The Enteric Nervous System and the Microenvironment of the Gut: The Translational Aspects of the Microbiome-Gut-Brain Axis  
[PERSON]  
1 Department of Anatomy, Histology and Embryology, Semmelweis University, Tuzolto St. 58, 1094 Budapest, Hungary; [EMAIL_ADDRESS] (F.M. );  
IECs have a role in the pro-inflammatory pathway, providing chemical protection by producing antimicrobials, cytokines, and IgA [5] (Figure 1). Figure 1: (**1**) M-cells in the vicinity of [PERSON]’s patches sample the luminal microbes via transcytosis. (**2**) Goblet cells deliver antigens to the subepithelial space. (**3**) Lamina propria mucosae macrophages (MP\({}_{\text{LM}}\)-s) grow transepithelial dendrites (TED) to phagocytose the antigens of the luminal microbial flora directly. (**4**) MP\({}_{\text{LM}}\)-s pass on their antigens to CD103\({}^{+}\) lamina propria mucosae dendritic cells (DC\({}_{\text{LM}}\)) through connexin-43-dependent gap junctions. (**5**) DC\({}_{\text{LM}}\)-s migrate to the  
nearest lymph node. (**6**) Naive TCs differentiate to T\({}_{\text{reg}}\) cells. (**7**) T\({}_{\text{reg}}\) cells migrate to the mucosa where they produce anti-inflammatory interleukin 10 (IL-10). (**8**) T\({}_{\text{reg}}\) cells induce the IL-10 production of MP\({}_{\text{LM}}\) cell. (**9**) Naive TCs differentiate into T\({}_{\text{h17}}\) cells. (**10**) T\({}_{\text{h17}}\) cells migrate to the mucosa and produce IL-17 (IL-17A, IL-17F) which recruit further neutrophil granulocytes and ILC3 cells. (**11**) T\({}_{\text{h17}}\) cells also produce IL-22 which induces IECs to produce antimicrobial peptides (RegIII-\(\beta\) and RegIII-\(\gamma\)) and IgA. (**12**) B\({}_{\text{reg}}\) cells fine-tune the quantities of T\({}_{\text{reg}}\) and T\({}_{\text{h17}}\) cells. (**13**) MP\({}_{\text{SM}}\): submucosal macrophage. (**14**) MP\({}_{\text{My}}\): hypernteric macrophage. (**15**) MP\({}_{\text{M}}\): muscular macrophage. (**16**) MP\({}_{\text{IG}}\): intraganglionic macrophage. _Created with BioRender_. Subepitheilally, in the _lamina propria mucose_ (LM), reside the mononuclear population of lamina propria macrophages (MP\({}_{\text{LM}}\)-s) and lamina propria dendritic cells (DC\({}_{\text{LM}}\)-s), ordained to phagocytose antigens from the subepitheilal space by growing transepithelial dendrites (TEDs) to sample the antigens of the luminal microbial flora [6]. TEDs do not compromise the integrity of the epithelial barrier, as they keep the adhesive structures of IECs intact (Figure 1, (3)). MP\({}_{\text{LM}}\)-s pass on their antigens to CD103\({}^{+}\) DC\({}_{\text{LM}}\)-s through connexin-43-dependent gap junctions [7; 8] (Figure 1, (4)). Once equipped with antigens, CD103\({}^{+}\) DC\({}_{\text{LM}}\)-s migrate to the nearest lymph node, where they activate naive TCs with TGF-\(\beta\) and retinoic acid [9] (Figure 1, (5)). By presenting their antigens to TCs, handing over the response to the adaptive immune system, DC\({}_{\text{LM}}\)-s delimit their role to a continuous'surveillance' [10]. When friendly antigens (food or commensal microbiota) prime naive TCs, those differentiate to CD4\({}^{+}\)CD25\({}^{+}\)Foxp3\({}^{+}\) T\({}_{\text{reg}}\) cells [9] (Figure 1, (6)). T\({}_{\text{reg}}\) cells migrate to the LM where they produce anti-inflammatory interleukin 10 (IL-10) and induce the IL-10 production of MP\({}_{\text{LM}}\) cells as well (Figure 1, (7),(8)). IL-10 leads to the expansion of T\({}_{\text{reg}}\) cells, as a self-reinforcing effect, while T\({}_{\text{reg}}\) cells also inhibit effector TCs [5]. The latter phenomenon is called 'oral tolerance', an active immunosuppressive process. The presence of commensal flora in the gut is essential in developing oral tolerance. This is underpinned by the fact that, in germ-free animals, the host becomes susceptible to food allergies [11]. Moreover, certain kinds of intestinal bacteria (e.g., _Clostridia_ spp.) increase oral tolerance by priming TCs towards T\({}_{\text{reg}}\) phenotype [12; 13].