Slimy partners: the mucus barrier and gut microbiome in ulcerative colitis

Abstract

Ulcerative colitis (UC) is a chronic recurrent intestinal inflammatory disease characterized by high incidence and young onset age. Recently, there have been some interesting findings in the pathogenesis of UC. The mucus barrier, which is composed of a mucin complex rich in O-glycosylation, not only provides nutrients and habitat for intestinal microbes but also orchestrates the taming of germs. In turn, the gut microbiota modulates the production and secretion of mucins and stratification of the mucus layers. Active bidirectional communication between the microbiota and its 'slimy' partner, the mucus barrier, seems to be a continually performed concerto, maintaining homeostasis of the gut ecological microenvironment. Any abnormalities may induce a disorder in the gut community, thereby causing inflammatory damage. Our review mainly focuses on the complicated communication between the mucus barrier and gut microbiome to explore a promising new avenue for UC therapy.

Fig. 1. The gut microbiome acts as orchestrator of the mucus barrier.

a During homeostasis, the gut microbiome at the outer mucus layer modulates mucin production and secretion and mucus stratification mediated by HCO₃⁻ to maintain mucus barrier integrity. Dysbiosis induces impairment of the mucus barrier, accompanied by increased epithelium damage, bacterial translocation, goblet cell depletion, and host inflammation. b Gut microbiome-generated short-chain fatty acids enter colonocytes and are oxidized to generate CO₂ that can be converted by carbonic anhydrase into HCO₃⁻, which is the ideal physiological solution for precipitating calcium and raising the pH at the epithelial surface. This in turn promotes the stratification of the mucus layer. c Intestinal bacteria have evolved several strategies to adhere to the mucus barrier, including the use of adhesins, flagella, and fimbriae; achieve cross-feeding by mucin degradation; and maintain colonization resistance by means of a commensal type VI secretion system.

Fig. 2. The mucus barrier functions to modulate bacterial colonization.

a The mucus barrier forms a fundamental niche for gut microbiome colonization, where the major O-glycan epitopes are sialic acid, fucose, N-acetylneuraminic acid (Neu5Ac), type A antigen [GalNAcα1,3(Fucα1,2)Galβ], and type 1 H antigens [Fucα1,2Galβ1,3(GlcNAc)]. b The mucus barrier dictates the spatial organization of microbes, forming a steric and orderly microorganism network to inhibit pathogen colonization. c The mucus barrier is also a scaffold containing antimicrobial agents [including RELM-β (purple solid circle), ZG16 (blue solid circle), Ang4 (red solid circle), Lypd8 (green solid circle), sIgA (orange solid circle), and bacteriophages] protecting epithelial cells against microbes.