**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. onecomponent system, two-component system, extra-cytoplasmic sigma factors), they

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

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 gramnegative 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 membranebound 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:

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].

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

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:


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].
