**2. The gut-associated lymphoid tissue (GALT)**

#### **2.1 Anatomy and physiology**

The gut-associated lymphoid tissue (GALT) is a specialized component of mucosal-associated lymphoid tissue (MALT) or mucosal immune system that protects the individual's intestine from invading pathogens. The intestine-associated

**197**

**Figure 2.**

*Anatomy of gut-associated lymphoid tissue (GALT).*

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

tissue extends throughout the small and large intestine, covering an area of

tion, where an epithelial cells monolayer (also called enterocytes) separates the GALT from lumen and its content. The enterocytes monolayer on luminal surface is coated by a glucocalix layer, which protects them from acidic pH. The intestinal mucosal surface can function as a permeable barrier to the inside of the body. This permeability increases the vulnerability to infections by a variety of infectious agents that invade the human body orally. Therefore, the largest populations of plasma cells that produce antibodies are enriched on GALT, generating a local and systemic humoral immune response with high production of immunoglobulin A (IgA), promoting a robust cellular immunity with cytotoxic, regulatory, and memory functions [8]. GALT can be divided into: (a) inductive sites, composed by lymphoid aggregates or follicles, and (b) effectors sites formed by the lamina propria and the lumen. In **Figure 2** there is a complete description of GALT, thus GALT forms nodules disseminated into the submucosa and the lamina propria. The largest aggregates form "Peyer's patches," which in the small intestine are located in front of the mesenteric tissue. Locally, new epithelial cells derived from stem cells are constantly produced to regenerate the epithelium. In addition to conventional enterocytes, there are also Paneth cells at the bottom of the epithelial crypts. These cells secrete lysozyme and other antibacterial substances to control the growth of pathogens. These cells are found in the small intestine, especially in the jejunum, and their granules become visible after several hours of fasting. Also, the mucus goblet cells are scattered between other cell types. On the other hand, enteroendocrine cells produce polypeptides and are distributed diffusely throughout the gastrointestinal tract. On the surface of Peyer's patches, "M cells" also called "caveolate cells" are located, which capture antigens and function as intestinal chemoreceptors.

Beneath the epithelial lining is an underlying layer of connective tissue called lamina propria, which is connected to the lymphatic circulation and mesenteric

approximately. An important function of intestine is nutrient absorp-

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

260–300 m2

### *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*

to the functions above described, it has been proposed that intestinal microbiota exerts indirect functions in other organs such as the liver and brain. Studies performed in humans and in animal models suggest that intestinal dysbiosis has an important role in the development of mood disorders such as depression, anxiety, and Parkinson's disease [5–7]. For these reasons, the interest in exploring the interactions between immune system, intestinal microbiota, and central nervous system

*Microbiota-GALT-brain axis. The vagus nerve makes the connection of the intestine to the brain and vice versa. Dysbiosis causes local alterations in the GALT and in the brain. When there is no dysbiosis, the bacterial* 

*metabolites participate in the state of local and systemic health and even more so over the brain.*

On the other hand, when bacterial probiotics are administered in adequate amounts, they confer benefits on host health. The main functions of probiotics are to prevent and ameliorate several digestive and allergic disorders. Also, the microbiota modulates ontogeny and immune system functions, as well as the interactions of the intestine-brain axis to regulate some neurological functions. However, the microbiota effects are not only in intestine but also in peripheral tissues, such as in immune system modulation and interacting with the gut-brain axis to regulate

The gut-associated lymphoid tissue (GALT) is a specialized component of mucosal-associated lymphoid tissue (MALT) or mucosal immune system that protects the individual's intestine from invading pathogens. The intestine-associated

**196**

(CNS) has increased (**Figure 1**).

**Figure 1.**

some neurologic functions.

**2.1 Anatomy and physiology**

**2. The gut-associated lymphoid tissue (GALT)**

tissue extends throughout the small and large intestine, covering an area of 260–300 m2 approximately. An important function of intestine is nutrient absorption, where an epithelial cells monolayer (also called enterocytes) separates the GALT from lumen and its content. The enterocytes monolayer on luminal surface is coated by a glucocalix layer, which protects them from acidic pH. The intestinal mucosal surface can function as a permeable barrier to the inside of the body. This permeability increases the vulnerability to infections by a variety of infectious agents that invade the human body orally. Therefore, the largest populations of plasma cells that produce antibodies are enriched on GALT, generating a local and systemic humoral immune response with high production of immunoglobulin A (IgA), promoting a robust cellular immunity with cytotoxic, regulatory, and memory functions [8]. GALT can be divided into: (a) inductive sites, composed by lymphoid aggregates or follicles, and (b) effectors sites formed by the lamina propria and the lumen.

In **Figure 2** there is a complete description of GALT, thus GALT forms nodules disseminated into the submucosa and the lamina propria. The largest aggregates form "Peyer's patches," which in the small intestine are located in front of the mesenteric tissue. Locally, new epithelial cells derived from stem cells are constantly produced to regenerate the epithelium. In addition to conventional enterocytes, there are also Paneth cells at the bottom of the epithelial crypts. These cells secrete lysozyme and other antibacterial substances to control the growth of pathogens. These cells are found in the small intestine, especially in the jejunum, and their granules become visible after several hours of fasting. Also, the mucus goblet cells are scattered between other cell types. On the other hand, enteroendocrine cells produce polypeptides and are distributed diffusely throughout the gastrointestinal tract. On the surface of Peyer's patches, "M cells" also called "caveolate cells" are located, which capture antigens and function as intestinal chemoreceptors.

Beneath the epithelial lining is an underlying layer of connective tissue called lamina propria, which is connected to the lymphatic circulation and mesenteric

**Figure 2.** *Anatomy of gut-associated lymphoid tissue (GALT).*

lymph nodes. The intestine is constantly exposed to several antigens derived from the diet, microbiota, and a wide variety of bacterial, viral, fungal, and other pathogens. The immunity of this compartment is highly specialized because it is capable of both functions: (a) triggering an immune response and (b) inducing tolerance by suppressing immune response through the interaction of epithelial cells and microbiota [9, 10].

The induction of intestinal mucosa tolerance depends on several factors, such as: (a) nature of antigen (mainly protein antigens) [11]; (b) dose and frequency of antigen exposition [12–14]; (c) kinetics of antigen uptake, because antigenic exposition time with the immune system is key to induce tolerance [15]; and (d) genetic background and age of the host, because there is different susceptibility to infection, depending on age and genetic inheritance. The main antigens reaching GALT are a mixture of free amino acids and short oligopeptides, generated by gastric, pancreatic, or protease action on large proteins, which are absorbed by intestinal epithelial cells [16]. However, some intact proteins or incomplete proteolysis products can reach inductive sites through the following three non-exclusive pathways:


It is well known that the intestinal epithelium provides a physical barrier that separates the trillions of commensal bacteria present into intestinal lumen from both underlying lamina propria and deeper intestinal layers. The intestinal epithelium is composed of four cellular subsets derived from a common pluripotent stem cell progenitor: (1) enterocytes which constitute the majority of intestinal epithelial cells (IECs), (2) goblet cells producing mucus, (3) enteroendocrine cells producing hormones, and (4) Paneth cells that produce antimicrobial peptides and lectins. In addition, below the intestinal epithelium, stromal cells, B cells (especially plasma IgA producing cells), T cells, macrophages, and dendritic cells are found in lamina propria. In addition, strategically positioned are intraepithelial lymphocytes or iIELs (specialized T cells) and some dendritic cells, which are located between the IECs to sample the luminal content [20–22]. Thus, intraepithelial lymphocytes are considered the first line of cellular defense against any antigen that enters orally. The iIELs belong to the lymphoid tissue associated to intestine and they are found in a ratio of 1:10 with respect to the epithelial cells along 300 m2 of intestinal surface [23]. Most iIELs contain abundant cytoplasmic granules for cytotoxic activity; also, effector cytokines such as interferon gamma (IFN-γ), interleukin-2 (IL-2), IL-4, and IL-17 can be secreted [24, 25]. The iIELs are cells that provide an immediate and efficient immune protection to prevent the spread of pathogens. However, to avoid excessive or unnecessary inflammatory responses on intestinal barrier, the iIELs also have regulatory functions [26].

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

**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].

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

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

microbiota [9, 10].

pathways:

lymph nodes. The intestine is constantly exposed to several antigens derived from the diet, microbiota, and a wide variety of bacterial, viral, fungal, and other pathogens. The immunity of this compartment is highly specialized because it is capable of both functions: (a) triggering an immune response and (b) inducing tolerance by suppressing immune response through the interaction of epithelial cells and

The induction of intestinal mucosa tolerance depends on several factors, such as: (a) nature of antigen (mainly protein antigens) [11]; (b) dose and frequency of antigen exposition [12–14]; (c) kinetics of antigen uptake, because antigenic exposition time with the immune system is key to induce tolerance [15]; and (d) genetic background and age of the host, because there is different susceptibility to infection, depending on age and genetic inheritance. The main antigens reaching GALT are a mixture of free amino acids and short oligopeptides, generated by gastric, pancreatic, or protease action on large proteins, which are absorbed by intestinal epithelial cells [16]. However, some intact proteins or incomplete proteolysis products can reach inductive sites through the following three non-exclusive

a.The epithelium responds to stimuli from different antigens expressing chemokine and cytokine genes [17]. Consequently, different subsets of cells

b.M cells, specialized cells in both internalizing and transportation of intestinal antigens [19]. The antigens are endocytosed or phagocytosed, transported in vesicles through the M cells cytoplasm, and released on the basal surface where they are captured by antigen-presenting cells and transported to inductive

c.Lamina propria (LP) dendritic cells (CDs) can go through the epithelial cells to capture antigens directly from the intestinal lumen, preserving the epithelial

It is well known that the intestinal epithelium provides a physical barrier that separates the trillions of commensal bacteria present into intestinal lumen from both underlying lamina propria and deeper intestinal layers. The intestinal epithelium is composed of four cellular subsets derived from a common pluripotent stem cell progenitor: (1) enterocytes which constitute the majority of intestinal epithelial cells (IECs), (2) goblet cells producing mucus, (3) enteroendocrine cells producing hormones, and (4) Paneth cells that produce antimicrobial peptides and lectins. In addition, below the intestinal epithelium, stromal cells, B cells (especially plasma IgA producing cells), T cells, macrophages, and dendritic cells are found in lamina propria. In addition, strategically positioned are intraepithelial lymphocytes or iIELs (specialized T cells) and some dendritic cells, which are located between the IECs to sample the luminal content [20–22]. Thus, intraepithelial lymphocytes are considered the first line of cellular defense against any antigen that enters orally. The iIELs belong to the lymphoid tissue associated to intestine and they are found

[23]. Most iIELs contain abundant cytoplasmic granules for cytotoxic activity; also, effector cytokines such as interferon gamma (IFN-γ), interleukin-2 (IL-2), IL-4, and IL-17 can be secreted [24, 25]. The iIELs are cells that provide an immediate and efficient immune protection to prevent the spread of pathogens. However, to avoid excessive or unnecessary inflammatory responses on intestinal barrier, the iIELs

of intestinal surface

carrying antigens are recruited to inductive sites [18].

in a ratio of 1:10 with respect to the epithelial cells along 300 m2

sites, which will be presented to T and B cells.

barrier integrity [20].

also have regulatory functions [26].

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