Lypd8 inhibits attachment of pathogenic bacteria to colonic epithelia.

Mucosal barriers segregate commensal microbes from the intestinal epithelia to maintain gut homeostasis. Ly6/Plaur domain-containing 8 (Lypd8), a highly glycosylated glycosylphosphatidylinositol-anchored protein selectively expressed on colonic enterocytes, promotes this segregation by inhibiting bacterial invasion of the inner mucus layer and colonic epithelia. However, it remains unclear whether Lypd8 prevents infection with enteric bacterial pathogens. Here, we demonstrate that Lypd8 strongly contributes to early-phase defense against Citrobacter rodentium, which causes colitis by inducing attachment and effacement (A/E) lesions on colonic epithelia. Lypd8 inhibits C. rodentium attachment to intestinal epithelial cells by binding to intimin, thereby suppressing the interaction between intimin and translocated intimin receptor. Lypd8 deficiency leads to rapid C. rodentium colonization in the colon, resulting in severe colitis with Th17-cell and neutrophil expansion in the lamina propria. This study identifies a novel function for Lypd8 against A/E bacteria and highlights the role of enterocytes as crucial players in innate immunity for protection against enteric bacterial pathogens.