Muc2 Protects against Lethal Infectious Colitis by Disassociating Pathogenic and Commensal Bacteria from the Colonic Mucosa

Abstract

Despite recent advances in our understanding of the pathogenesis of attaching and effacing (A/E) Escherichia coli infections, the mechanisms by which the host defends against these microbes are unclear. The goal of this study was to determine the role of goblet cell-derived Muc2, the major intestinal secretory mucin and primary component of the mucus layer, in host protection against A/E pathogens. To assess the role of Muc2 during A/E bacterial infections, we inoculated Muc2 deficient (Muc2−/−) mice with Citrobacter rodentium, a murine A/E pathogen related to diarrheagenic A/E E. coli. Unlike wildtype (WT) mice, infected Muc2−/− mice exhibited rapid weight loss and suffered up to 90% mortality. Stool plating demonstrated 10–100 fold greater C. rodentium burdens in Muc2−/− vs. WT mice, most of which were found to be loosely adherent to the colonic mucosa. Histology of Muc2−/− mice revealed ulceration in the colon amid focal bacterial microcolonies. Metabolic labeling of secreted mucins in the large intestine demonstrated that mucin secretion was markedly increased in WT mice during infection compared to uninfected controls, suggesting that the host uses increased mucin release to flush pathogens from the mucosal surface. Muc2 also impacted host-commensal interactions during infection, as FISH analysis revealed C. rodentium microcolonies contained numerous commensal microbes, which was not observed in WT mice. Orally administered FITC-Dextran and FISH staining showed significantly worsened intestinal barrier disruption in Muc2−/− vs. WT mice, with overt pathogen and commensal translocation into the Muc2−/− colonic mucosa. Interestingly, commensal depletion enhanced C. rodentium colonization of Muc2−/− mice, although colonic pathology was not significantly altered. In conclusion, Muc2 production is critical for host protection during A/E bacterial infections, by limiting overall pathogen and commensal numbers associated with the colonic mucosal surface. Such actions limit tissue damage and translocation of pathogenic and commensal bacteria across the epithelium.

Muc-2–Deficient Mice Display a Sex-Specific, COX-2–Related Impairment of Gastric Mucosal Repair

“…6 The Muc2 gene has been implicated as crucial in colonic mucosal defense, based on observations that Muc-2-deficient mice exhibit lowgrade mucosal inflammation in the basal state, and have an increased susceptibility to colitis. 11,22,29,30 MUC-2 is not a major form of mucin in the healthy stomach of humans or rodents, but has been shown to be expressed in gastric carcinoma. 9,10 The results of the present study, however, clearly demonstrate that Muc-2-deficient mice exhibit impaired gastric mucosal repair.…”

“…22 The expression of mRNA for Muc-5ac, the most abundant gastric mucin, was therefore examined. There were no significant differences in expression of Muc-5ac between the Muc-2-deficient and wild-type mice, either in males or females; that is, in Muc-2-deficient mice, the expression of Muc5ac ranged between 60% and 160% of that observed in the corresponding wild-type mice (not significant).…”

Design of a Specific Colonic Mucus Marker Using a Human Commensal Bacterium Cell Surface Domain

“…The gastrointestinal mucus layer establishes a physical barrier between the luminal content and the epithelial surface and provides efficient protection against luminal aggressions (1). It is continuously removed (enzymatic destruction and mechanical shearing, i.e.…”

Protein kinases are potential targets to treat inflammatory bowel disease

“…The sterility of the inner layer accredits to the preservation of huge amounts of defensins, cathelicidins, and cryptidens with important function of anti-intestinal pathogens. Mucin coding gene muc2 -/-mice demonstrated spontaneous colitis because of increased transepithelial permeability [40] , in which bacteria can stick to the surface of the intestinal mucosa, which facilitates the translocation of bacteria into lower crypts and epithelial cells, thus triggering an inflammatory response [39,41] . Protein kinases are involved in the integrity and maintenance of these mucus layers (Figure 2).…”