**3. Gut-to-brain axis**

The basis of the GBA cross-communication includes an array of multichannel sensing and trafficking pathways (neural, endocrine, immune, and metabolic) to transfer the enteric signals to the brain (**Figure 1**), which ultimate results in keeping proper maintenance of GI homeostasis, although its multiple effects likely impacts on brain performance and higher cognitive functions [1–3, 68].

The GBA comprises highly interconnected body systems. Those systems are the CNS, the autonomic nervous system (vagal and spinal nerves), and the ENS

**225**

**Figure 1.**

*Interplay between Human Intestinal Microbiota and Gut-to-Brain Axis…*

(the arrangement of neurons and supporting cells throughout and embedded within GI tract, from the esophagus to the anus). Other critical components of GBA include the hypothalamic pituitary adrenal axis (HPA; release of gut hormones), the immune system (release of multiple cytokines), and bacteria-derived metabolites (SCFAs and free amino acids). In fact, gut microbes have evolved alongside their host, through complex relationships, so influencing their own genotypic and phenotypic features [1–3]. However, failures in the GBA cross talk may lead to a number of health disorders, from inflammatory to metabolic and neurodevelop-

*The bidirectional pathways of the gut-to-brain axis and their effects. Modulation of the CNS by the gut microbiome (through microbial-derived molecules such as SCFAs, neurotransmitters, hormones and tryptophan metabolites) occurs primarily via neuro-immune and neuroendocrine mechanisms. Those microbial molecules reach brain sites directly or only induce central responses through long-distance neural signaling by vagal and/or spinal afferents. The autonomic nervous system regulates gut functions (motility, secretion, intestinal permeability, and mucosal immune response), which ultimately affect the microbial habitat, thereby* 

The following pathways may explain the influence of the gut microbiota on neurologic disorders through GBA: (a) production of neurotransmitters, (b) triggering release of gut hormones from entero-endocrine cells, (c) stimulation of the ENS and signaling to the brain via ascending neural pathways, and (d) activation of the immune

At physiological conditions, GBA modulates the digestive processes like motility and secretion, immune function, and perception and emotional response to visceral stimuli [17]. The high comorbidity of stress-related neurologic disorders with GI

ASD is a group of neurodevelopmental abnormalities whose clinical manifestations begin in early childhood (although their diagnosis may delay months to years later in life). Clinically ASDs show complex and heterogeneous features but

system via cytokine release by the mucosa-associated immune cells.

disorders proves the impact of altered function of GBA [3].

*DOI: http://dx.doi.org/10.5772/intechopen.89998*

mental conditions, including ASD [1].

*modulating microbiota composition and activity.*

**4. Autism spectrum disorders**

*Interplay between Human Intestinal Microbiota and Gut-to-Brain Axis… DOI: http://dx.doi.org/10.5772/intechopen.89998*

#### **Figure 1.**

*Microorganisms*

**2.2 Stability of HIM**

maternal bacterial load [17].

belonging to *Streptococcus* and *Enterococcus* produce serotonin, and *Bacillus* produce norepinephrine and dopamine [17]. Those bacteria-derived neurotransmitters released directly to the intestinal lumen may either induce epithelial cells to in turn release molecules that modulate neural signaling within the enteric nervous system (ENS) or, after passing through the gut wall, gain entry into the portal circulation to exert direct effects on afferent axons [63, 64]. Indeed, several reports documented elevated levels of noradrenaline and adrenaline in the plasma of subjects coursing with systemic infections by gram-negative Proteobacteria, like *Escherichia coli*. (Reviewed in [64]).

Bacterial colonization of the human gut likely occurs at the time of birth, when infants born via vaginal delivery are inoculated with a complex mixture of maternal vaginal microorganisms. According to Dominguez-Bello et al. [65], those infants had colonizing *Lactobacillus*, *Prevotella*, or *Sneathia* species in their skin and mucosae, which resembled their own mother's vaginal microbiota. In contrast, infants delivered by cesarean section had predominantly *Staphylococcus*, *Corynebacterium*, and *Propionibacterium* species, akin to their mothers' skin microbiota. Thus, there is concern that babies delivered via cesarean section may receive an insufficient

After birth, breastfeeding is the main factor defining the composition of newborn's GI microbiota, since breast milk provides a variety of specific antibodies and immediate immunity molecules that neutralize pathogenic bacteria. Breast milk also contains more than 200 oligosaccharides (prebiotics) that favor the growth of bifidobacteria [66, 67], which have been reported to prevent gastrointestinal infections by competitive exclusion of pathogens based on common binding sites on epithelial cells [67]. Therefore, in breastfed children, bifidobacteria reaches up to 90% of GI microbiota, followed by lactobacilli, *Bacteroides*, coliforms, and clostridia. In contrast, infants fed with infant formula have predominance of *Bacteroides*, enterococci, coliforms, and clostridia, with much lesser bifidobacteria,

The initial breastfeeding-driven colonization is essential for induction of adaptive immunity and for early metabolic programming. After the introduction of complementary feeding, the microbiota differences between breastfed children and those fed with formula tend to disappear. It is assumed that the predominant bacteria in the intestinal microbiome of 3-year-olds are similar to those of adults

Daily variability of the HIM composition has been assessed in controlled feeding studies, specifically short-term administration of extreme amount of fat and fiber intake, which revealed disturbance of the intestinal microbiome, but this effect was of low-scale and transient that not changed the individual's enterotype

The basis of the GBA cross-communication includes an array of multichannel sensing and trafficking pathways (neural, endocrine, immune, and metabolic) to transfer the enteric signals to the brain (**Figure 1**), which ultimate results in keeping proper maintenance of GI homeostasis, although its multiple effects likely impacts

The GBA comprises highly interconnected body systems. Those systems are the

CNS, the autonomic nervous system (vagal and spinal nerves), and the ENS

resembling the more diverse GI microbiota of adults [66, 67].

on brain performance and higher cognitive functions [1–3, 68].

and remain relatively stable lifelong [66, 67].

designation [66, 67].

**3. Gut-to-brain axis**

**224**

*The bidirectional pathways of the gut-to-brain axis and their effects. Modulation of the CNS by the gut microbiome (through microbial-derived molecules such as SCFAs, neurotransmitters, hormones and tryptophan metabolites) occurs primarily via neuro-immune and neuroendocrine mechanisms. Those microbial molecules reach brain sites directly or only induce central responses through long-distance neural signaling by vagal and/or spinal afferents. The autonomic nervous system regulates gut functions (motility, secretion, intestinal permeability, and mucosal immune response), which ultimately affect the microbial habitat, thereby modulating microbiota composition and activity.*

(the arrangement of neurons and supporting cells throughout and embedded within GI tract, from the esophagus to the anus). Other critical components of GBA include the hypothalamic pituitary adrenal axis (HPA; release of gut hormones), the immune system (release of multiple cytokines), and bacteria-derived metabolites (SCFAs and free amino acids). In fact, gut microbes have evolved alongside their host, through complex relationships, so influencing their own genotypic and phenotypic features [1–3]. However, failures in the GBA cross talk may lead to a number of health disorders, from inflammatory to metabolic and neurodevelopmental conditions, including ASD [1].

The following pathways may explain the influence of the gut microbiota on neurologic disorders through GBA: (a) production of neurotransmitters, (b) triggering release of gut hormones from entero-endocrine cells, (c) stimulation of the ENS and signaling to the brain via ascending neural pathways, and (d) activation of the immune system via cytokine release by the mucosa-associated immune cells.

At physiological conditions, GBA modulates the digestive processes like motility and secretion, immune function, and perception and emotional response to visceral stimuli [17]. The high comorbidity of stress-related neurologic disorders with GI disorders proves the impact of altered function of GBA [3].

### **4. Autism spectrum disorders**

ASD is a group of neurodevelopmental abnormalities whose clinical manifestations begin in early childhood (although their diagnosis may delay months to years later in life). Clinically ASDs show complex and heterogeneous features but generally are defined by a core symptomatology including impaired social communication (oral and nonverbal languages, eye contact), behavioral problems (fixated interests in the daily routine, engagement in repetitive manners, exacerbated responses to external stimuli), and self-isolation, with or without impairment of cognitive abilities and competences [9, 69].

According to the latest American Psychiatric Association's diagnostic criteria [69], ASDs include conditions known as autism disorder (AD), Asperger's syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS).

Noteworthy ASD clinical features show extensive heterogeneity among affected subjects, according to the developmental stage, to chronological age, and to specific disorder within the spectrum (and even within the same disorder) [9, 69].

Until of April 2018, ASD were estimated to affect, in average, 1 in every 160 children worldwide, with a yearly rising incidence, and an estimated boy to girl ratio of 5:1 [70]. Data from the USA reveal that prevalence of ASDs has dramatically increased from 4.5 in 10,000 children in 1966 to 1 in 68 in 2010 and finally to 1 in 59 children in 2014 [71].

This recent outburst in frequency may be partly attributed to increased public awareness and or to better diagnosis; however, the occurrence of other factors, such as exposure to environmental chemicals, diet alterations, metabolic status, and changes in microbiota composition, cannot be excluded [17].

Despite the alarming rise trend in frequency of diagnosed cases in developed countries, the etiopathogenesis of ASD is still unknown; thus, there are no consensus in medical, neurologic, or psychiatric treatments [10]. Moreover, a diversity of comorbidities also affect ASD individuals, including one or more of the following: anxiety, intellectual disability, epilepsy/seizures, attention deficit and hyperactivity disorder, GI disorders, sleep disorders, obesity, depression, bipolar disorder, and Tourette's syndrome, among others (**Figure 2**) [6, 7, 9].

Among the most frequent GI comorbidities in ASD subjects are exacerbated flatulence (60%), bloating (38%), abdominal pain (37%), diarrhea (28%), burping/belching (25%), gastroesophageal reflux symptoms (16%), and constipation (10%) [8].

#### **Figure 2.**

*Relevant features of ASD and their most frequent comorbidities. The colored figures represent typical features defining ASD, while colorless figures represent the most prevalent of its comorbidities. ADHD, attention deficit and hyperactivity disorder; GI, gastrointestinal, OCD, obsesive –compulsive disorder.*

**227**

*Interplay between Human Intestinal Microbiota and Gut-to-Brain Axis…*

**5. Interplay between HIM and GBA in the context of ASD**

Research on ASD was primarily focused on genetic associations, but recent evidence has suggested that other environmental factors, including pre- or postnatal exposure to chemicals and drugs, air pollution, stress, maternal infection, the HIM, and dietary factors, may play a role in the clinical manifestations of the ASD [17].

About 40–60% of ASD children suffer from gastrointestinal comorbidities [8], although due to their social and communicative impairments, the real prevalence of gastrointestinal issues among ASD patients may be higher. Such intestinal dysfunction in this group of patients may be caused by disturbances in the pathways underlying the GBA, with a central role of the HIM and including an immune component. Several studies have demonstrated HIM dysbiosis in ASD subjects; however, little or null correlation between studies has been obtained, mainly due to variations in study groups, control groups, and the use of diverse methods for microbiota/ microbiome determinations and analysis (**Table 2**) [67, 72]. In short, 13 of the 15 studies showed some degree of dysbiosis among ASD patients as compared with controls (total combined sample of 585 individuals, 339 ASD, 61 control siblings, and 185 unrelated neurotypical controls), whereas 2 of the 15 studies found no significant differences among ASD subjects as compared with siblings controls (no

Altogether the microbiome data from the studies showed in **Table 2** suggests some important features among stool samples of ASD subjects: (a) levels of clostridia, *Desulfovibrio*, and *Sutterella* seem consistently elevated; (b) on the opposite, levels of *Prevotella* and bifidobacteria appears to be reduced; (c) the Bacteroidetes/ Firmicutes ratio showed inconsistent results over different cohorts. There are significant, but not consistent, distinctive different microbiome compositions in ASD patients, regardless of gastrointestinal problems, compared to controls [73–90]. Moreover, the presence of HIM dysbiosis may correlate with ASD phenotype [91]. Dysbiosis in ASD is also associated with increased permeability of the GI tract, the leaky gut, which leads to the entry of endotoxins, and other bacterial products into the bloodstream [92]. Bacterial lipopolysaccharide (LPS) can alter neuronal as well as microglial activity in brain regions involved in emotional control [93–95]. In fact, serum levels of LPS were significantly higher among ASD subjects compared to healthy individuals and correlated with impaired social behavioral scores [96]. Serotonin synthesis in the gut and the brain depends on the availability of dietary tryptophan. High levels of blood serotonin were found in children with ASD [97–99], which contrasts with finding of decreased brain serotonin synthesis in ASD subjects [100]. A significant correlation between whole-blood serotonin levels and low-grade intestinal inflammation in ASD was demonstrated [101]. Regarding these findings, a likely explanation was proposed by de Theije et al. (2011) [91]: After GI inflammation, the intestinal serotonin release provokes changes in motility, secretion, vasodilation, and permeability, leading to functional intestinal dysmotility, stool inconsistency, and abdominal pain. Since the majority of dietary tryptophan is transformed in serotonin by HIM during inflammation, less tryptophan (and serotonin) will be available for the brain resulting in mood and cognitive

*DOI: http://dx.doi.org/10.5772/intechopen.89998*

neurotypical controls were included).

dysfunction in ASD and increased autistic behavior [102].

Propionic acid, a major SCFA produced by clostridia, *Bacteroides*, and

elevated levels of SCFAs are described in the stool of ASD children [82, 105].

*Desulfovibrio,* has been associated with ASD, since it can induce ASD-like behavioral deficits in rats [103, 104]. Detrimental effects of propionic acid are suggested to be through mitochondrial and epigenetic modulation of ASD-associated genes. In fact, *Microorganisms*

cognitive abilities and competences [9, 69].

not otherwise specified (PDD-NOS).

children in 2014 [71].

generally are defined by a core symptomatology including impaired social communication (oral and nonverbal languages, eye contact), behavioral problems (fixated interests in the daily routine, engagement in repetitive manners, exacerbated responses to external stimuli), and self-isolation, with or without impairment of

According to the latest American Psychiatric Association's diagnostic criteria [69], ASDs include conditions known as autism disorder (AD), Asperger's syndrome, childhood disintegrative disorder, and pervasive developmental disorder

Noteworthy ASD clinical features show extensive heterogeneity among affected subjects, according to the developmental stage, to chronological age, and to specific

Until of April 2018, ASD were estimated to affect, in average, 1 in every 160 children worldwide, with a yearly rising incidence, and an estimated boy to girl ratio of 5:1 [70]. Data from the USA reveal that prevalence of ASDs has dramatically increased from 4.5 in 10,000 children in 1966 to 1 in 68 in 2010 and finally to 1 in 59

This recent outburst in frequency may be partly attributed to increased public awareness and or to better diagnosis; however, the occurrence of other factors, such as exposure to environmental chemicals, diet alterations, metabolic status, and

Despite the alarming rise trend in frequency of diagnosed cases in developed countries, the etiopathogenesis of ASD is still unknown; thus, there are no consensus in medical, neurologic, or psychiatric treatments [10]. Moreover, a diversity of comorbidities also affect ASD individuals, including one or more of the following: anxiety, intellectual disability, epilepsy/seizures, attention deficit and hyperactivity disorder, GI disorders, sleep disorders, obesity, depression, bipolar disorder, and

Among the most frequent GI comorbidities in ASD subjects are exacerbated flatulence (60%), bloating (38%), abdominal pain (37%), diarrhea (28%), burping/belching (25%), gastroesophageal reflux symptoms (16%), and constipation (10%) [8].

*Relevant features of ASD and their most frequent comorbidities. The colored figures represent typical features defining ASD, while colorless figures represent the most prevalent of its comorbidities. ADHD, attention deficit* 

*and hyperactivity disorder; GI, gastrointestinal, OCD, obsesive –compulsive disorder.*

disorder within the spectrum (and even within the same disorder) [9, 69].

changes in microbiota composition, cannot be excluded [17].

Tourette's syndrome, among others (**Figure 2**) [6, 7, 9].

**226**

**Figure 2.**

Research on ASD was primarily focused on genetic associations, but recent evidence has suggested that other environmental factors, including pre- or postnatal exposure to chemicals and drugs, air pollution, stress, maternal infection, the HIM, and dietary factors, may play a role in the clinical manifestations of the ASD [17].
