**3. Microbial ecosystem of the gastrointestinal tract**

The human intestine contains a wide variety of microorganisms, approximately 500–1000 different species, of which the Bacteria, Archaea and Eukarya are the principal ones [1, 27]. The predominant bacteria populations in the intestine are the Bacteroidetes and Firmicutes, constituting about 90% [28]. This diverse ecosystem is called "gut microbiota," which has a symbiotic and mutualism relationship with the host [29, 30]. The intestinal microbiota exerts its own functions and has both direct and indirect influence on host's physiology and health, especially on metabolism. However, several pathologies, including neurological disorders such as irritable bowel syndrome, depression, anxiety, and Parkinson's disease have been associated with alteration of the intestinal microbiota known as "dysbiosis" [5–7].

With respect to dysbiosis, the wide diversity and abundance of gut microbiota population can be modified importantly by host's diet and age, as well as by other factors. The newborn is colonized by bacteria from birth and initially, there are no differences between bacteria population localized on different parts of body. Infants who are born via vaginal delivery are mainly colonized by Lactobacillus and Prevotella, microbial populations closely related to maternal vaginal bacteria populations [31]. In contrast, infants born by cesarean-section (C-section) are exposed to *Staphylococcus* and *Corynebacterium*, which are skin microbes [32]. Thus, vaginal delivery or cesarean section as well as lactation or weaning are important factors that influence intestinal microbiota establishment. On the other hand, initially it was proposed that the prenatal environment is sterile; however, the presence of several bacterial species has been detected on placentas, amniotic fluid, and in meconium of healthy mothers, which suggests that, in the intrauterine stage there is already contact with microbes [33]. The diversity and functionality of the bacterial ecosystem is modified and increased in subsequent years of childhood [33]. Thus, in adult life, the predominant populations are both Bacteroidetes and Firmicutes, while the phylum Actinobacteria, Proteobacteria, Verrucomincrobia, archaea, and eukaryotes decrease importantly [34, 35]. Commonly, intestinal microbiota is very stable in adulthood, although a greater proportion of both Bifidobacteria and Clostridia has been found in the gut of young adults in comparison with older adults [36]. Important changes in composition and function of intestinal microbiota occur on aging. Aging has been associated with changes in intestinal microbiota composition, inducing alterations of multiple physiological functions, including intestine and immune system malfunctioning. An increased proportion of facultative anaerobes bacteria as well as an imbalance of Bacteroidetes/Firmicutes ratio in microbiota are age-related differences. Also, in people over 60 years of age, when the immune system function begins to decline, a significant decrease in Bifidobacteria has been found [37]. These previous findings were also supported by studies performed in intestinal mucosal tissue of aged and young mice, where a reduction in *Akkermansia muciniphila* proportion as well as decrease of antimicrobial factors Ang4 and lysozyme were detected in aged mice. Moreover, an important decrease in genes expression related to immunity was found, including T cell activation and other gene signaling pathways [38].

The high-carbohydrate and high-fat diet composition may produce dysbiosis. It was described that in mice, a Western diet (WD: high-carbohydrate and high-fat diet) intake caused dysbiosis and dysregulated bile acids (BA) synthesis with reduced endogenous ligands for BA receptors, that is, farnesoid X receptor and G-proteincoupled bile acid receptor in the liver and brain [39]. More relevantly, a ketogenic lowcarbohydrate high-fat diet induced changes in the oral microbiome of elite endurance athletes; the relative abundances of *Haemophilus*, *Neisseria*, and *Prevotella* spp. were decreased, and the relative abundance of *Streptococcus* spp. was increased [40].

## **3.1 Functions of the gut microbiota in the host**

The main biological functions regulated by the gut microbiota are related to the efficiency to metabolize food and obtain energy. Polysaccharides are the main source of energy in bacterial metabolism, which are transformed into short-chain fatty acids (SCFAs). Bacterial metabolism is not limited only to SCFAs production and obtaining energy. The intestinal microbiota can synthesize several vitamins, aryl hydrocarbon receptor (AHR) ligands on host cells, polyamines [41], folate [42], indole [43], serotonin [44], and other compounds. In addition, intestinal microbiota also produces bacterial toxins called bacteriocins. To date, 13 species of bacteriocins have been found in human feces [45].

The major SCFAs produced by the gut microbiota are acetate, propionate, and butyrate, which are found at 80–130 mM [46, 47]. In this way, the SCFAs represent approximately 70% of the total energy captured by the intestinal epithelial cells. Interestingly, butyrate produced by *Butyrivibrio fibrisolvens* protects against autophagy and energy starvation in the epithelium of gnotobiotic mice [48, 49]. While acetate and propionate have an important role in lipid metabolism, activation of the Gpr43 receptor promotes adipogenesis [50]. Therefore, using antibiotics at subtherapeutic doses, as commonly used in animal production, a dysbiosis is generated by increasing SCFA levels, which consequently induces lipogenesis and hepatic triglycerides synthesis [50].

It is well known that microbiota strongly impacts on the expression of genes and proteins on host intestinal epithelial cells. In axenic mice, it has been found that in intestinal colonization by *Bacteroides thetaiotaomicron,* an important gene expression was induced. Expression of these genes is involved in protection, intestinal barrier function regulation, epithelium vascularization, and digestion/absorption of nutrients by increasing amino acid metabolism [50, 51]. It also participates in the regulation of endocrine, neurological, and bone density functions [33], as well as in the metabolism and absorption of phytochemicals such as polyphenols and drugs [50].

Additionally, several studies have shown that microbiota has an important role in peripheral and intestinal immune system ontogeny, as well as intestinal epithelium renewal [52, 53]. Also, microbiota-epithelial cell interaction indirectly controls the expenditure and storage of energy in the host [54]. Dysbiosis has been associated with a several pathologies affecting directly the digestive tract, including chronic inflammatory bowel diseases, colorectal cancer, constipation, and diarrhea; but in peripheral organs, it can also induce allergies, arthritis, or neurological disorders [55]. In this way, correcting the dysbiosis could improve the symptoms of diseases like irritable bowel syndrome (IBS) and functional diarrhea [56].

Intestinal bacteria are importantly involved in development and regulation of the immune system [57–59]. On this regard, mice grown under germ-free conditions exhibited several abnormalities, including hypoplastic Peyer's patches, IgA-producing cells reduction, relatively poorly structured spleen and lymph nodes, and decrease in proportion of Treg cells in colon [53]. Interestingly, when mice were exposed to intestinal bacteria for several weeks, the structure and function of immune system cells were restored [60]. Moreover, it has been shown that lipopolysaccharides from gram negative bacteria, as well as peptidoglycans from gram positive bacteria, activate Toll-like receptors (TLRs), inducing different immune responses [61]. Also, the expression of angiogenin 4 by *Bacteroides thetaiotaomicron* is induced. Angiogenin 4 is an important immune response regulator with microbicidal activity against a wide range of intestinal microbes, including bacterial and fungal pathogens [62]. A zwitterionic capsular polysaccharide of *Bacteroides fragilis* is an antigen related to T CD4 + effector cells function [63]; it also protects mice from *Helicobacter hepaticus* infections by suppressing IL-17 production and other immunological mechanisms [64]. Moreover, the genus Bifidobacteria is a producer

**201**

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

of acetate that inhibits the translocation of Shiga toxin from *E.coli* 0157 suppressing colon inflammation [65]. In addition, *Bacteroides*, *Turicibacter*, and *Barnesiella* bacteria strains interact with T CD8 + cytotoxic cells in the mucosal compartment of both the small intestine and the colon [66]. Finally, the gut microbiota also regulates the interaction of dendritic cells with regulatory T cell through TLR 2 signaling, which induces an

The interactions between environmental signals and intestinal immune system are necessary to maintain a stable equilibrium and regulate the protective function of the intestinal barrier. Thus, in order to prevent microbial colonization and transepithelial migration, several chemical substances are produced by the intestinal epithelial cells, such as gastric acid, enzymes (lactoferrin, lysozyme), antimicrobial peptides (defensins), mucins, and nitric oxide [68]. On the other hand, signaling through Toll-like receptors (TLRs) is very important for the activation of innate immune system. TLRs recognize a wide range of common antigens present in pathogens, activating the adaptive immune system for the generation of multiple

increased susceptibility to chronic inflammatory diseases such as colitis [67].

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

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

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

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

corresponding to each plexus (myenteric and submucosal) (**Figure 3**).

**3.2 Host's immunomodulatory activity on the gut microbiota**

highly specific and immunocompetent clones [69].

**nervous system (CNS)**

able to function independently [71].

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

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

*Prebiotics and Probiotics - Potential Benefits in Nutrition and Health*

The main biological functions regulated by the gut microbiota are related to the efficiency to metabolize food and obtain energy. Polysaccharides are the main source of energy in bacterial metabolism, which are transformed into short-chain fatty acids (SCFAs). Bacterial metabolism is not limited only to SCFAs production and obtaining energy. The intestinal microbiota can synthesize several vitamins, aryl hydrocarbon receptor (AHR) ligands on host cells, polyamines [41], folate [42], indole [43], serotonin [44], and other compounds. In addition, intestinal microbiota also produces bacterial toxins called bacteriocins. To date, 13 species of

The major SCFAs produced by the gut microbiota are acetate, propionate, and butyrate, which are found at 80–130 mM [46, 47]. In this way, the SCFAs represent approximately 70% of the total energy captured by the intestinal epithelial cells. Interestingly, butyrate produced by *Butyrivibrio fibrisolvens* protects against autophagy and energy starvation in the epithelium of gnotobiotic mice [48, 49]. While acetate and propionate have an important role in lipid metabolism, activation of the Gpr43 receptor promotes adipogenesis [50]. Therefore, using antibiotics at subtherapeutic doses, as commonly used in animal production, a dysbiosis is generated by increasing SCFA levels, which consequently induces lipogenesis and hepatic

It is well known that microbiota strongly impacts on the expression of genes and proteins on host intestinal epithelial cells. In axenic mice, it has been found that in intestinal colonization by *Bacteroides thetaiotaomicron,* an important gene expression was induced. Expression of these genes is involved in protection, intestinal barrier function regulation, epithelium vascularization, and digestion/absorption of nutrients by increasing amino acid metabolism [50, 51]. It also participates in the regulation of endocrine, neurological, and bone density functions [33], as well as in the metabolism and absorption of phytochemicals such as polyphenols and drugs [50]. Additionally, several studies have shown that microbiota has an important role in peripheral and intestinal immune system ontogeny, as well as intestinal epithelium renewal [52, 53]. Also, microbiota-epithelial cell interaction indirectly controls the expenditure and storage of energy in the host [54]. Dysbiosis has been associated with a several pathologies affecting directly the digestive tract, including chronic inflammatory bowel diseases, colorectal cancer, constipation, and diarrhea; but in peripheral organs, it can also induce allergies, arthritis, or neurological disorders [55]. In this way, correcting the dysbiosis could improve the symptoms of

diseases like irritable bowel syndrome (IBS) and functional diarrhea [56]. Intestinal bacteria are importantly involved in development and regulation of the immune system [57–59]. On this regard, mice grown under germ-free conditions exhibited several abnormalities, including hypoplastic Peyer's patches, IgA-producing cells reduction, relatively poorly structured spleen and lymph nodes, and decrease in proportion of Treg cells in colon [53]. Interestingly, when mice were exposed to intestinal bacteria for several weeks, the structure and function of immune system cells were restored [60]. Moreover, it has been shown that lipopolysaccharides from gram negative bacteria, as well as peptidoglycans from gram positive bacteria, activate Toll-like receptors (TLRs), inducing different immune responses [61]. Also, the expression of angiogenin 4 by *Bacteroides thetaiotaomicron* is induced. Angiogenin 4 is an important immune response regulator with microbicidal activity against a wide range of intestinal microbes, including bacterial and fungal pathogens [62]. A zwitterionic capsular polysaccharide of *Bacteroides fragilis* is an antigen related to T CD4 + effector cells function [63]; it also protects mice from *Helicobacter hepaticus* infections by suppressing IL-17 production and other immunological mechanisms [64]. Moreover, the genus Bifidobacteria is a producer

**3.1 Functions of the gut microbiota in the host**

bacteriocins have been found in human feces [45].

triglycerides synthesis [50].

**200**

of acetate that inhibits the translocation of Shiga toxin from *E.coli* 0157 suppressing colon inflammation [65]. In addition, *Bacteroides*, *Turicibacter*, and *Barnesiella* bacteria strains interact with T CD8 + cytotoxic cells in the mucosal compartment of both the small intestine and the colon [66]. Finally, the gut microbiota also regulates the interaction of dendritic cells with regulatory T cell through TLR 2 signaling, which induces an increased susceptibility to chronic inflammatory diseases such as colitis [67].

#### **3.2 Host's immunomodulatory activity on the gut microbiota**

The interactions between environmental signals and intestinal immune system are necessary to maintain a stable equilibrium and regulate the protective function of the intestinal barrier. Thus, in order to prevent microbial colonization and transepithelial migration, several chemical substances are produced by the intestinal epithelial cells, such as gastric acid, enzymes (lactoferrin, lysozyme), antimicrobial peptides (defensins), mucins, and nitric oxide [68]. On the other hand, signaling through Toll-like receptors (TLRs) is very important for the activation of innate immune system. TLRs recognize a wide range of common antigens present in pathogens, activating the adaptive immune system for the generation of multiple highly specific and immunocompetent clones [69].
