*3.2.1 ANS modulation of the gut microbial environment*

Impaired intestinal transit caused by compromised migratory motor complexes (under parasympathetic modulation) is associated with an increased microbial colonization in the small intestine [5, 35–37]. The frequency of regular migrating motor complex is influenced by the number of feeds, quality of sleep and stress. Acute stress is associated with increased parasympathetic output to the small and large intestine and decreased vagal output to the stomach [38]. ANS affects the mechanisms of immune activation at the level of intestinal epithelium. This process could be influenced trough modulation of the intestinal immune cells such as macrophages and mast cells against gut luminal microbes through antimicrobial peptides or indirectly via changing the access of gut microbiota to the intestinal immune cells [1, 39]. This process could be influenced trough modulation of the intestinal immune cells such as macrophages and mast cells against gut luminal microbes through antimicrobial peptides or indirectly via changing the access of gut microbiota to the intestinal immune cells.

Preclinical studies proved that increased permeability of intestinal epithelium after exposure to different stressors is result of easier translocation of gut microbiota followed by driving of immune response [1, 40, 41].

## *3.2.2 Effects of host's signal molecules on the function of the intestinal microbiota*

Neuronal and neuroendocrine signaling molecules as catecholamines, serotonin, cytokines, GABA, dinorphine, etc. dispersed into the gut lumen through neurons, immune and enterochromaffin cells can also play a role in the modification of intestinal environment [1, 8, 42], probably regulated by the CNS [43]. Many stress factors result to increasing of both plasma and luminal gut levels of catecholamines as norepinephrine [8, 44]. In vitro experiments indicated that some pathogen microbes could change their proliferative ability after exposition to exogenous catecholamines. Norepinephrine may accelerate the proliferation of several strains of intestinal pathogenic microorganisms and could increase the virulence of *Campylobacter jejuni* [1, 45, 46].

#### *3.2.3 Microbe-to-host signaling by microbial signaling molecules*

Metabolites produced by intestinal microbiota, including short chain fatty acids (SCFAs), bile acid metabolites and neuroactive agents such as GABA, tryptophan precursors and metabolites, serotonin and catecholamines, including free metabolites and cytokines released during the immune response to microbes may deliver

the signal to the host via local cell receptors in the intestine [37, 47]. These factors can also give signals via neurokines through afferent vagal and spinal pathways and endocrine mechanisms to target non-GI tracts, including vagal afferents in the portal vein and receptors in the brain. A significant part of the metabolites identified in the circulation are with intestinal microbial origin [48, 49]. The enteroendocrine cells, as well as the neurons forming the submucosal and myenteric ganglia, express different types of SCFA receptors [50] A diet that includes *Bifidobacterium breve* leads to elevated levels of fatty acids in the brain, but unfortunately there is not a clear explanation for that mechanism [1].

Actual studies confirm that multiple nuclear receptors (NRs) are expressed in the GI tract and several microbe-produced metabolites act as ligands of NRs. Intestinal bacteria secrete metabolites including indole derivatives, hormones and secondary BAs, which play role of natural ligands for the host's NRs [51]. In this way the microbial metabolites can realize biological effects in the human body via regulation of the host's gene expression. These dynamic interactions permit overall control on the health or disease development in the host through direct effect of the microbiota on the human physiology [11]. Via signaling to the brain, the microbiota regulates metabolism, CNS development, inflammation as well as mood and behavior. It is essential that the human host has the ability to voluntarily influence and meliorate its own microbiota through nutritional or probiotic interventions [52].

Latest research found that, in the presence of the microbiota, the intestinal epithelial lining generates physiological levels of oxidative stress. On the other hand, these interfere both with the composition and functionality of the microbiota (e.g., anaerobes thrive in the presence of electron acceptors) and directly with the gut permeability. This lead to increased probability of xenobiotic molecules to reach the systemic circulation as well as the CNS [53].

Another well-known interaction between the microbiota and CNS involves astrocytes. Astrocytes represent a functionally diverse group of glial cells, which are responsible for ion homeostasis, neurotransmitter balance, storage of glycogen, the integrity of the blood brain barrier (BBB), realizing of the neuronal signaling, which play a main role in the neuroinflammation process [54]. The inflammation could be suppressed by modulation of type I interferon signaling in astrocytes, initiated by microbial metabolite products, which activate the aryl hydrocarbon receptors (AhRs), The indoles, released from gut microbiota, act as AhR agonists [55]. The dietary tryptophan in intestinal cavity, which is undigested, is transformed into indole in the presence of the microbial enzyme tryptophanase. Then the indoles could be modified through microbial or viler enzymes to indole derivate with various affinity [10, 56].
