Maintenance of intestinal homeostasis by mucosal barriers

Abstract

Background: The intestine is inhabited by a tremendous number of microorganisms, which provide many benefits to nutrition, metabolism and immunity. Mucosal barriers by intestinal epithelial cells make it possible to maintain the symbiotic relationship between the gut microbiota and the host by separating them. Recent evidence indicates that mucosal barrier dysfunction contributes to the development of inflammatory bowel disease (IBD). In this review, we focus on the mechanisms by which mucosal barriers maintain gut homeostasis.

Main text: Gut mucosal barriers are classified into chemical and physical barriers. Chemical barriers, including antimicrobial peptides (AMPs), are chemical agents that attack invading microorganisms, and physical barriers, including the mucus layer and the cell junction, are walls that physically repel invading microorganisms. These barriers, which are ingeniously modulated by gut microbiota and host immune cells, spatially segregate gut microbiota and the host immunity to avoid unnecessary immune responses to gut commensal microbes. Therefore, mucosal barrier dysfunction allows gut bacteria to invade gut mucosa, inducing excessive immune responses of the host immune cells, which result in intestinal inflammation.

Conclusion: Gut mucosal barriers constructed by intestinal epithelial cells maintain gut homeostasis by segregating gut microbiota and host immune cells. Impaired mucosal barrier function contributes to the development of IBD. However, the mechanism by which the mucosal barrier is regulated by gut microbiota remains unclear. Thus, it should be further elucidated in the future to develop a novel therapeutic approach to IBD by targeting the mucosal barrier.

Keywords: Gut microbiota; Inflammatory bowel disease; Intestinal epithelial cells; Mucosal barrier.

Fig. 1

Mucosal barriers in the gut. Chemical barriers including AMPs and Reg3γ secreted by Paneth cells mainly contribute to the separation between intestinal bacteria and IECs in the small intestine. By contrast, in the large intestine where a tremendous number of bacteria exist, intestinal bacteria and IECs are largely segregated by physical barriers such as the inner mucus layer composed of polymerized MUC2 mucin. Lypd8, a highly glycosylated GPI-anchored protein expressed on IECs, inhibits the bacterial invasion of the inner mucus layer by binding to intestinal bacteria, especially flagellated bacteria. AMP: antimicrobial peptide

Fig. 2

Regulation of mucosal barrier functions by gut microbes and host immune cells. Mucosal barrier function is modulated by gut microbes and host immune cells. SFB colonization or C. rodentium infection promotes the induction of helper T cells producing IL-17 and simulates ILC3 to secrete IL-22. Both cytokines enhance the production of antimicrobials such as AMPs and Reg3γ from IECs. In the case of parasite infection, activated tuft cells produce IL-25, which stimulates ILC2 to secrete IL-13. IL-13 promotes the proliferation of goblet cells and mucus production from them. Metabolites from gut microbes also directly influence the mucosal barrier function of IECs. SCFA promotes mucus production from goblet cells, and indole upregulates the expression of cell junction-related molecules through PXR activation SFB: segmented filamentous bacteria, SAA: serum amyloid A, ILC: innate lymphoid cell, TLR: Toll-like receptor, NOD2: nucleotide-binding oligomerization domain-containing 2, AMP: antimicrobial peptide, IEC: intestinal epithelial cell, SCFA: short-chain fatty acid, PXR: Pregnane X receptor.

Fig. 3

The imbalance between mucosal barriers and gut microbes promotes susceptibility to intestinal inflammation. In the steady state, intestinal bacteria and mucosal barriers maintain a well-balanced relationship, and thus intestinal bacteria and IECs are clearly segregated in the gut. However, dysfunction of mucosal barriers including decreased production of mucin or AMPs due to genetic factors and dysbiosis induced by environmental factors such as high-fat diet or various antibiotics disrupt the well-balanced relationship, and thereby intestinal bacteria can gain access to the gut immune cells, leading to the progression of IBD. IBD: inflammatory bowel disease