Intestinal Flora and Disease Mutually Shape the Regional Immune System in the Intestinal Tract

Abstract

The intestinal tract is the largest digestive organ in the human body. It is colonized by, and consistently exposed to, a myriad of microorganisms, including bifidobacteria, lactobacillus, Escherichia coli, enterococcus, clostridium perfringens, and pseudomonas. To protect the body from potential pathogens, the intestinal tract has evolved regional immune characteristics. These characteristics are defined by its unique structure, function, and microenvironment, which differ drastically from those of the common central and peripheral immune organs. The intestinal microenvironment created by the intestinal flora and its products significantly affects the immune function of the region. In turn, specific diseases regulate and influence the composition of the intestinal flora. A constant interplay occurs between the intestinal flora and immune system. Further, the intestinal microenvironment can be reconstructed by probiotic use or microbiota transplantation, functioning to recalibrate the immune homeostasis, while also contributing to the treatment or amelioration of diseases. In this review, we summarize the relationship between the intestinal flora and the occurrence and development of diseases as an in-turn effect on intestinal immunity. We also discuss improved immune function as it relates to non-specific and specific immunity. Further, we discuss the proliferation, differentiation and secretion of immune cells, within the intestinal region following remodeling of the microenvironment as a means to ameliorate and treat diseases. Finally, we suggest strategies for improved utilization of intestinal flora.

Keywords: fecal microbiota transplantation; intestinal flora; intestinal tract; probiotic; regional immune system.

Figure 1

Intestinal flora affects the development of the regional immune system. Many factors affect the structure and development of the regional immune system by affecting the type and quantity of intestinal flora. Cesarean section, formula-feeding and the use of antibiotics after birth may lead to abnormally colonized intestines compared with fetuses delivered vaginally and breast fed. In a healthy normal intestinal tract with abundant microbial flora, the isolated lymphoid follicles and Peyer's patches in the intestine are unchanged. Upon stimulation, antigen-presenting cells migrate to the mesenteric lymph node and promote differentiation of T cells. IgA-producing plasma cells secrete IgA and perform a mucosal protective function; while macrophages migrate to the lamina propria of the intestinal tract and perform their normal function. When the species abundance and diversity of intestinal flora are relatively low, the intestinal immune system does not become appropriately stimulated and only isolated lymphoid follicles are formed.

Figure 2

Mechanism of Th17 activation of the regional immune system in the intestinal tract. Th17 cells play an important role in the activation of the regional immune system induced by the intestinal flora. Bacteria and their products are recognized by receptors expressed on the surface of various immune cells by direct adhesion or translocation to the lamina propria, thereby inducing various cytokines and chemokines, and activating the intestinal mucosal immune system. Molecules recognized by TLR receptors promote the secretion of cytokines, hence promoting the differentiation of Th17 cells. Th17 cells secrete cytokines to promote the activation of inflammatory pathways in immune cells and recruit macrophages.

Figure 3

Intestinal flora and metabolites interact with the regional immune system in the intestinal tract. PRRs such as NOD1, TLRs expressed on the intestinal mucosal epithelium, recognize PAMPs and SCFAs of the intestinal flora, thereby activating inflammatory pathways and the production of inflammatory cytokines. This induces the differentiation of myeloid cells, recruitment of macrophages and neutrophils, and so on, elicits an inflammatory response, and activates the regional immune system. The interaction also promotes the expression of inflammatory factors. In addition, the intestinal flora also induces the production of cytokines in the intestinal mucosal epithelium through TLRs.

Figure 4

The interactions among intestinal flora, regional immune system, disease, and treatment. The structure and function of intestinal microorganisms have a duo-impact on disease by affecting the immune system in the intestinal region. In the digestive system, Fusobacterium nucleatum induces the production of cytokines IL-10 and IFN-γ, and the differentiation of macrophages to aggravate the progress of ulcerative colitis. In the nervous system, the increase of Deltaproteobacteria abundance and decrease in Rhodocyclales abundance affect the intestinal microenvironment, and subsequently affect the course of schizophrenia via the “gut–brain” axis. In metabolic diseases, B. fragilis aggravates the development of type 1 diabetes by changing the expression of cytokines. In addition, the intestinal microenvironment can be reconstructed by probiotics or microbiota transplantation, with typically occurring organisms reconstituted via fecal microbiota transplantation, so as to recalibrate immune homeostasis in the intestinal region, and contribute to the treatment and amelioration of disease.