Mechanisms of IL-33-mediated protection during C. difficile colitis

Clostridium difficile (C. difficile) incidence has tripled over the past 15 years and is attributed to the emergence of hypervirulent strains. While it is clear that C. difficile toxins cause damaging colonic inflammation, the host immune mechanisms protecting from tissue damage require further investigation. Through a transcriptomics array, we identify IL-33 as an immune target upregulated in response to hypervirulent C. difficile infection. We demonstrate that IL-33 prevents C. difficile-associated mortality and epithelial disruption independently of bacterial burden or toxin expression. IL-33 drives ILC2 activation during infection and IL-33 activated ILC2s are sufficient to prevent disease. Furthermore, IL-33 expression in the colon is regulated by the microbiota as fecal microbiota transplantation rescues antibiotic-depleted IL-33. Lastly, dysregulated IL-33 signaling via the decoy receptor, sST2, predicts mortality in humans patients. Thus, IL-33 signaling to ILC2s is an important mechanism of recovery from C. difficile colitis.