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

By K. Bergstrom, Vanessa Kissoon‐Singh, Deanna L. Gibson, Caixia Ma, M. Montero, H. P. Sham, Natasha R. Ryz, Tina Huang, A. Velcich, B. Finlay and 2 more. PLoS Pathogens, 2010

619 citations recorded by the source corpus.

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.

Subfields: Endocrinology, Food Science, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/61999680ec2c6bf84a51e62909312d636f1b8329

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Citations in the corpus

The composition of the gut microbiota shapes the colon mucus barrier (2014, neutral): “Such capacities can be expected among pathogenic bacteria as these have developed specific mechanisms to circumvent the mucus protective system [36–38].”
NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. (2014, positive): “As an important line of defense, the host utilizes mucus secretion as a method to prevent attachment and remove the adherent load from the mucosal surface (Bergstrom et al., 2010).”
A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility (2016, positive): “Toward this point, a previous study demonstrated that mice genetically lacking the dominant colonic mucin glycoprotein (Muc2 / ), but not wild-type mice, develop lethal colitis following infection with Cr, highlighting that the mucus layer is an important initial barrier to this pathogen (Bergstrom ”
The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system (2014, neutral): “Despite this, clearance of this pathogen still requires Muc2, as colonization of Muc2 / mice results in a more severe, and often lethal, infection as the mice are unable to clear the pathogen from the gut (55, 56).”
Shifting the balance: antibiotic effects on host–microbiota mutualism (2011, background): “The disruption of mucus layer integrity, as is seen in mucin 2 ( Muc2 )-knockout mice, allows bacteria to contact the epithelium and, indeed, results in increased attachment of the enteric pathogen Citrobacter rodentium”