IL 33 regulates the IgA microbiota axis to restrain IL 1a dependent colitis and tumorigenesis.
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 have shown that Il33 deficient mice are highly susceptible to colitis and CAC. Mechanistically, we observed that IL 33 promoted IgA production from B cells, which is important for maintaining microbial homeostasis in the intestine. Il33 deficient mice developed a dysbiotic microbiota that was characterized by increased levels of mucolytic and colitogenic bacteria. In response to chemically induced colitis, this microbial landscape promoted the release of IL 1a, which acted as a critical driver of colitis and CAC. Consequently, reconstitution of symbiotic microbiota or IL 1a ablation markedly ameliorated colitis susceptibility in Il33 deficient animals. Our results demonstrate that IL 33 promotes IgA production to maintain gut microbial homoeostasis and restrain IL 1a dependent colitis and CAC. This study therefore highlights modulation of IL 33, IgA, IL 1a, and the microbiota as a potential therapeutic approach in the treatment of IBD and CAC.
The Journal of clinical investigation