Commensal gut fungi promote inflammasome activation to regulate colitis and colon cancer

Fungi represent a significant proportion of the gut microbiota and aberrant immune responses to fungi are frequently observed in IBD and CRC. However, the role of fungi in modulating IBD and CRC pathogenesis is still unclear. Further, mutations in molecules involved in the fungal sensing pathways are highly associated with IBD, but how they modulate immune responses in the gut is unclear. Here, we show that gut fungi promote inflammasome activation during experimental colitis. IL-18 maturation by the inflammasome promotes tissue-restitutive and anti-tumorigenic immune responses. Loss of critical molecules involved in the fungal recognition pathway, caspase recruitment domain-containing protein 9 (CARD9) and spleen tyrosine kinase (SYK), within the myeloid cells also leads to reduced inflammasome activation and increased susceptibility to colitis and CRC. Overall, our results demonstrate that gut fungi signal via SYK-CARD9 pathway to promote inflammasome activation and restrain colitis and colon tumorigenesis.