Ankit Malik, Deepika Sharma, Qifan Zhu, Rajendra Karki, Clifford S. Guy, Peter Vogel, and Thirumala-Devi Kanneganti

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Inflammatory bowel diseases (IBD) affect over 5 million individuals in the industrialized world, with an increasing incidence rate worldwide. IBD also predisposes affected individuals to development of colorectal cancer, which is a leading cause of cancer-related deaths in adults. Mutations in genes encoding molecules in the IL-33 signaling pathway are associated with colitis and colitis-associated cancer (CAC), but how IL-33 modulates gut homeostasis is unclear. Here, we show that Il33-deficient mice are highly susceptible to colitis and CAC. IL-33 promotes IgA production in the intestine, which is important for maintaining gut microbial homeostasis. Consequently, Il33-deficient mice develop a dysbiotic microbiota characterized by increased level of mucolytic and colitogenic bacteria. In response to DSS administration, this microbial landscape promotes the release of IL-1α, which acts as a critical driver of colitis and CAC. Consequently, reconstitution of symbiotic microbiota or IL-1α ablation markedly ameliorates colitis susceptibility in Il33-/- animals. Our results demonstrate that IL-33 promotes IgA production to maintain gut microbial homoeostasis, and restrain IL-1α dependent colitis and CAC. This study therefore highlights modulation of IL-33, IgA, IL-1α and the microbiota as potential therapeutic targets in the treatment of IBD and CAC.

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