**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 [6–8].

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].
