Large Association of GI Tract Microbial Community with Immune and Nervous Systems

Abstract

The gut microbial community has amazing effects on our immune system and nervous system through three pathways: cell signaling, electron transfer, and biological cycles. However, this relationship is two-way and has its own risks or benefits. Except for the brain, there is no place in the body that does not have cytokines (but not all of them). Cytokines are one of the most important immune molecules that play an important role in maintaining homeostasis in our body and the connection between the central nervous system and our immune system. So it is clear that many beneficial microbes in the gut are stimulated when we are hungry or when our nervous system is under pressure from external stimuli. These microbes die or damage intestinal epithelial tissues and stimulate immune molecules such as interleukins or IFNs upstream.

1. Introduction

The digestive system includes all the structures between the mouth and the anus. The gastrointestinal tract (GI-tract) begins at the end of the esophagus and ends at the anus, and includes the stomach, duodenum, small intestine, large intestine, and rectum. The weight of microbial communities living in the human gut is about the same as the weight of the human brain. The brain weight of an adult human is between 1 and 1.3 kg, in contrast to about 1 to 1.5 kg of human body weight forms the intestinal microbial community [1, 2]. This microbial community consists of more than 1000 different and heterogeneous bacteria that provide environmental factors to the digestive system and play an important role in the maturation of the host immune system [3].

This microbial colonization in intestinal mucosal tissues plays an important role in promoting host innate- immunity [4]. The diverse and resident microbial populations in the gut promote the growth and maturation of the host immune system through a variety of methods, including the development of lymphatic structures, differentiation and maturation of B and T immune cells, intestinal immune tolerance, and response to T-cell CD4 receptors [5]. Interactions and metabolism by intestinal microbes directly affect the activity of the intestine; How? This is very simple, most of the microorganisms who live in the gut have anaerobic respiration (e.g. citric-acid cycle, oxidative phosphorylation, amino acid, and fatty acid metabolism, etc.). These respirations systems can stimulate, activate, or regulate many immune molecules called cytokines [6, 7, 8].

Cytokines are commonly known as inflammatory mediators and immune responses that have very low molecular weight and function similarly to hormones. Also, cytokines can affect the secretory cells and other cells that receive them [9]. In fact, they regulate all the mechanisms of the vertebrate body and respond to external stimuli. Some cytokines play critical roles in our bodies and transmit immune messages (e.g. IL-1, IL-6, TNF-α, and IFNs), which we see as fever, inflammation, pain, and fatigue in the presence of injury or complication; but this is not all their function, even they can affect the hypothalamic–pituitary–adrenal axis (HPA-axis) pathways and most of the biomarkers [10]. The network of cytokine activity is such that it communicates between all cells and the immune system. A cytokine can also stimulate its target cell to produce more cytokines or completely disrupt their production [11]. Cytokines perform their functions by binding to specific receptors on the target cell membrane, four receptor proteins for cytokines have been identified that are classified into five families, including immunoglobulin receptors, class I cytokine receptors (hematopoietin), class II cytokine receptors (interferons), TNF receptors, and chemokine family receptors [12].

Many observations suggest that the intestinal microbiome interacts with inflammation of the brain and CNS function. The nervous system and GI-tract communicate with each other through a two-way network of signaling pathways consisting of several connections including the vagus nerve, immune system, metabolites, and bacterial products [13]. The gut microbiota and the brain can affect each other directly CNS and indirectly autonomic nervous system (ANS). The vagus nerve is the most important part of the sympathetic and parasympathetic system (dependent on the ANS) that controls many of our essential functions and daily activities (e.g., mood control, immune response, digestion, and heart rate) [14, 15]. In direct signaling, endocrine secretion by the central nervous system (CNS) can stimulate intestinal bacteria. This direct signaling usually involves the concentration of catecholamine, which is also effective in physical and psychological stress. But in the indirect signaling method in addition to CNS. The ANS is also involved. So the ANS plays an important role in maintaining the integrity, modulating, and regulating the permeability of epithelial surfaces, intestinal physiology, and microbial function [15].

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, 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, 16, 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]:

1. Firmicutes $\left\{\begin{array}{c}\text{Ruminococcus}\\ \text{Clostridium}\\ \text{Lactobacillus}\\ \text{Eubacterium}\\ \text{Faecalibacterium}\\ \text{Roseburia}\end{array}\right.$

2. Bacteroidetes $\left\{\begin{array}{c}\text{Bacteriodes}\\ \text{Prevotella}\\ \text{Xylanibacter}\end{array}\right.$

3. Actinobacteria $\left\{\begin{array}{c}\text{Collinsella}\\ \text{Bifidobacterium}\end{array}\right.$

4. Verrucomicrobia $\left\{\text{Akkermansia}\right.$

5. Proteobacteria $\left\{\begin{array}{c}\text{Escherichia}\\ \text{Desulfovibrio}\end{array}\right.$

6. Euryarchaeota $\left\{\text{Methanobrevibacter}\right.$

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, 21, 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, 23, 24, 25, 26]:

1. Ascomycota $\left\{\begin{array}{c}\mathbf{\text{Paecilomyces}}\\ \mathbf{\text{Penicillium}}\\ \mathbf{\text{Candida}}\\ \mathbf{\text{Aspergillus}}\\ \mathbf{\text{Fonsecaea}}\\ \mathbf{\text{Geotrichum}}\\ \mathbf{\text{Saccharomyces}}\end{array}\right.$

2. Basidiomycota $\left\{\begin{array}{c}\mathbf{\text{Trichosporon}}\\ \mathbf{\text{Rhodotorula}}\end{array}\right.$

3. Zygomycota $\left\{\begin{array}{c}\mathbf{\text{Rhizopus}}\\ \mathbf{\text{Mucor}}\end{array}\right.$

GI-tract viruses after bacteria and fungi constitute the predominant population of the intestinal microbiome. It can be expected that more than 10¹² 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]:

1. Bacteriophages $\left\{\begin{array}{c}\mathit{\text{Siphoviridae}}\\ \mathit{\text{Podoviridae}}\\ \mathit{\text{Myoviridae}}\\ \mathit{\text{Microviridae}}\\ \mathit{\text{inoviridae}}\end{array}\right.$

2. Eukaryotic Viruses $\left\{\begin{array}{l}\mathit{\text{adenoviridae}}\\ \mathit{\text{alphaflavoviridae}}\\ \mathit{\text{astroviridae}}\\ \mathit{\text{Arenaviridae}}\\ \mathit{\text{circoviridae}}\\ \mathit{\text{Geminiviridae}}\\ \mathit{\text{Genemoviridae}}\\ \mathit{\text{papilomaviridae}}\\ \mathit{\text{picornaviridae}}\\ \mathit{\text{polyomaviridae}}\\ \mathit{\text{parvoviridae}}\\ \mathit{\text{Virgaviridae}}\\ \mathit{\text{Rudiviridae}}\end{array}\right.$

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]:

1. $\mathrm{Thaumarchaeota}\left\{\mathbf{\text{Nitrososphaerales}}\right.$

2. $\mathrm{Crenarchaeota}\left\{\mathbf{\text{Sulfolobales}}\right.$

3. $\mathrm{Euryarchaeota}\left\{\begin{array}{c}\mathbf{\text{Archaeoglobales}}\\ \mathbf{\text{Halobacteriales}}\\ \mathbf{\text{Methanopyrales}}\\ \mathbf{\text{Methanobacteriales}}\\ \mathbf{\text{Methanococcales}}\\ \mathbf{\text{Methanomassiliicoccales}}\\ \mathbf{\text{Methanomicrobiales}}\\ \mathbf{\text{Methanocellales}}\\ \mathbf{\text{Methanosarcinales}}\\ \mathbf{\text{Thermococcales}}\\ \mathbf{\text{Thermoplasmatales}}\end{array}\right.$

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 m² 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 pro-inflammatory 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 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, 43, 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:

1. Triggering of Foxp3+ T regulatory (Treg) cells and tolerance

2. Induction of IgA secretion from B cells

3. Bacterial competitive exclusion

4. Promotion of mucus secretion by gut epithelial cells

5. Contribution to the intestinal barrier integrity

6. Inhibition of the pro-inflammatory transcription factor (NF-κB) and decreasing of oxidative stress

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].

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-protein-coupled 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].

3. GI-tract communications anatomy

Before describing signaling pathways, we need to get a little familiar with the anatomy of the GI-tract and involved systems. Depending on the physiological structure of males and females, the structure of the pelvis will be different. Actually, the outlined subdivision of the pelvic connective tissue is identical in the male and female. The only difference is that in women the uterus is located between the bladder and the rectum and divides the pelvic peritoneum into two sacks, but this is not the case in the male pelvic cavity [64].

3.1 GI-tract neuroanatomy

A complex set of nerve masses and fibers extending from the brainstem to the sacrum, together with neurons in the sympathetic and parasympathetic systems, control a variety of functions, including swallowing, digestion, and excretion. Intestinal-associated neurons and neural networks are generally classified as belonging to the enteric nervous system (ENS) [65], which is described in terms of function and action as follows:

Functions:

Brainstem $\left\{\begin{array}{c}\mathbf{DRG}\to \left(\mathbf{\text{afferent nerves}}\right)\to \mathbf{\text{nodose ganglia}}\left\{\begin{array}{c}\mathbf{\text{stomach}}\\ \mathbf{\text{small intestine}}\end{array}\right.\\ \left(\mathbf{\text{efferent nerves}}\right)\to \mathbf{\text{vagal nerve}}\left\{\begin{array}{c}\mathbf{\text{stomach}}\\ \mathbf{\text{small intestine}}\mathbf{.}\end{array}\right.\end{array}\right.$

Spinalcord $\left\{\begin{array}{c}\mathbf{\text{Celiac ganglia}}\left\{\begin{array}{c}\mathbf{DRG}\to \left(\mathbf{\text{afferent nerves}}\right)\to \left\{\mathbf{\text{small intestine}}\right.\\ \left(\mathbf{\text{efferent nerves}}\right)\to \left\{\begin{array}{c}\mathbf{\text{stomach}}\\ \mathbf{\text{small intestine}}\end{array}\right.\end{array}\right.\\ \mathbf{\text{Superior Mesenteric ganglia}}\{\left(\mathbf{\text{efferent nerves}}\right)\to \left\{\begin{array}{c}\mathbf{\text{small intestine}}\\ \mathbf{\text{large intestine}}\end{array}\right.\\ \mathbf{\text{Inferior Mesenteric ganglia}}\{\left(\mathbf{\text{efferent nerves}}\right)\to \mathbf{\text{large intestine}}\\ \mathbf{\text{pelvic nerve}}\left\{\begin{array}{c}\mathbf{DRG}\to \left(\mathbf{\text{afferent nerves}}\right)\to \left\{\begin{array}{c}\mathbf{\text{large intestine}}\end{array}\right.\\ \left(\mathbf{\text{efferent nerves}}\right)\to \left\{\begin{array}{c}\mathbf{\text{large intestine}}\end{array}\right.\end{array}\right.\end{array}\right.$

Actions:

Sympathetic $\stackrel{\mathit{\text{catecholamines}}}{\to }$α- or β-adrenergic receptors $\to \left\{\begin{array}{c}\mathit{\text{postganglionic vasoconstrictor neurons}}\\ \mathit{\text{secretion inhibitory neurons}}\\ \mathit{\text{motility inhibitory neurons}}\end{array}\right.$

Parasympathetic $\left\{\begin{array}{c}\stackrel{\mathbf{\text{vagus nerve}}}{\Rightarrow }\mathbf{\text{Intestinal nerve innervation}}\\ \stackrel{\mathbf{\text{neurotransmitter acetylcholine}}}{\Rightarrow }\left\{\begin{array}{c}\mathbf{\text{motility}}\\ \mathbf{\text{digestion}}\\ \mathbf{\text{secretory function}}\end{array}\right.\end{array}\right.$

The GI-tract is innervated through its connections to the CNS and by the ENS in the wall of the GI-tract, ENS works in coordination with the CNS reflex to the command center and in the neural pathways that pass through the sympathetic ganglia to control gastrointestinal function [66].

3.2 GI-tract lymphatic system anatomy

The anatomy of the lymphatic system include the thymus, GI-tract, lymph nodes, spleen, and tonsils, and is very similar to the circulatory system expansion. In many organs of the body (e.g., neck, chest, pelvis, etc.), this system is seen in the form of lymph vessels in cooperation with these organs. The lymphatic vascular system consists of a network of vessels that extends to every part of the body except the brain and spinal cord. Of course, lymphatic vessels are found only in the hard palate [67, 68].

Even though the body fluids can move between blood vessels and tissues through very small pores. So in this system, lymphoid organs and lymph nodes monitor and control the composition of body fluids (ie. blood and hemolymph), which includes the following activities [67, 68]:

1. Absorption of pathogens

2. Strengthening the immune response

3. Treatment of infection

Also, many endocrine functions require the lymphatic system and even the absorption and transfer of fats and fat-soluble vitamins from the digestive system to the lymph. From there, most organs with the lymphatic system drain their by-products into the lymphatic system and enter the circulatory system from there. That is why this system has a one-way function [67]. There is an extensive network of lymph nodes and lymph vessels in the pelvis that are connected to the tissues and organs of the pelvis, especially the intestines. The gut-associated lymphoid tissues (GALT) perform many functions including monitoring the proliferation and regeneration of gut epithelial cells, Peyer’s patches in the small intestine, controlling water absorption from the intestine, and intestinal health conditions [69].

3.3 GI-tract tissues anatomy

If we want to look at the mechanism of action of the digestive system under a magnifying glass, it is necessary to know which organs and which tissues we should examine.

The GI-tract, which begins in the esophagus and ends in the anus (i.e., esophagus, stomach, liver, gallbladder, pancreas, small-intestine, appendix, large intestine, rectum, and anus), has different tissues, biochemical and biophysical functions, and mechanisms [70]. Each of which must be examined separately and their functions considered together. After swallowing, food enters the stomach through the esophagus (passes through the muscular cuff) and by mechanical and chemical activity in the stomach, food enters the duodenum (beginning of the small intestine) entirely as a concentrated liquid containing digestive acids and enzymes (i.e., gastric juice) then, due to physical and chemical activities, the intestine is fully digested to provide the materials and compounds needed by the body. To make it easier, two important GI-tract organs (i.e., stomach and intestines), tissues, and their physical and chemical functions are summarized below [70, 71, 72]:

$$\begin{array}{l}\mathrm{Gaster}\\ \left\{\begin{array}{c}\mathbf{\text{Tissue}}=\left\{\begin{array}{c}\mathbf{\text{mucosa}}=\left\{\begin{array}{c}\mathbf{\text{gastric glands}}\\ \mathbf{\text{muscularis mucosae}}\end{array}\right.\\ \mathbf{\text{submucosa}}=\{\mathbf{\text{blood vessels}}\\ \mathbf{\text{muscularis}}=\left\{\begin{array}{c}\mathbf{\text{oblique muscle}}\\ \mathbf{\text{circular muscle}}\\ \mathbf{\text{longitudinal muscle}}\end{array}\right.\\ \mathbf{\text{serosa}}=\{\mathbf{\text{connective tissu layer}}\end{array}\right.\\ \mathbf{\text{physical function}}=\left\{\begin{array}{c}\mathbf{1}.\mathbf{\text{fundus}}=\mathbf{\text{fundus muscular}}=\mathbf{\text{increase gastric accommodation}}\\ \mathbf{2}.\mathbf{\text{corpus}}=\mathbf{\text{Peristaltic muscular}}=\mathbf{\text{contraction waves}}\\ \mathbf{3}.\mathbf{\text{antrum}}=\mathbf{\text{ring}}-\mathbf{\text{shaped muscular}}=\mathbf{\text{peristaltic food pump}}\end{array}\right.\\ \mathbf{\text{chemichal function}}=\left\{\begin{array}{c}\mathit{\text{Decomposition}}=\mathit{\text{reduces the size of food particles}}\\ \mathit{\text{Destruction}}=\mathit{\text{tenderize the food matrix}}\end{array}\right.\end{array}\right.\end{array}$$

$$\begin{array}{c}\mathrm{Intestine}\\ \left\{\begin{array}{c}\mathbf{\text{Tissue}}=\left\{\begin{array}{c}\mathbf{1}-\mathbf{\text{Mesentery}}\\ \mathbf{2}-\mathbf{\text{Vesseles}}=\left\{\begin{array}{c}\mathbf{\text{Vein}}\\ \mathbf{\text{Artery}}\\ \mathbf{\text{Nerve}}=\left\{\begin{array}{c}\mathbf{\text{Submucosal plexus}}\\ \mathbf{\text{Myenteric plexus}}\end{array}\right.\end{array}\right.\\ \mathbf{3}-\mathbf{\text{Muscularis}}=\left\{\begin{array}{c}\mathbf{\text{Circular muscle}}\\ \mathbf{\text{Longitudinal muscle}}\end{array}\right.\\ \mathbf{4}-\mathbf{\text{Serosa}}=\left\{\begin{array}{c}\mathbf{\text{Areolar connective tissue}}\\ \mathbf{\text{Epitheulium}}\end{array}\right.\\ \mathbf{5}-\mathbf{\text{Submucosa}}=\left\{\begin{array}{c}\mathbf{\text{Lymphatic tissue}}\\ \mathbf{\text{Glands}}\\ \mathbf{\text{Lumen}}\end{array}\right.\\ \mathbf{6}-\mathbf{\text{Mucosa}}=\left\{\begin{array}{c}\mathbf{\text{Epithelium}}\\ \mathbf{\text{Lamina propia}}\\ \mathbf{\text{Muscularis mucosae}}\end{array}\right.\end{array}\right.\\ \mathbf{\text{Physical function}}=\left\{\begin{array}{c}\frac{\mathbf{\text{Small intestine}}}{\left(\mathbf{\text{Ileum}},\mathbf{\text{Duodenu}},\mathbf{\text{jejunum}}\right)}=\left\{\begin{array}{c}\mathit{\text{Peristalsis}}\\ \mathit{\text{Segmentation}}\\ \mathit{\text{Absorption}}\end{array}\right.\\ \frac{\mathbf{\text{Large intestine}}}{\left(\mathit{\text{ascending}},\mathit{\text{descending and sigmoid colon}}\right)}=\left\{\begin{array}{c}\mathit{\text{Peristalsis}}\\ \mathit{\text{Segmentation}}\\ \mathit{\text{Absorption}}\end{array}\right.\end{array}\right.\\ \mathbf{\text{Chemichal function}}=\left\{\begin{array}{c}\mathbf{\text{Small intestine}}=\left\{\begin{array}{c}\mathbf{\text{Lipid Breackdown}}\left\{\begin{array}{c}\mathbf{\text{Pancreatic lipases}}\\ \mathbf{\text{Phospholipase}}\end{array}\right.\\ \mathbf{\text{protein Breakdown}}\left\{\begin{array}{c}\mathbf{\text{Trypsin}}\\ \mathbf{\text{Chymotrypsin}}\\ \mathbf{\text{Carbopeptidase}}\\ \mathbf{\text{Elastase}}\end{array}\right.\\ \mathbf{\text{Strach Breakdown}}\left\{\begin{array}{c}\mathbf{\text{Pancreatic amylase}}\\ \mathbf{\text{Dextrinase}}\\ \mathbf{\text{Sucrose}}\\ \mathbf{\text{Maltase}}\\ \mathbf{\text{Lactase}}\\ \mathbf{\text{Amyloglucosidase}}\end{array}\right.\\ \mathbf{\text{Nucleic Acid Breakdown}}\left\{\begin{array}{c}\mathbf{\text{Nucleases}}\\ \mathbf{\text{Nucleosidases}}\\ \mathbf{\text{Phosphatases}}\end{array}\right.\end{array}\right.\\ \mathbf{\text{Large intestine}}=\{\mathbf{\text{Fermentation}}=\mathbf{\text{fermentation products}}\end{array}\right.\end{array}\right.\end{array}$$

3.4 GI-tract immune system anatomy

The immune system can be defined as a complex system that protects the body against microorganisms, infectious agents, and a variety of autoimmune diseases and carcinogens, immune system can respond to any antigen in both specific and non-specific forms. The immune system function can also be seen in both innate and adaptive forms in all systems, infrastructures, and various cellular and molecular mechanisms to stop or eliminate invasive antigens [73].

Apart from the lymphoid cell, various organs and cells are also involved in intestinal immunity (i.e., goblet cells, entero-endocrine cells, macrophages, mast cells), these appropriate subsets of lymphoid cells are usually found in the epithelium (e.g., T suppressor) or in the lamina propria (e.g., T helper), IgA is also mostly produced by plasma cells [74]. The inductive sites are organized into specialized aggregations of lymphoid follicles called Peyer’s patches, are demonstrated as typical organized lymphatic structures of the intestine. They are present and found in large numbers from before birth to the senescence and also present in the ileum, duodenum, and jejunum [74, 75]. In superior vertebrates, such as mammalians, the immune system is made up of primary and secondary lymphatic organs that are organized in an almost identical morphology. The thymus and bone marrow are the major organs of the primary lymphatic system, and the spleen, lymph nodes, and mucosal- associate lymphoid tissue (MALT) are the secondary lymphatic system. Innate immunity is found in all living things and can detect protected and common molecular structures in pathogens and microorganisms. These include the identification of polysaccharides, lipopolysaccharides (LPS), peptidoglycans, bacterial and viral DNA and RNA through the interaction of specific receptors (e.g., toll-like receptor TLR) [73].

The GI-tract has the largest volume of microbes in the human body, maintaining an elegant balance between immunity against pathogens and tolerance toward commensal microbiome, such as immune balance, or intestinal homeostasis, is accomplished by fine-tuning and cooperating with various branches of the immune system, including the innate and adaptive immune system [76]. The gastrointestinal mucosa separates the digestive fluid inside the duct, which contains a large number of antigens from various sources, and prevents the antigens from freely reaching the body, it also allows for some vital host and peripheral intestinal interactions. The mucosal immunity is related to secretory IgA; The IgA is derived from mucosal plasma cells after the proliferation of its precursors in antigen-induced Peyer patches. In fact, IgA is transported to the intestinal tract after binding to the secretory component (SC) as a dimer. However, the induction of local immunity and intestinal systemic tolerance may be a specific immune response to the gut-associated lymphoid tissue (GALT) [77].

Therefore, the immune system can deal with any pathogen in different conditions, depending on the location, amount and type of damage, and all this is due to the chemical structures at the cellular and molecular levels of organisms. Chemical structures help identify the invasive agent and the type of response to them. These structures, which are generally proteins, are produced and secreted by epithelial, endothelial, dendritic cells (DCs), and lymph nodes and are commonly known as cytokines [73].

In total, the number of proteins that have cytokine activity reaches more than 200, their secretion depends on the effective concentrations of cytokines that are created in the vicinity of target cells [78]. Cytokines are involved in the interaction of lymph cells, hematopoietic cells, and inflammatory cells. They are usually having a short half-life but the network of cytokine activity is such that it communicates between all cells and factors involved in the immune system. Also, the inflammatory responses, regulation of hematopoiesis, proliferation control, and cellular differentiation are different biological responses that can induce by cytokines [11, 79].

Cytokines are a general name for a complex of proteins that are involved in our immunity in the form of structural molecules. This complex including of lymphokine (cytokines produced by lymphocytes), chemokines (cytokines with chemical activity), interleukins (cytokines produced by leukocytes that affect other leukocytes), and monokine (cytokines produced by monocytes). All of these cytokines can work together and can even counteract the effects of each other. Also, cytokines stimulate B- and T-cell-dependent responses. In the immune system, T-cells respond well to the activation of B-cells in response to antigens, the proliferation and the activation of eosinophils, neutrophils, and basophils by cytokines. The cytokines act by binding to specific receptors on the target cell membrane. So far, four types of receptor proteins for cytokines have been identified that are classified into five families including immunoglobulin receptors, class I cytokine receptors (hematopoietins), class II cytokine receptors (interferons), TNF receptors, and chemokine family receptors [11, 12].

As mentioned earlier, the gut contains the largest immune system and intestinal mucus is considered as the primary site of interaction with common and pathogenic organisms. The innate immune system acts to restrict the passage of microbiota through the mucosal barrier, so intestinal epithelial cells, in coordination with antigen-presenting cells (APCs), form the first line of defense in the intestine. Cytokine binding to the T-cell receptor promotes T-cell expansion or expression of distinct Th subsets or to regulatory T cells (Tregs). Th1 cells produce proinflammatory cytokines, including IFN-γ and TNF-α, which are important for cell-mediated immunity against most bacteria. In contrast, Th2 cells produce anti-inflammatory cytokines, including IL-4 and IL-13, which are critical for humoral mediated immunity against extracellular pathogens. Cytokines bind to cell surface receptors in immune and non-immune cells, activating the JAK–STAT signaling pathway and positively regulating intestinal function by regulating the expression of specific target genes [80].

4. GI-tract signaling pathway

The gut-brain axis (GBA) is a two-way communication between the CNS and the intestines that connects the emotional and cognitive centers of the brain to the functions of the peripheral intestine. The interaction between the microbiota and the GBA is two-way, meaning that they can communicate with each other through signaling from the gut microbiota to the brain and from the brain to the gut microbiota using neural, endocrine, immune, and humoral connections. This communication from brain to gut includes the CNS, autonomic nervous system (ANS), enteric nervous system (ENS), hypothalamic–pituitary–adrenal (HPA) axis, and vice versa from gut to brain pathway including the ascending pain pathways, cytokines (e.g. TNF-α, IL) and entero-endocrine cells (e.g. serotonin) [81, 82].

Evidence suggests that gut microorganisms can stimulate the vagus nerve and play an important role in mediating effects on the brain and behavior. The vagus nerves distinguish between non-pathogenic and potentially pathogenic bacteria, and can even mediate signals in the absence of overt inflammation and vagal pathways that, depending on the nature of the stimulus, can induce anxiolytic and anti-anxiety effects. By interacting with immune cells, mediators are released that reduce inflammation. This role of modulating vagal nerve immunity has consequences for modulating brain function and even a variety of moods [83]. Also, the response to HPA with the initial modification of the gastrointestinal flora, and the effects of the initial stress on the barrier function of the GI-tract and the flora, demonstrates the ability of both systems to prepare each other for future problems [82].

All responses to food stimuli occur in the small intestine and also, especially the colon. The colon is an essential part of the GI-tract and acts as a filter and facilitates the absorption of nutrients from food, water, electrolytes, and vitamins through the intestinal tract. Within these, “macro” environments are several “micro” environments where bacteria can live, such as the lumen of the bowel, the mucus layer overlying the epithelium, mucus within intestinal crypts, and the surface of mucosal epithelial cells. The intestinal epithelial cells (IECs) produce multiple tubular injections that form crypts that increase tissue uptake levels. In the crypt domain, the intestinal stem cell (ISC) niche enables continuous regeneration of the intestinal lining (e.g., enterocytes, neuroendocrine cells, tuft cells, Paneth cells, M cells, and goblet cells), IECs can proliferate, differentiate, and move upward (mucus) until they are replaced in the human colon five to seven days later. IECs also communicate with microbiota, coordinate innate and adaptive effector cell functions. The IECs form a continuous epithelium of cells that are tightly linked by different types of cell–cell junctions that assist in maintaining the integrity of the barrier [84, 85].

The RAS superfamily of small GTPase including RAS, Rho/Rac, Arf, and Rab subfamilies are critical regulators of intestinal epithelial homeostasis and barrier function. At the molecular level, RAS proteins cycle between an inactive state, where they are bound to guanosine diphosphate (GDP), and an active STAT, bound to guanosine triphosphate (GTP) [84].

To better understand the signaling pathways from gut to brain and brain to gut, we need to examine these signaling pathways in two structures (prokaryote, eukaryote), Since intestinal bacteria are the most active in terms of communication, in this section, the focus will be on bacteria, which we will discuss below:

4.1 GI-tract prokaryotes signaling

Bacteria constantly monitor and interpret the conditions inside their cells and their environment to maintain their survival to be able to adjust and provide appropriate responses to the environmental changes around them. Therefore, they use a variety of small molecules for extracellular and intracellular signaling. Hence, these bacterial signals, which are seen in both intracellular and extracellular forms, play an important role in creating or responding to environmental changes in establishing communication between bacteria with other members of their community or other living bacteria that share environmental conditions [86]. Bacterial signaling systems located on their cell membranes are complex and is recognized in three major types (i.e. one-component system, two-component system, extra-cytoplasmic sigma factors), they can also communicate with each other and transmit functional signals as a cell-to-cell signaling mechanism called Quorum Sensing(QS) [85, 87].

The adaptive responses to peripheral signals are mainly generated by transcriptional regulators through two systems, one-component, and two-component signal transmission systems. These systems scan small molecular proteins inside and outside the cell and modulate gene expression to provide the appropriate physiological response to the prevailing conditions [88].

One-component signaling systems include members of the ToxR family and they do not contain a phosphoryl acceptor domain, therefore, representing the simplest form of bacterial transmembrane signaling systems. In two-component systems, integrated membrane histidine kinase generally acts as a sensor for various stimuli and is also responsible for transmitting information across the membrane. The number of systems regulating the histidine kinase reaction varies widely between bacterial species. But the signaling system of the ECF sigma factors is small regulatory proteins that bind to RNA polymerase and stimulate transcription of specific genes. Many bacteria, particularly those with more complex genomes, contain multiple ECF sigma factors, and these regulators often outnumber all other types of sigma factors [87].

Quorum Sensing (QS) may be used as a system for bacteria to prevent the population from growing to levels that are unsustainable in their environment. If all the nutrients are depleted and waste products are not removed from their environment, it will be deleterious for the community as a whole. In fact, QS is used to determine the fitness of a bacterial population. The QS is found in three major forms in bacteria: one is used primarily by gram-negative bacteria, one is used primarily by gram-positive bacteria, and one has been proposed to be universal. The paradigm for QS in gram-negative bacteria is the LuxIR system. The LuxIR system uses the LuxI protein, or a homolog of this protein, to synthesize an autoinducer (AIs) and LuxR (or a homolog of LuxR) as a regulator that binds to the AIs and modulates gene expression. The QS system used by gram-positive bacteria utilizes peptides as AIs signaling molecules. These autoinducing polypeptides (AIPs) are produced in the cytoplasm as precursor peptides and then cleaved, modified, and exported. The extracellular AIPs are detected via two-component systems in which the external portion of a membrane-bound sensor kinase protein detects the AIP and then phosphorylates and activates a response regulator that binds to DNA and modulates transcription. And the third QS system present in bacteria is found in a wide numbers of bacteria, including both gram-negative and gram-positive species. This system, called the LuxS or autoinducer-2 (AI-2) system, has been detected in more than 55 species by sequence analysis or functional assays. This system is called LuxS/AI-2 system, which is effective in communication between bacterial species [85].

4.2 GI-tract eukaryote cell signaling

The first gut signaling system is related to cell regulation. As mentioned earlier, the RAS superfamily is critical regulator of intestinal epithelial homeostasis and barrier function cells, the RAS superfamily has nine main effectors for several pathways which are briefly described below:

$$\mathrm{RAS.GTP}\stackrel{\mathbf{\text{Effectors}}}{\Rightarrow }\left\{\begin{array}{l}\mathbf{PIK}\mathbf{3}\mathbf{C}\mathbf{2}\mathbf{A}=\mathbf{\text{Pathway}}\left\{\begin{array}{c}\mathbf{PIP}\mathbf{3}\\ \mathbf{AKT}\\ \mathbf{BAD}\\ \mathbf{P}\mathbf{53}\\ \mathbf{\text{NFkB}}\\ \mathbf{\text{mTORC}}\mathbf{1}\end{array}\right.\\ ⟨\mathbf{RGL}\mathbf{2}|\mathbf{\text{RALGDS}}|\mathbf{RGL}\mathbf{1}⟩=\mathbf{\text{Pathway}}\left\{\begin{array}{c}\mathbf{Ral}\\ \mathbf{PLD}\\ \mathbf{Sec}\mathbf{5}\\ \mathbf{\text{RalPBP}}\\ \mathbf{Arf}\mathbf{6}\end{array}\right.\\ ⟨\mathbf{\text{RASSF}}\mathbf{5}|\mathbf{\text{RASSF}}\mathbf{2}|\mathbf{\text{RASSF}}\mathbf{4}⟩=\mathbf{\text{Pathway}}\left\{\begin{array}{c}\mathbf{MST}\mathbf{1}\\ \mathbf{MST}\mathbf{2}\\ \mathbf{\text{LATS}}\end{array}\right.\\ ⟨\mathbf{\text{ARAF}}|\mathbf{\text{BRAF}}|\mathbf{RAF}\mathbf{1}⟩=\mathbf{\text{Pathway}}\left\{\begin{array}{c}\mathbf{MEK}\\ \mathbf{ERK}\\ \mathbf{ETS}\end{array}\right.\\ \mathbf{ARP}\mathbf{1}=\mathbf{\text{pathway}}\left\{\begin{array}{c}\mathbf{RAC}\\ \mathbf{PAC}\\ \mathbf{RHO}\end{array}\right.\\ ⟨\mathbf{RIN}\mathbf{2}|\mathbf{SNX}\mathbf{27}⟩=\mathbf{\text{Pathway}}\left\{\begin{array}{c}\mathbf{ABL}\\ \mathbf{RAB}\mathbf{4}\\ \mathbf{RAB}\mathbf{5}\end{array}\right.\\ \mathbf{\text{MLLT}}\mathbf{4}=\mathbf{\text{Pathway}}\left\{\begin{array}{c}\mathbf{\text{Actin}}\\ \mathbf{\text{Nectin}}\\ \mathbf{\text{Cadherin}}\end{array}\right.\\ ⟨\mathbf{\text{RAPGEF}}\mathbf{5}|\mathbf{\text{RASIP}}\mathbf{1}⟩=\mathbf{\text{Pathway}}\left\{\begin{array}{c}\mathbf{RAP}\\ \mathbf{\text{Signaling}}/\mathbf{\text{adhesion}}\end{array}\right.\\ \mathbf{MYO}\mathbf{9}\mathbf{B}=\mathbf{\text{Pathway}}\{\mathbf{\text{Myosin}}/\mathbf{\text{actin adhesion}}\end{array}\right.$$

All the effector pathways had responses and effects on colon physiology (e.g., actin or nectin and cadherin or RAP, signaling/adhesion can respond to cell–cell junctions).

RalGDS effector and the activation of Ral GTPases are critical for the regeneration of intestinal stem cells, and also the RASSF-MST-LATS pathway coordinates intestinal regeneration through cell proliferation, apoptosis, and differentiation functions. AFDN is involved in the formation of cell–cell junctions and thereby controls adhesion between different IECs [84].

The second gut signaling system is related to immune regulation, which is regulated by cytokines. As mentioned earlier the cytokine can be present in many tissue or cells as regulator immune molecules, they are essential mediators of the interactions between activated immune cells and non-immune cells, including epithelial and mesenchymal cells [89]. So, the cytokines regulate the intensity and duration of the immune response by stimulating or inhibiting proliferation, differentiation, trafficking, or emigration of lymphocytes all the while acting as a messenger for both the arms of the immune system [90]. Cytokine production by Peyer’s patch (PP) cells was examined in response to probiotic and pathogenic bacteria, some probiotics bacteria (e.g., Lacticaseibacillus casei) have the ability to induced (e.g. IL-6, IL-8, IL-12) or reduced (e.g. Th1 cells by IFN-γ secretion in PP cells) other cytokines as well [91].

The third gut signaling system is related to hormones. The gut hormones (e.g., cholecystokinin and glucagon-like peptide-1) released following a meal and act on local receptors to regulate glycemia via a neuronal gut-brain axis and provide feedback via nutrient sensing and local hormonal signaling. The small intestine contains a variety of regulatory signals including:

1. Proximal hormones within the duodenum and jejunum, cholecystokinin (CCK) in I cells, and glucose-dependent insulinotropic polypeptide (GIP) in K cells.

2. Distal hormones in the ileum and large intestine within L cells, glucagon-like peptide-1/2 (GLP-1/2), oxyntomodulin (OXN), and peptide YY (PYY).

The secretion of these hormones is stimulated by nutrients within the intestine that then act on their respective receptors either centrally, or locally on vagal afferents that are in close proximity to enteroendocrine cells, to regulate metabolic homeostasis through various changes in food intake, gastric emptying, intestinal motility, and/or energy expenditure [92].

5. Interaction and regulation between microbiota and the CNS and immune system

The human immune system has evolved to maintain a symbiotic relationship between the host and the microbiota, and disruption of the dynamic immune-microbial interaction leads to profound effects on human health (e.g., interaction between resident microbiota and immune signals, CNS development) as described in below [94].

5.1 Inflammasome signaling pathway

Inflammasome is an innate immune signaling complex, which is activated in response to diverse microbial and endogenous danger signals. Also, the various pattern-recognition receptors (PRRs) in different families, including NLRP1, NLRC3, NLRP6, NLRP7, NLRC4, and AIM2, have been identified to effect in inflammasome activity. Inflammasomes activation recruits ACS (apoptosis-associated speck-like protein containing a caspase recruitment domain) and the cysteine protease caspase 1 through caspase activation and recruitment domain (CARD) to induce the proteolytic cleavage of pro-caspase1 to generate mature and active caspase 1, which further process pro-IL-1β and pro-IL-18 to the final production of bioactive IL-1β and IL-18 proteins [93].

5.2 IFN-I signaling pathway

IFN-I is a pleiotropic and ubiquitous cytokine that plays an essential role in both innate and adaptive immunity and maintenance of host homeostasis. IFN-I is induced by pathogen-associated molecular patterns (PAMPs). Secretion of endogenous IFN-I depends on activation of several classes of PRRs. They play a significant role in priming the host to various viral, bacterial, or tumor components. Effects of IFN-I on inflammation and host hemostasis have been linked to the recruitment of Tregs. Also, the commensal lactic acid bacteria have been shown to trigger TLR3-mediated IFN-β secretion by DCs in the intestine [93].

5.3 NF-κB signaling pathway

The interaction between microbiota and NF-κB signaling is also responsible for CNS inflammation. NF-κB family of transcription factors contribute to both innate and adaptive immune responses and maintenance of the immune system. So, the NF-κB family of transcription factors contribute to both innate and adaptive immune responses and maintenance of the immune system [93].

6. Conclusion

In summary, the gut microbiome binds to intestinal epithelial cells and uses cell signaling and junctions to communicate with each other and with the host CNS. A complex diverse of microorganisms live in the GI-tract which is called gut microbiome, profoundly affect many aspects of host physiology, including nutrient metabolism, infection resistance, and immune system development. The GI-tract is strongly innervated by a complex network of neurons that coordinate vital physiological functions. In addition to CNS; ENS senses and response to the dynamic ecosystem of the GI-tract by converting chemical signals from the environment into nerve impulses that propagate throughout the intestine and other organs of the body, also the local axonal reflexes and autonomic long-range sensory reflexes in GI-tract play an important role in the regulation of immunity by parasympathetic or sympathetic nerves. As a result, the interactions between the nervous system and the immune system enable the gut to respond to the variety of food products it absorbs, and the wide variety of pathogens and microbiomes it holds. Gut microbiota can promote different subsets of immune cells through antigen stimulation and activation of immune signaling pathways. All the interactions that the gut microbiome creates reflect both on our mental states and in our immune system, and vice versa.

We can say that we and our gut microbes talk to each other through these signal pathways, solve each other’s needs, and ensure each other’s safety.