Antifungal therapy improves microbiome dynamics in inflammatory bowel disease

Gut fungal dysbiosis has been implicated in inflammatory bowel disease (IBD), yet strategies for targeting the gut mycobiota in IBD remain unexplored. Here we leveraged the observation that Candida albicans strains are shared between the oral cavity and gut in patients with IBD with mild oral thrush, a condition caused by Candida overgrowth, to design a prospective observational study comparing oral antifungal therapy (swish-and-spit nystatin; oral nystatin fungal targeting (ORNT); n = 18) with orogastrointestinal antifungal therapy (fluconazole; gastrointestinal and oral fluconazole fungal targeting (GIFT); n = 35). Among 53 patients with mild-to-moderate ulcerative colitis or Crohn's disease, fluconazole, but not nystatin, effectively reduced intestinal Candida burden and reshaped gut fungal-community composition. Fluconazole treatment was accompanied by increased bacterial diversity, expansion of short-chain fatty-acid-producing taxa, restoration of anti-inflammatory microbial metabolites and durable shifts in cross-kingdom microbial networks. These microbiome and metabolomic changes coincided with improved disease activity indices and a decreased risk of disease progression over the 8-week follow-up period. These findings demonstrate the feasibility of mycobiome-based patient stratification, provide evidence that targeted antifungal therapy can reshape the intestinal microbiota in IBD and establish a framework for implementing antifungal cotherapy in patients with fungal-associated disease manifestations.