Abstract

Inflammatory bowel disease (IBD) is characterized by alterations in the intestinal microbiota and altered immune responses to gut microbiota. Evidence is accumulating that IBD is influenced by not only commensal bacteria but also commensal fungi. We characterized fungi directly associated with the intestinal mucosa in healthy people and Crohn's disease patients and identified fungi specifically abundant in patients. One of these, the common skin resident fungus Malassezia restricta, is also linked to the presence of an IBD-associated polymorphism in the gene for CARD9, a signaling adaptor important for anti-fungal defense. M. restricta elicits innate inflammatory responses largely through CARD9 and is recognized by Crohn's disease patient anti-fungal antibodies. This yeast elicits strong inflammatory cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9 and exacerbates colitis via CARD9 in mouse models of disease. Collectively, these results suggest that targeting specific commensal fungi may be a therapeutic strategy for IBD.