Nlrp6 limits inflamation in mouse colon by regulating microbiota

Abstract

Abstract Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that involves chronic inflammation involving the colon. We have previously shown that NLRP6 protects against the development of chemically-induced colitis. Here, we demonstrate that NLRP6 is important for suppressing the development of spontaneous colitis in the IL-10−/− mice model of IBD. IL10−/−Nlrp6−/− mice have significantly increased inflammation based on histologic scoring, spleen weight, fecal lipocalin levels, intestinal permeability, infiltration of immune cells, and upregulation of proinflammatory mediators. To determine whether NLRP6 protects against colitis by modulating the microbiome, we generated and recolonized germ-free (GF) Nlrp6−/− mice with the microbiota from WT donors and compared the composition of the microbiome to that of recolonized GF WT mice. We determined that GF WT and Nlrp6−/− mice acquire distinct microbiota upon re-colonization. Importantly, Nlrp6−/− mice have reduced a-diversity and dramatically increased colonization of Akkermansia muciniphila, which was also observed in IL10−/−Nlrp6−/− mice. To determine whether Akkermansia contributes to increased inflammation in IL-10−/− mice, we monocolonized GF IL-10−/− mice with Akkermansia muciniphila and found that these mice developed increased colitis compared to GF IL-10−/− mice gavaged with a control non-colitogenic Bacteroides strain. Altogether these results demonstrate that NLRP6 regulates the colonization of Akkermansia, which in turn, can precipitate colitis in a genetically susceptible host. Our work furthered the insight into the pathogenesis of UC and will be instrumental in the development of therapeutics that reduce pathobionts colonization to treat IBD.