**4. Connection between enteric nervous system (ENS) and central nervous system (CNS)**

The enteric nervous system (ENS) extends from the esophagus to the anal region. The main functions are: (1) stimulation of glandular secretions, (2) motor functions such as peristalsis, and (3) ions and water exchange. The neurons found in CNS are subdivided into two main plexuses: the myenteric plexus and the submucosal plexus [70]. The former is responsible for peristalsis and second regulates the glandular secretions and control of blood flow. There are extrinsic fibers connecting these two plexuses, which are stimulated by both sympathetic and parasympathetic nervous system, communicating directly to spinal cord, part of the vagus nerve, and pre-vertebral ganglia of the sympathetic nervous system, although the ENS is able to function independently [71].

Generally, there are different types and subtypes of neurons throughout the ENS: excitatory neurons of the intestine, secretomotor, vasodilator, and non-vasodilator; some of them innervate whole endocrine cells and others intrinsic visceral afferent neurons. Most of the different types of neurons participate in reflexes corresponding to each plexus (myenteric and submucosal) (**Figure 3**).

The neurotransmitters secreted by enteric neurons are varied, the acetylcholine (excitatory effect) and noradrenaline (inhibitory effect) being the most studied [72]. In addition, the communication of the ENS with the CNS is not only through the secretion of these neurotransmitters. Several studies have shown that bacterial metabolites generated in the intestinal ecosystem have a direct impact on the brain. Thus, it is well known that the intestinal microbiota has an important effect on CNS, because the homeostasis and intestinal functions can be regulated by the CNS [73]. The CNS and intestine connection may occur through several pathways, including: neuronal, hormonal, immune system, and intestinal bacterial metabolites [74]. Regarding the neuronal connection, the intestine is directly connected to the brain through the vagus nerve; thus, intestinal microbiota may stimulate the enteric nervous system [75]. In addition, several reports have shown that a defective communication between the brain and intestine microbiota is associated to anxiety, depression, inflammatory bowel disease, and other diseases

#### **Figure 3.**

*Structure of the enteric nervous system. Both plexuses can be identified (myenteric and submucosal). The extension goes from the intestinal wall to the enteric plexuses and from there to the pre-vertebral ganglia of the spinal cord and brainstem. SNS, sympathetic nervous system; PSNS, parasympathetic nervous system.*

[76–78]. Interestingly, behavior changes in elderly have been associated with decreased immune function, resulting in alteration of intestinal microbiota-brain connection [79].

#### **4.1 Dysbiosis and its effect on the neuroplasticity and behavior**

In the first weeks of life, microbiota diversifies into a microbial community in which anaerobic microorganisms predominate [80]. This early colonization coincides with hypothalamic-pituitary-adrenal (HPA) axis activation, which has an important role in the innervation of the gastrointestinal (GI) tract and enteric nervous system (ENS) function. Likewise, the production of 5HT by enterochromaffin cells is regulated by the intestinal microbiota, inducing de *novo* synthesis of 5HT [44].

Several reports have shown the relation between intestine and the CNS through metabolic, neuroendocrine, and immunological pathways, impacting neuronal plasticity and cognition. Production of proinflammatory cytokines (IL-1) in intestinal lumen may affect the brain through vagus nerve [81]. Also, bacterial products like lipopolysaccharide (LPS) can increase cytokines production, as well as induce both neuroinflammation and neurodegeneration [82]. In addition, it was shown that WD-fed mice had intestinal dysbiosis, which was accompanied by inflammatory signaling in the brain, microglial activation, and reduced neuroplasticity [83]. Therefore, dysbiosis of gut microbiota may increase the cytokines production and neuroinflammation, affecting mood, or it could induce psychiatric disorders such as depression and anxiety as was described in animal models [56] as well as in comparative studies performed in humans [5, 84]. Moreover, in maternal immune activation (MIA) mouse model, intestinal dysbiosis induced both higher production of both 4-ethylphenylsulfate (4EPS) and indolepyruvate, leading to autism spectrum disorder (ASD). Interestingly, with *Bacteroides fragilis* administration, these behavioral symptoms were ameliorated [85].

**203**

as bacteriocins [94].

**5.1 Types and sources**

**5. Prebiotics**

*Prebiotics and the Modulation on the Microbiota-GALT-Brain Axis*

A mechanism by producing substrates from bacterial metabolism such as SCFAs from the fermentation of dietary fiber has been described. The SCFAs regulate the metabolism of glucose and cholesterol [86]. Most importantly, the SCFAs (acetate, propionate, and butyrate) treatment alleviated the psychosocial stress-induced alterations in mice; the effect observed was selective, because the stress-induced body weight gain, fecal SCFAs, and the colonic gene expression of the SCFAs receptors free fatty acid receptors 2 and 3 remained unaffected by SCFAs supplementation [87]. Other studies also have shown that dysbiosis may induce mood alterations. For example, dysbiosis induced by antibiotics treatment in mice leads to cognitive and behavioral alterations as well as to neurological changes [88, 89]. In addition, in juvenile mice with dysbiosis, after a 2-week antibiotic treatment, the levels of mRNA and protein of brain-derived neurotrophic factor (BDNF) and tropomyosin-related receptor kinase B (TrKB) in hippocampus CA3 and dentate gyrus subregions, respectively, significantly increased [89]. Most importantly, patients with disorders like depression, anxiety, and eating disorder psychopathology have a significantly lower microbial alpha diversity as compared with healthy subjects [5]. Interestingly, depression and anxiety symptoms may be improved by fecal microbiota transplantation in patients with irritable bowel syndrome (IBS), functional diarrhea (FDR), or functional constipation (FC). Thus, the increase of microbiota diversity may improve the patient's mood [56].

Since its initial description in 1995, the concept of prebiotic has been in constant

It is well known that proliferation of bifidobacteria and lactobacilli is favored by prebiotics; moreover, the proliferation of bacterial pathogenic strains such as *Clostridium*, *Escherichia*, *Campylobacter*, *Enterobacterium,* or *Salmonella* is inhibited. It has been proposed that intestinal microbiota is in involved in inhibition prebiotics mechanisms, by either competition for adhesion sites to the mucosa, or changes in the intestinal environment, such as (a) a reduction in pH as result of the synthesis of SCFA and (b) production of metabolites inhibiting pathogens proliferation, such

As already mentioned, prebiotics are normally ingested in the diet; however, only some carbohydrates (poly and oligosaccharides), whose chemical structure has β-type bonds, some peptides, some proteins, and certain lipids such as esters and

evolution. Currently, according to Gibson and Roberfroid, a probiotic has been defined as "any substance present in diet, which specifically stimulates the growth and/or the fermentative activity of one or a limited number of bacteria species of intestinal microbiota, generating beneficial effects on health of host as a consequence of changes on either bacterial composition or metabolic activity" [90]. Generally, a food ingredient is considered as a prebiotic when it has the following characteristics: (a) it must be kept in good condition until reaching the distal portions of the intestine; that is, it is not absorbed in the anterior part of the gastrointestinal tract and resists the hydrolysis of digestive enzymes [91] such as α-glucosidase, maltase, isomaltase, and sucrase [92]; (b) it must act as a selective substrate in the growth and/or metabolism of one or a limited number of beneficial bacterial species, such as Lactobacillus spp. and Bifidobacterium spp.; and finally (c) it must positively stimulate the microbiota, by increasing beneficial microorgan-

*DOI: http://dx.doi.org/10.5772/intechopen.89690*

isms and reducing pathogenic bacteria [93].

ethers are food ingredients qualified as prebiotics [95].

*Prebiotics and the Modulation on the Microbiota-GALT-Brain Axis DOI: http://dx.doi.org/10.5772/intechopen.89690*

A mechanism by producing substrates from bacterial metabolism such as SCFAs from the fermentation of dietary fiber has been described. The SCFAs regulate the metabolism of glucose and cholesterol [86]. Most importantly, the SCFAs (acetate, propionate, and butyrate) treatment alleviated the psychosocial stress-induced alterations in mice; the effect observed was selective, because the stress-induced body weight gain, fecal SCFAs, and the colonic gene expression of the SCFAs receptors free fatty acid receptors 2 and 3 remained unaffected by SCFAs supplementation [87].

Other studies also have shown that dysbiosis may induce mood alterations. For example, dysbiosis induced by antibiotics treatment in mice leads to cognitive and behavioral alterations as well as to neurological changes [88, 89]. In addition, in juvenile mice with dysbiosis, after a 2-week antibiotic treatment, the levels of mRNA and protein of brain-derived neurotrophic factor (BDNF) and tropomyosin-related receptor kinase B (TrKB) in hippocampus CA3 and dentate gyrus subregions, respectively, significantly increased [89]. Most importantly, patients with disorders like depression, anxiety, and eating disorder psychopathology have a significantly lower microbial alpha diversity as compared with healthy subjects [5]. Interestingly, depression and anxiety symptoms may be improved by fecal microbiota transplantation in patients with irritable bowel syndrome (IBS), functional diarrhea (FDR), or functional constipation (FC). Thus, the increase of microbiota diversity may improve the patient's mood [56].
