**2. GI-tract microbiome**

The gut microbiota is a complex collection of bacteria, archaea, viruses, and fungi that enter our digestive system daily through swallowing foods or swallowing saliva, so they can be colonized in our GI tract. The classification composition of the intestinal microbiome varies greatly from person to person due to the internal microbiome and external microbiome agents. The first factor (microbiome-intrinsic) depends on the condition of the microbiome after puberty during life and through species interactions [16]. The second factor (microbiome-external) refers to the various layers of the environment that affect or interact with the gut microbiome. Experimentally, they overlap into three categories: external hosting factors, intrinsic hosting factors, and environmental factors [16].

The intestinal microbial community contains 1000–1500 species of bacteria. However, about 160 species of bacteria can be present in a person's gut. That is why there is a fundamental difference in the composition of the microbiome between individuals,

*Large Association of GI Tract Microbial Community with Immune and Nervous Systems DOI: http://dx.doi.org/10.5772/intechopen.104120*

which indicates the dependence of the microbiome on environmental changes and genetic inheritance [17].

Studies of human dietary changes in the intestinal microbiome and gene expression patterns in adults are associated with changes in the diversity, structure, and function of the intestinal microbiome. In fact, the same dietary changes in the gut microbiome are associated with some changes in brain function or activity [15–17]. The symbiotic relationship between the gut microbial community and humans is beneficial to both parties. As human hosts, we provide important habitat and nutrients for our intestinal microbiome, and the gut microbiome supports the development of our metabolic system and the maturation of our intestinal immune system by providing beneficial nutrients. Each intestinal microbial community regulates a number of homeostatic mechanisms, including immune function and protection of the intestinal barrier in a healthy host [17, 18].

The composition of the gut microbiome is influenced by factors such as diet, antibiotic use, disease status ways of being born, and many other elements throughout human life. However, microbes form a complex symbiotic relationship with the host, where the host provides the microbiota with a nutrient-dense environment, and the microbiota, in turn, provides metabolic, protective, and structural functions that are not encoded or produced by the host genome [19].

Each person's gastrointestinal microbiome has six major phylum of bacteria and approximately 15 predominant species, as shown below [19]:


In addition to bacteria, studies have shown that 101 species belonging to 85 fungal genera isolated from the oral cavity of healthy volunteers, which represent three dominant phyla (*Ascomycota*, *Basidiomycota,* and *Zygomycota*) and more than ten classes of fungi which accounted for 99% of the population in all of the studies. Yeasts of

the genus *Saccharomyces*, *Malassezia,* and *Candida* are also the predominant fungi found in fecal samples in most studies [20–22]. So the intestinal fungal populations can be called "silent populations". This is because the population of fungal species, also known as "microbiome" occupies a very small volume of our GI-tract [23].

Most commensal fungi that live in our gut are uncultivable, but many of these fungi are pathogenic and under normal circumstances are not harmful to our bodies. The amount of fungus that lives in a person's gut is related to that person's eating habits and intestinal pH level. Also, their presence in the GI-tract of monogastric animals is only 0.1% of the total intestinal microbiome. According to observations, *Candida* and *Phialemonium* can survive in the acidic environment of the stomach, there are also many types of fungi that survive in the acidic environment and grow in the human GI-tract. However, the most common phylum and predominant species of fungi who live in the GI-tract based on their morphological and reproductive traits are as shown below [22–26]:


GI-tract viruses after bacteria and fungi constitute the predominant population of the intestinal microbiome. It can be expected that more than 10<sup>12</sup> viruses can live in the human gut and play an important role in regulating complex microbial networks active in the gut habitat [27]. Viruses, like the other microbes in the GI-tract, have a significant variation in their species among other people. However, not enough information is available on the functional role of most intestinal viruses, but they appear to be effective in some bacterial functions, such as generating or transmitting resistance and protection against other intestinal pathogens [28]. Also, about more than 90% of intestinal viruses communities are composed mainly of bacteriophages, while eukaryotic viruses are less than 10%. Now, two types of virus variants and the most common phylum have been identified in the human gut, which are as shown below [28, 29]:

i. Bacteriophages *Siphoviridae Podoviridae Myoviridae Microviridae inoviridae* 8 >>>>>>< >>>>>>:

*Large Association of GI Tract Microbial Community with Immune and Nervous Systems DOI: http://dx.doi.org/10.5772/intechopen.104120*

ii. Eukaryotic Viruses *adenoviridae alphaflavoviridae astroviridae Arenaviridae circoviridae Geminiviridae Genemoviridae papilomaviridae picornaviridae polyomaviridae parvoviridae Virgaviridae Rudiviridae* 8 >>>>>>>>>>>>>>>>>>>>>>>>>>>< >>>>>>>>>>>>>>>>>>>>>>>>>>>:

Although archaea have a very small fraction of the microbiota, but some of them (e.g. *Methanobrevibacter*) play a very important role in intestinal methanogens. The archaea domain contains a wide range of organisms that share properties with prokaryotic and eukaryotic domains [28, 30]. Methanogens are the unique and specific metabolism of some archaea species that are widespread in environments (e.g., freshwater, marine sediments, soils and intestines of humans, and many animal species). The archea that lives in our body is found in our mouth, esophagus, and intestines. But each of them is colonized in a specific part of our digestive system. However, archaea extracted from the human body are classified into three kingdoms and more than ten phyla as shown below [30]:

i. Thaumarchaeota f**Nitrososphaerales**

ii. Crenarchaeota f**Sulfolobales**


The microbial ecology of the GI tract is composed of chemically and physically diverse micro-environment habitats stretching from the esophagus to the rectum; colonization or transient occupation by microbes is about 150–200 m<sup>2</sup> of the gut

surface [28]. The symbiotic relationship between the gut microbiota and the host, mediated by a complex metabolic network, includes immunity, nerves, and glands. These symbiotic relationships can lead to severe interference with synthesized microbial metabolites. The predominant functions of the gut microbiota and key metabolites are associated with host health control, reflecting the multifaceted function of the host microbiome, immune system, nerves, and vital organs [31].

### **2.1 Encounter and interaction of microbial ecology of the GI-tract**

Thousands of microbial species inhabit the GI-tract, and observations show that microbial communities such as bacteria and fungi interact with each other, in such a way that targeting bacteria or fungi can inadvertently lead to fungal or bacterial dysbiosis. Many of these studies have shown that some fungi have a strong effect on the reassembly of intestinal bacterial communities after antibiotic treatment (e.g., *Candida albicans*) [24]. Studies on the colonization of *C. albicans* in animal models showed that the fungus partially increased the host's immunity against pathogenic agents (e.g., *Clostridium difficile*) by increasing the level of IL-17, a proinflammatory cytokine. It has also been shown that dysbiosis of intestinal microbial agents can reduce the abundance of anti-inflammatory bacteria (e.g., *Lacticaseibacillus*) and increase pro-inflammatory bacteria (e.g., *Escherichia* and *Shigella*) [24, 32].

The physical structure between the microbiome and the epithelial cells is one of the most important factors in enhancing the selective acceptance of the intestinal microbiome, as the secretion of moderate amounts by the intestinal epithelium causes a complete change in the growing strains at the epithelial level [33]. In distinct intestinal habitats, environmental and competitive microbial filters are the driving force behind the removal and formation of microbial diversity, these factors during colonization and evolution probably explain the diversity of species [34]. *Actinobacteria* can be considered as a keystone phylum, because they are rare and have many connections between bacteria species outside and inside the host body. The number of *Bacteroidetes* is large and they are very widespread in GI-tract, so we can consider them as the predominant phyla [35]. However, the level of intestinal bacterial microbiome phyla can be considered relatively stable over time. Many factors may affect their sustainability (e.g., microbial energy and metabolites produce) [28].

Unhealthy nutrition or poor diets can alter intestinal microbial interactions and dietary diversity, resulting in changes in the availability of microbial nutrients and/or ligands that carry information from the gut to the brain in response to food intake [36]. As a result, they disrupt energy homeostasis, host energy, and metabolites interactions with intestinal microbiota have a significant effect on overall human health, including energy reabsorption and immune system regulation [28, 36]. In humans, digestible carbohydrates are digested by enzymes secreted by the dominant members of the large intestinal microbiota, most of these microbiota are located in the colon (e.g., *Bacteroides* and *Prevotella* species), but healthy nutrition and proper diet can induce beneficial and proper functions by human gastrointestinal microbes (e.g., breakdown of food, synthesis of vitamins and biomolecules, and interaction with the immune system) [37, 38].

Gastrointestinal diseases have been shown to be directly detectable by changes in the microbiome as well as an increase in invasive microbial strains or a decrease in intestinal regulatory microbiome species [39]. Host genetics and horizontal transmission of microbial genes are important factors that play a key role in the composition of

### *Large Association of GI Tract Microbial Community with Immune and Nervous Systems DOI: http://dx.doi.org/10.5772/intechopen.104120*

the gut microbiome and the frequent replacement of gut microbes, although the horizontal transmission of peripheral microbes can lead to the development of common microbes in the intestinal microbiome ecosystem or alter their colonization patterns by altering the horizontal transfer of interspecific genes, which in turn diversifies the gut microbiota [40].

If the two microbes are positively correlated, they are more likely to facilitate each other but this approach increases colonization-resistant Bacteroides species, whereby the invasive microbial strain cannot colonize the host unless the same microbial species has already been colonized from a common microbial phylum in the GI-tract [41]. The dimensions of this issue can be expressed as: Some important members of the class *Enterobacteriaceae* are responsible for many gastrointestinal complications and significant mortality rates (e.g. *Salmonella*, *Shigella*, and *Yersinia*) [42], as mentioned earlier the *Escherichia* is also a species of *Enterobacteriaceae*, but the interesting and important thing is that *E. coli* and *Shigella* have genetically similarity to each other (about 80 to 90%), and both of them carry the virulence plasmid (pINV) as extra genome; so, it can be considered that *Shigella* and *E. coli* transmit their potentials to bind to intestinal epithelial surfaces, pathogenesis, and even antibiotic resistance by horizontal gene transfer of their plasmid together [42, 43].

It is clear that any pathogen that enters the GI-tract can attach to epithelial surfaces and colonize itself through similar groups, emphasizing and using mechanisms of microbial agents that are genetically similar to them. Conversely, some probiotic microbial groups extracted from the human gut environment (e.g., *Lactobacillus* and *Bifidobacterium*) compete for nutrients and growth medium with this group of pathogen gut microbial colonies, which can act as controlling or killing agents for these bacteria [42–44].

### **2.2 GI-tract microbiome products**

The food we eat throughout the day is the main source of precursors for the production of GI-tract microbial metabolites [44, 45]. Our diet modulates the gut microbiome because the food we eat is also consumed by the gut microbiome and causes changes in the ecosystem and the microbial metabolic properties of the gut [45]. The intestinal microbial ecosystems can change their function in response to changes in our diet. In fact, the type of diet we eat over a long period of time affects the microbial activity of other microbial species in our gut [45], bacteria produce a large number of metabolites that contain structural components and act as signaling molecules for a number of types of our mucosal cells [46].

Enteroendocrine (EE) cells respond differently to many nutrients and intestinal conditions. The intestinal microbiome affects the hormonal secretion of enteroendocrine (EE) cells downstream and facilitates host metabolism or pathogenic metabolites [46]. The gut microbiota plays an important role in human metabolism by enzymes that are not encoded in the human genome (e.g., breakdown of polysaccharides or polyphenols and the synthesis of vitamins) [47]. In the composition of intestinal microbiome metabolites, the processing and absorption of several nutrients and metabolites, including bile acids, lipids, amino acids, vitamins, and short-chain fatty acids (SCFA) derived from intestinal bacteria, are directly related to diet and digestion, and can facilitate or modulate immune cells through direct and indirect mechanisms [45]. The product of microbial degradation of food sources in the gut are bioactive metabolites that bind to target receptors, activate signaling cascades, and modulate several metabolic pathways with local and systemic effects [48].

### *2.2.1 SCFA metabolite*

SCFAs are the main metabolite and the end products of food fiber fermentation by intestinal anaerobic microbiota and have several beneficial effects on mammalian energy metabolism [49]. Acetate, propionate, and butyrate act as post-biological molecules and are present in the large intestine, all three of which SCFAs that are produced by bacterial species consume lactate and succinate [48, 49]. For the microbial community, SCFAs are an essential extra end products that is needed to balance the production of equivalent redox in the anaerobic environment of the intestine [49]; the SCFAs, which are produced in the colon, are absorbed into the tissues through the circulatory system (e.g. Acetate), metabolized in the liver (e.g. Propionate), and consumed by local colonocytes as their primary fuel source (e.g. Butyrate) [46]. Past studies have shown that some bacterial strains excreted from the gut (e.g. *E. coli*) can metabolize acetate by converting acetate to acetyl coenzyme-A (acCoA) by using the reversible pathway of acetate kinase (AckA)-phosphotransacetylase (Pta) pathway [50]. In addition to modulating redox stress, the SCFAs increased the colon defense barrier and can be involved in many of the intestinal activities as shown below:


Observations have shown that butyrate, a molecule of SCFAs, can modulate neuronal functions by gene expression of neurotransmitters as well as gastrointestinal stimulation, and also shown that butyrate increases the proportion of choline acetyltransferase by the Src-kinase signaling pathway and the acetylation of histone H3K9 in enteric neurons [45].

### *2.2.2 Amino-acids metabolite*

Another metabolite that is a product by the colon microbiome is amino acids. Some of these amino acids (e.g., Serotonin and tryptophan) have a direct impact on host cell metabolism. Disorders caused by these two bacterial amino acids, can have several effects on the gut-brain axis and vice versa [51, 52]. The GI-tract has three main pathways for tryptophan (Trp) metabolism, which lead to serotonin (5-hydroxytryptamine), kynurenine (Kyn), and indole derivatives, which are directly or indirectly controlled by microbiota [53]. Also, the GI-tract contains large amounts of serotonin (5-hydroxytryptamine) and its receptors (5-HT). Some of the spore-forming (SP) bacteria (e.g. *Bacillus* and *Clostridium* species) have been shown to enhance the level of serotonin receptor biosynthesis by intestinal enterochromaffin cells (ECs) [54].

*Large Association of GI Tract Microbial Community with Immune and Nervous Systems DOI: http://dx.doi.org/10.5772/intechopen.104120*

### *2.2.3 Bile-acids metabolite*

Bile acids are the end products of cholesterol catabolism. They are also signaling molecules that regulate metabolic systems that activate nuclear receptors and G protein-coupled receptors (GPCRs) to regulate hepatic lipid, glucose, and energy homeostasis and impound metabolic homeostasis [55]. To convert cholesterol to bile acids, there are 17 separate enzymes located in the cytosol, endoplasmic reticulum, mitochondria, and peroxisomes. These enzymes can catalyze steroid chain changes and oxidative cleavage of three carbons from the cholesterol side-chain to form C24 bile acids. There are two main pathways of bile acid biosynthesis [55].

Primary bile acids (BAs) are produced inside the liver cells and then released into the duodenum to facilitate the absorption of lipids or fat-soluble vitamins. Both nutritional and microbial factors have been shown to affect the composition of the intestinal BA pool and modulate an important population of FOXP3 + regulatory T (T reg) cells that express transcription factor RORγ [56].

Secondary bile acid is produced by the microbial biotransformation of cholate, deoxycholate enhances gastrointestinal motility by activating TGR5 G-proteincoupled receptors on ECs, Sp-induced metabolites increase 5-HT levels in ECs, and Sp colonization improves GI-tract motility [54].

### *2.2.4 Lipid metabolite*

Some intestinal microbiome bacteria, by consuming lipids, can act both as a substrate for bacterial metabolic processes and as a factor to inhibit bacterial growth in the structural and ecological changes of gut microbiota [57]. Several potential lipid mediators have been identified that act as metabolic messengers to communicate energy status and regulate substrate use between tissues. Also, these mediators can be exogenously distributed in the intestine and effect glucose and lipid metabolism [58]. It has been shown that some intestinal bacteria (e.g., *Lactobacillus*, *Butyrivibrio*, and *Megasphaera*) can react with fatty acid double bonds to produce metabolites that we are unable to synthesize. Many of these metabolites may affect the physiological functions and health of the host. The conjugated linoleic acid (CLA) is one of these metabolites that exerts opposite or different effects [57].

The gut microbiota processes lipids and other digestion nutrient factors to produce metabolites with impacts on host lipid homeostasis and putative effects on pathophysiological functions [57], lipogenesis is controlled by several rate-limiting enzymes that convert acetyl-CoA to palmitate, palmitoleate, stearate, and oleate [58]. The effect of butyrate on vagal inputs to NPY neurons has been identified. Butyrate can also promote the oxidation of fatty acids by consuming carbohydrates, especially in conditions of reduced nutrition throughout the day [36, 59].

Also, lipids play a protective role in the structure of intestinal gram-negative bacteria. Gram-negative bacteria have lipopolysaccharide in their structure, which consists of lipids and polysaccharides. The important point is that this structure acts as a pathogen for this group of bacteria. What we need to know is that LPS is a large glycolipid composed of three structural domains: lipid A, core oligosaccharide, and O antigen [60, 61].

Lipoproteins are absorbed by fat cells with or without LPS. However, LPS are directly and indirectly involved in the inflammatory response in adipose tissue. The LPS is also involved in the transfer of macrophages from the M2 phenotype to M1; in addition, LPS within adipocytes may activate the caspase [62]. The exact structure of LPS varies from

bacteria to bacteria and is highly regulated in host cells and is closely related to bacterial virulence. It should be noted that additional enzymes and gene products can modify the basic structure of LPS in some bacteria (especially pathogenic bacteria) [63].
