Human intestinal fungus Clavispora lusitaniae attenuates colitis through Pyruvate decarboxylase-derived Indole-3-ethanol

Gut mycobiome dysbiosis has been implicated in inflammatory bowel disease (IBD). However, it remains unknown whether specific fungal species identified by sequencing directly contribute to IBD pathogenesis. Here, based on analysis of three fecal metagenome datasets of IBD cohorts and a previously established cultivated gut fungi catalog, we identify an IBD-depleted intestinal fungus Clavispora lusitaniae strain P4013B. We show P4013B attenuates DSS-induced colitis in wild-type, antibiotics-treated, and germ-free mice through activation of aryl hydrocarbon receptor (AHR). Using an activity-guided isolation strategy, we identify the P4013B metabolite indole-3-ethanol (IEt) as the AHR agonist mediating the anti-colitis activity. We further validate the role of IEt via engineering strains that overexpress pyruvate decarboxylases producing high yields of IEt. Tea polysaccharide enhanced the anti-colitis activity of P4013B by promoting its proliferation and colonization in the colon. Together, these results suggest that C. lusitaniae P4013B may be explored as a potential probiotic for the treatment and prevention of IBD.