters. 2008;**29**(1):117-124

[32] Bravo JA et al. Communication between gastrointestinal bacteria and the nervous system. Current Opinion in Pharmacology. 2012;**12**(6):667-672

[33] Ait-Belgnaoui A et al. Acute stressinduced hypersensitivity to colonic distension depends upon increase in paracellular permeability: Role of myosin light chain kinase. Pain. 2005;**113**(1-2):141-147

[34] Park AJ et al. Altered colonic function and microbiota profile in a mouse model of chronic depression. Neurogastroenterology and Motility. 2013;**25**(9):733-e575

[35] Dinan TG, Borre YE, Cryan JF. Genomics of schizophrenia: Time to consider the gut microbiome? Molecular Psychiatry. 2014;**19**(12):1252-1257

**97**

*Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications*

development to correct brain disorders. Acta Paediatrica. 2013;**102**(4):331-334

[46] Kaye WH et al. Anxiolytic effects of acute tryptophan depletion in anorexia nervosa. The International Journal of Eating Disorders. 2003;**33**(3):257-267.

[47] Kaye WH et al. Effects of acute tryptophan depletion on mood in bulimia nervosa. Biological Psychiatry.

[48] Smith KA, Fairburn CG, Cowen PJ. Symptomatic relapse in bulimia nervosa following acute tryptophan depletion. Archives of General Psychiatry.

[49] Weltzin TE et al. Acute tryptophan depletion and increased food intake and irritability in bulimia nervosa. The American Journal of Psychiatry.

[50] Zheng P et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Molecular Psychiatry. 2016;**21**(6):786-796

[51] Bravo JA et al. Ingestion of lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences of the United States of America. 2011;**108**(38):16050-16055

[52] Najjar S et al. Neurovascular unit dysfunction and blood-brain barrier hyperpermeability contribute to schizophrenia neurobiology: A theoretical integration of clinical and experimental evidence. Front

[53] Logsdon AF et al. Gut reactions:

How the blood-brain barrier connects the microbiome and the brain. Experimental Biology

Psychiatry. 2017;**8**:83

Discussion 268-70

2000;**47**(2):151-157

1999;**56**(2):171-176

1995;**152**(11):1668-1671

*DOI: http://dx.doi.org/10.5772/intechopen.85253*

[36] Nemani K et al. Schizophrenia and the gut-brain axis. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2015;**56**:155-160

[37] Severance EG et al. Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in

2013;**148**(1-3):130-137

2007;**7**(7):789-796

2017;**174**(9):850-858

2016;**21**(6):738-748

[40] Rogers GB et al. From gut dysbiosis to altered brain function and mental illness: Mechanisms and pathways. Molecular Psychiatry.

[41] Erspamer V. Pharmacology of indole-alkylamines. Pharmacological

[42] O'Mahony SM et al. Serotonin, tryptophan metabolism and the braingut-microbiome axis. Behavioural Brain

[43] Ruddick JP et al. Tryptophan metabolism in the central nervous system: Medical implications. Expert Reviews in Molecular Medicine.

[44] Yano JM et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell.

[45] Ben-Ari Y. Neuropaediatric and neuroarchaeology: Understanding

Reviews. 1954;**6**(4):425-487

Research. 2015;**277**:32-48

2006;**8**(20):1-27

2015;**161**(2):264-276

schizophrenia. Schizophrenia Research.

[38] Fan X, Goff DC, Henderson DC. Inflammation and schizophrenia. Expert Review of Neurotherapeutics.

[39] Duncan L et al. Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa. The American Journal of Psychiatry.

*Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications DOI: http://dx.doi.org/10.5772/intechopen.85253*

[36] Nemani K et al. Schizophrenia and the gut-brain axis. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2015;**56**:155-160

*Anorexia and Bulimia Nervosa*

[18] Kennedy PJ et al. Irritable bowel syndrome: A microbiomegut-brain axis disorder? World Journal of Gastroenterology. 2014;**20**(39):14105-14125

Neuropsychiatric effects and psychotropic interactions. Harvard Review of Psychiatry. 1997;**5**(4):214-226

[20] Bercik P et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011;**141**(2):599-609, 609 e1-3

[21] Liu Z et al. High-fat diet induces hepatic insulin resistance and

One. 2015;**10**(5):e0128274

impairment of synaptic plasticity. PLoS

[22] Daniel H et al. High-fat diet alters gut microbiota physiology in mice. The ISME Journal. 2014;**8**(2):295-308

[23] Sharma S, Fernandes MF, Fulton S. Adaptations in brain reward circuitry underlie palatable food cravings and anxiety induced by high-fat diet withdrawal. International Journal of Obesity. 2013;**37**(9):1183-1191

[24] Magnusson KR et al. Relationships between diet-related changes in the gut microbiome and cognitive flexibility. Neuroscience. 2015;**300**:128-140

neurobehavioral changes in the absence of obesity. Biological Psychiatry.

[26] Davey KJ et al. Gender-dependent consequences of chronic olanzapine in the rat: Effects on body weight, inflammatory, metabolic and microbiota parameters. Psychopharmacology.

[25] Bruce-Keller AJ et al. Obesetype gut microbiota induce

2015;**77**(7):607-615

2012;**221**(1):155-169

[27] Ley RE et al. Microbial ecology: Human gut microbes

[19] Sternbach H, State R. Antibiotics:

associated with obesity. Nature. 2006;**444**(7122):1022-1023

[28] Davey KJ et al. Antipsychotics and the gut microbiome: Olanzapine-induced metabolic dysfunction is attenuated by antibiotic administration in the rat. Translational Psychiatry. 2013;**3**:e309

[29] Hansen AK et al. A review of applied aspects of dealing with gut microbiota impact on rodent models. ILAR Journal. 2015;**56**(2):250-264

[30] Neufeld KM et al. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterology and Motility. 2011;**23**(3):255-264, e119

2008;**29**(1):117-124

2005;**113**(1-2):141-147

2013;**25**(9):733-e575

2014;**19**(12):1252-1257

[34] Park AJ et al. Altered colonic function and microbiota profile in a mouse model of chronic depression. Neurogastroenterology and Motility.

[35] Dinan TG, Borre YE, Cryan JF. Genomics of schizophrenia: Time to consider the gut

microbiome? Molecular Psychiatry.

[31] Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: Intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinology Letters.

[32] Bravo JA et al. Communication between gastrointestinal bacteria and the nervous system. Current Opinion in Pharmacology. 2012;**12**(6):667-672

[33] Ait-Belgnaoui A et al. Acute stressinduced hypersensitivity to colonic distension depends upon increase in paracellular permeability: Role of myosin light chain kinase. Pain.

**96**

[37] Severance EG et al. Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophrenia Research. 2013;**148**(1-3):130-137

[38] Fan X, Goff DC, Henderson DC. Inflammation and schizophrenia. Expert Review of Neurotherapeutics. 2007;**7**(7):789-796

[39] Duncan L et al. Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa. The American Journal of Psychiatry. 2017;**174**(9):850-858

[40] Rogers GB et al. From gut dysbiosis to altered brain function and mental illness: Mechanisms and pathways. Molecular Psychiatry. 2016;**21**(6):738-748

[41] Erspamer V. Pharmacology of indole-alkylamines. Pharmacological Reviews. 1954;**6**(4):425-487

[42] O'Mahony SM et al. Serotonin, tryptophan metabolism and the braingut-microbiome axis. Behavioural Brain Research. 2015;**277**:32-48

[43] Ruddick JP et al. Tryptophan metabolism in the central nervous system: Medical implications. Expert Reviews in Molecular Medicine. 2006;**8**(20):1-27

[44] Yano JM et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;**161**(2):264-276

[45] Ben-Ari Y. Neuropaediatric and neuroarchaeology: Understanding

development to correct brain disorders. Acta Paediatrica. 2013;**102**(4):331-334

[46] Kaye WH et al. Anxiolytic effects of acute tryptophan depletion in anorexia nervosa. The International Journal of Eating Disorders. 2003;**33**(3):257-267. Discussion 268-70

[47] Kaye WH et al. Effects of acute tryptophan depletion on mood in bulimia nervosa. Biological Psychiatry. 2000;**47**(2):151-157

[48] Smith KA, Fairburn CG, Cowen PJ. Symptomatic relapse in bulimia nervosa following acute tryptophan depletion. Archives of General Psychiatry. 1999;**56**(2):171-176

[49] Weltzin TE et al. Acute tryptophan depletion and increased food intake and irritability in bulimia nervosa. The American Journal of Psychiatry. 1995;**152**(11):1668-1671

[50] Zheng P et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Molecular Psychiatry. 2016;**21**(6):786-796

[51] Bravo JA et al. Ingestion of lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences of the United States of America. 2011;**108**(38):16050-16055

[52] Najjar S et al. Neurovascular unit dysfunction and blood-brain barrier hyperpermeability contribute to schizophrenia neurobiology: A theoretical integration of clinical and experimental evidence. Front Psychiatry. 2017;**8**:83

[53] Logsdon AF et al. Gut reactions: How the blood-brain barrier connects the microbiome and the brain. Experimental Biology

and Medicine (Maywood, N.J.). 2018;**243**(2):159-165

[54] Braniste V et al. The gut microbiota influences blood-brain barrier permeability in mice. Science Translational Medicine. 2014;**6**(263):263ra158

[55] Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: Roles of resistant starch and nonstarch polysaccharides. Physiological Reviews. 2001;**81**(3):1031-1064

[56] Leclercq S et al. Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior. Nature Communications. 2017;**8**:15062

[57] de Cossio LF et al. Impact of prebiotics on metabolic and behavioral alterations in a mouse model of metabolic syndrome. Brain, Behavior, and Immunity. 2017;**64**:33-49

[58] Di Spiezio A et al. The LepRmediated leptin transport across brain barriers controls food reward. Molecuar Metabolism. 2018;**8**:13-22

[59] Schwensen HF et al. A systematic review of studies on the faecal microbiota in anorexia nervosa: Future research may need to include microbiota from the small intestine. Eating and Weight Disorders. 2018;**23**(4):399-418

[60] Million M et al. Correlation between body mass index and gut concentrations of *Lactobacillus reuteri*, Bifidobacterium animalis, *Methanobrevibacter smithii* and *Escherichia coli*. International Journal of Obesity. 2013;**37**(11):1460-1466

[61] Mack I et al. Weight gain in anorexia nervosa does not ameliorate the faecal microbiota, branched chain fatty acid profiles, and gastrointestinal complaints. Scientific Reports. 2016;**6**:26752

[62] Morita C et al. Gut dysbiosis in patients with anorexia nervosa. PLoS One. 2015;**10**(12):e0145274

[63] Borgo F et al. Microbiota in anorexia nervosa: The triangle between bacterial species, metabolites and psychological tests. PLoS One. 2017;**12**(6):e0179739

[64] Kleiman SC et al. The intestinal microbiota in acute anorexia nervosa and during renourishment: Relationship to depression, anxiety, and eating disorder psychopathology. Psychosomatic Medicine. 2015;**77**(9):969-981

[65] Armougom F et al. Monitoring bacterial community of human gut microbiota reveals an increase in lactobacillus in obese patients and methanogens in anorexic patients. PLoS One. 2009;**4**(9):e7125

[66] Breton J et al. Elevated plasma concentrations of bacterial ClpB protein in patients with eating disorders. The International Journal of Eating Disorders. 2016;**49**(8):805-808

[67] Samuel BS, Gordon JI. A humanized gnotobiotic mouse model of host-archaeal-bacterial mutualism. Proceedings of the National Academy of Sciences of the United States of America. 2006;**103**(26):10011-10016

[68] Gottlieb K et al. Review article: Inhibition of methanogenic archaea by statins as a targeted management strategy for constipation and related disorders. Alimentary Pharmacology & Therapeutics. 2016;**43**(2):197-212

[69] Triantafyllou K, Chang C, Pimentel M. Methanogens, methane and gastrointestinal motility. Journal of Neurogastroenterology and Motility. 2014;**20**(1):31-40

**99**

*Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications*

[79] Spiller RC. Overlap between irritable bowel syndrome and inflammatory bowel disease.

[80] Ntranos A, Casaccia P. The microbiome-gut-behavior axis: Crosstalk between the gut microbiome and oligodendrocytes modulates behavioral responses. Neurotherapeutics. 2018;**15**(1):31-35

[81] Mack I et al. Is the impact of starvation on the gut microbiota specific or unspecific to anorexia nervosa? A narrative review based on a systematic literature search. Current Neuropharmacology.

[82] Everard A et al. Cross-talk between *Akkermansia muciniphila* and intestinal epithelium controls diet-induced obesity. Proceedings of the National Academy of Sciences of the United States of America.

2018;**16**(8):1131-1149

2013;**110**(22):9066-9071

2008;**74**(5):1646-1648

[83] Derrien M et al. The Mucin degrader *Akkermansia muciniphila* is an abundant resident of the human intestinal tract. Applied and Environmental Microbiology.

[84] Zhai Q et al. A next generation probiotic, *Akkermansia muciniphila*. Critical Reviews in Food Science and Nutrition. 2018:1-10. https://doi.org/10.

1080/10408398.2018.1517725

2019;**88**:58-60

[85] de Clercq NC, Frissen MN, Davids M, Groen AK, and Nieuwdorp M. Weight gain after fecal microbiota transplantation in a patient with recurrent underweight following clinical recovery from anorexia nervosa. Psychotherapy and Psychosomatics.

[86] Jesus P et al. Alteration of intestinal barrier function during activity-based

48-54

Digestive Diseases. 2009;**27**(Suppl 1):

*DOI: http://dx.doi.org/10.5772/intechopen.85253*

Clinical Gastroenterology. 2011;**45**(Suppl):S128-S132

[72] Aguirre M et al. In vitro characterization of the impact of different substrates on metabolite production, energy extraction and composition of gut microbiota from lean and obese subjects. PLoS One.

2014;**9**(11):e113864

2000;**15**(1):38-45

2007;**41**(1):24-31

[71] Cox LM, Blaser MJ. Pathways in microbe-induced obesity. Cell Metabolism. 2013;**17**(6):883-894

[73] Turnbaugh PJ et al. A core gut microbiome in obese and lean twins. Nature. 2009;**457**(7228):480-484

[74] Godart NT et al. Anxiety disorders in anorexia nervosa and bulimia nervosa: Co-morbidity and chronology of appearance. European Psychiatry.

[76] Kask J, Ekselius L, Brandt L, Kollia N, Ekbom A, and Papadopoulos FC. Mortality in women with anorexia nervosa: The role of comorbid psychiatric disorders. Psychosomatic

[75] Fernandez-Aranda F et al. Symptom profile of major depressive disorder in women with eating disorders. The Australian and New Zealand Journal of Psychiatry.

Medicine. 2016;**78**(8):910-919

2017;**26**(9):1031-1041

[78] Goyette P et al. Molecular pathogenesis of inflammatory bowel disease: Genotypes, phenotypes and personalized medicine. Annals of Medicine. 2007;**39**(3):177-199

[77] Herpertz-Dahlmann B, Seitz J, Baines J. Food matters: How the microbiome and gut-brain interaction might impact the development and course of anorexia nervosa. European Child & Adolescent Psychiatry.

[70] Flint HJ. Obesity and the gut microbiota. Journal of

*Dysbiosis of the Microbiota in Anorexia Nervosa: Pathophysiological Implications DOI: http://dx.doi.org/10.5772/intechopen.85253*

Clinical Gastroenterology. 2011;**45**(Suppl):S128-S132

*Anorexia and Bulimia Nervosa*

2018;**243**(2):159-165

2014;**6**(263):263ra158

2001;**81**(3):1031-1064

and Medicine (Maywood, N.J.).

[62] Morita C et al. Gut dysbiosis in patients with anorexia nervosa. PLoS

[63] Borgo F et al. Microbiota in anorexia nervosa: The triangle between bacterial species, metabolites and psychological tests. PLoS One. 2017;**12**(6):e0179739

[64] Kleiman SC et al. The intestinal microbiota in acute anorexia nervosa and during renourishment: Relationship to depression, anxiety, and eating disorder psychopathology.

[65] Armougom F et al. Monitoring bacterial community of human gut microbiota reveals an increase in lactobacillus in obese patients and methanogens in anorexic patients. PLoS

[66] Breton J et al. Elevated plasma concentrations of bacterial ClpB protein in patients with eating disorders. The International Journal of Eating Disorders. 2016;**49**(8):805-808

[67] Samuel BS, Gordon JI. A

humanized gnotobiotic mouse model of host-archaeal-bacterial mutualism. Proceedings of the National Academy of Sciences of the United States of America. 2006;**103**(26):10011-10016

[68] Gottlieb K et al. Review article: Inhibition of methanogenic archaea by statins as a targeted management strategy for constipation and related disorders. Alimentary Pharmacology & Therapeutics.

[69] Triantafyllou K, Chang C, Pimentel

M. Methanogens, methane and gastrointestinal motility. Journal of Neurogastroenterology and Motility.

[70] Flint HJ. Obesity and the gut microbiota. Journal of

2016;**43**(2):197-212

2014;**20**(1):31-40

One. 2015;**10**(12):e0145274

Psychosomatic Medicine. 2015;**77**(9):969-981

One. 2009;**4**(9):e7125

[54] Braniste V et al. The gut microbiota influences blood-brain barrier permeability in mice. Science Translational Medicine.

[55] Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: Roles of resistant starch and nonstarch polysaccharides. Physiological Reviews.

[56] Leclercq S et al. Low-dose

[57] de Cossio LF et al. Impact of prebiotics on metabolic and behavioral

alterations in a mouse model of metabolic syndrome. Brain, Behavior,

and Immunity. 2017;**64**:33-49

Metabolism. 2018;**8**:13-22

[58] Di Spiezio A et al. The LepRmediated leptin transport across brain barriers controls food reward. Molecuar

[59] Schwensen HF et al. A systematic review of studies on the faecal

microbiota in anorexia nervosa: Future research may need to include microbiota from the small intestine. Eating and Weight Disorders. 2018;**23**(4):399-418

*Escherichia coli*. International Journal of

[61] Mack I et al. Weight gain in anorexia nervosa does not ameliorate the faecal microbiota, branched chain fatty acid profiles, and gastrointestinal complaints.

[60] Million M et al. Correlation between body mass index and gut concentrations of *Lactobacillus reuteri*, Bifidobacterium animalis, *Methanobrevibacter smithii* and

Obesity. 2013;**37**(11):1460-1466

Scientific Reports. 2016;**6**:26752

penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior. Nature Communications. 2017;**8**:15062

**98**

[71] Cox LM, Blaser MJ. Pathways in microbe-induced obesity. Cell Metabolism. 2013;**17**(6):883-894

[72] Aguirre M et al. In vitro characterization of the impact of different substrates on metabolite production, energy extraction and composition of gut microbiota from lean and obese subjects. PLoS One. 2014;**9**(11):e113864

[73] Turnbaugh PJ et al. A core gut microbiome in obese and lean twins. Nature. 2009;**457**(7228):480-484

[74] Godart NT et al. Anxiety disorders in anorexia nervosa and bulimia nervosa: Co-morbidity and chronology of appearance. European Psychiatry. 2000;**15**(1):38-45

[75] Fernandez-Aranda F et al. Symptom profile of major depressive disorder in women with eating disorders. The Australian and New Zealand Journal of Psychiatry. 2007;**41**(1):24-31

[76] Kask J, Ekselius L, Brandt L, Kollia N, Ekbom A, and Papadopoulos FC. Mortality in women with anorexia nervosa: The role of comorbid psychiatric disorders. Psychosomatic Medicine. 2016;**78**(8):910-919

[77] Herpertz-Dahlmann B, Seitz J, Baines J. Food matters: How the microbiome and gut-brain interaction might impact the development and course of anorexia nervosa. European Child & Adolescent Psychiatry. 2017;**26**(9):1031-1041

[78] Goyette P et al. Molecular pathogenesis of inflammatory bowel disease: Genotypes, phenotypes and personalized medicine. Annals of Medicine. 2007;**39**(3):177-199

[79] Spiller RC. Overlap between irritable bowel syndrome and inflammatory bowel disease. Digestive Diseases. 2009;**27**(Suppl 1): 48-54

[80] Ntranos A, Casaccia P. The microbiome-gut-behavior axis: Crosstalk between the gut microbiome and oligodendrocytes modulates behavioral responses. Neurotherapeutics. 2018;**15**(1):31-35

[81] Mack I et al. Is the impact of starvation on the gut microbiota specific or unspecific to anorexia nervosa? A narrative review based on a systematic literature search. Current Neuropharmacology. 2018;**16**(8):1131-1149

[82] Everard A et al. Cross-talk between *Akkermansia muciniphila* and intestinal epithelium controls diet-induced obesity. Proceedings of the National Academy of Sciences of the United States of America. 2013;**110**(22):9066-9071

[83] Derrien M et al. The Mucin degrader *Akkermansia muciniphila* is an abundant resident of the human intestinal tract. Applied and Environmental Microbiology. 2008;**74**(5):1646-1648

[84] Zhai Q et al. A next generation probiotic, *Akkermansia muciniphila*. Critical Reviews in Food Science and Nutrition. 2018:1-10. https://doi.org/10. 1080/10408398.2018.1517725

[85] de Clercq NC, Frissen MN, Davids M, Groen AK, and Nieuwdorp M. Weight gain after fecal microbiota transplantation in a patient with recurrent underweight following clinical recovery from anorexia nervosa. Psychotherapy and Psychosomatics. 2019;**88**:58-60

[86] Jesus P et al. Alteration of intestinal barrier function during activity-based

anorexia in mice. Clinical Nutrition. 2014;**33**(6):1046-1053

[87] Monteleone P et al. Intestinal permeability is decreased in anorexia nervosa. Molecular Psychiatry. 2004;**9**(1):76-80

[88] Pals KL et al. Effect of running intensity on intestinal permeability. Journal of Applied Physiology (Bethesda, MD: 1985). 1997;**82**(2):571-576

[89] Kishi T, Elmquist JK. Body weight is regulated by the brain: A link between feeding and emotion. Molecular Psychiatry. 2005;**10**(2):132-146

[90] Raevuori A et al. The increased risk for autoimmune diseases in patients with eating disorders. PLoS One. 2014;**9**(8):e104845

Section 3

Patients and Their Carers:

Different Perspectives

and Family Support

101

[91] Devkota S et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature. 2012;**487**(7405):104-108

### Section 3
