MUC17 is an essential small intestinal glycocalyx component that is disrupted in Crohn's disease.

Crohn's disease (CD) is the chronic inflammation of the terminal ileum and colon triggered by a dysregulated immune response to bacteria, but insights into specific molecular perturbations at the critical bacteria-epithelium interface are limited. Here, we report that the membrane mucin MUC17 protected small intestinal enterocytes against commensal and pathogenic bacteria. In noninflamed CD ileum, reduced MUC17 levels and a compromised glycocalyx barrier allowed recurrent bacterial contact with enterocytes. Muc17 deletion in mice rendered the small intestine particularly prone to atypical bacterial infection while maintaining resistance to colitis. The loss of Muc17 resulted in spontaneous deterioration of epithelial homeostasis and in the extraintestinal translocation of bacteria. Finally, Muc17-deficient mice harbored specific small intestinal bacterial taxa observed in patients with CD. Our findings highlight MUC17 as an essential region-specific line of defense in the small intestine with relevance for early epithelial defects in CD.