Targeting the Mycobiome in Genetically Defined Patients with Crohns Disease

ABSTRACT Inflammatory bowel disease (IBD), divided largely into Crohn’s Disease (CD) and ulcerative colitis, is a chronic and serious disease that results from dysregulated inflammatory immune activity in the mucosa of the gastrointestinal tract. There has been much progress defining genetic, intestinal microbiome, host pathway, and environmental roles in disease, and a major goal in IBD research and care is to translate these observations into strategies to improve outcomes by better matching disease treatment with patients’ specific underlying mechanisms of disease. Studies on the role of the microbiome in influencing IBD have focused largely on the bacterial microbiota, while the potential role for commensal fungal microbiota to influence disease has been largely overlooked. We recently reported a strong association of the yeast Malassezia with Crohn’s Disease. Specifically, intestinal mucosa- associated Malassezia are elevated in patients carrying a previously described IBD risk polymorphism (S12N) in the gene for CARD9, a signaling molecule require for antifungal inflammatory immune responses. In mouse models, Malassezia exacerbates colitis via a mechanism requiring CARD9. This project is designed to test the hypothesis that oral antifungal treatment can reduce the burden of Malassezia spp. in CD patients with the CARD9 S12N allele and improve disease symptoms. The approach includes a two-center randomized, double- blind, placebo-controlled study of antifungal drug treatment in genetically defined patients with active Crohn’s disease. We will evaluate the consequences of antifungal drug treatment on the overall microbiome and metabolites it produces as well as regulation of immune cell function in the mucosa.