Targeting fungal overgrowth in the gut may help restore microbial balance and improve disease activity in a subset of patients with inflammatory bowel disease (IBD), according to new research led by Weill Cornell Medicine and published in Nature Medicine.
The study provides some of the first evidence that correcting fungal dysbiosis can help reshape both fungal and bacterial communities in the intestine for IBD patients, opening possibilities for new approaches to microbiome-targeted therapy. “These findings support the concept that disease-associated fungi play a role in the pathogenesis of inflammatory bowel disease in some patients,” says Iliyan Iliev, Ph.D., senior author and co-director of the microbiome core laboratory at the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine.
“Crohn’s disease and ulcerative colitis are chronic immune-mediated diseases driven by abnormal immune response to intestinal microbes,” adds Ellen Scherl, M.D., founding director of the Jill Roberts Center for Inflammatory Bowel Disease at NewYork-Presbyterian and Weill Cornell Medicine and coauthor of the study. “Until recently, most attention has focused on bacteria, but fungi are also residents of the gastrointestinal tract and may play an important role in driving inflammation in some patients.”
Candida as an IBD Biomarker
In the IVAN (IBD Therapy Via Antifungal-driven Microbiota Normalization) study, 53 patients with mild-to-moderate Crohn’s disease or ulcerative colitis who also had oral thrush caused by Candida overgrowth took either the antifungal medication fluconazole or the oral wash nystatin. Fluconazole reduced intestinal fungal burden and was associated with improvements in gut microbiome composition and clinical disease activity. The same benefits were not experienced by patients treated with nystatin.
A key challenge was determining which patients were most likely to respond to antifungal therapy. The researchers observed that genetically related Candida albicans strains were often shared between a patient’s oral cavity and their gastrointestinal tract, suggesting that oral fungal overgrowth could serve as a readily accessible biomarker of intestinal fungal dysbiosis.
To evaluate whether reducing fungal burden could influence disease activity, investigators compared the two antifungal strategies over an eight-week period. Researchers collected oral swabs, stool samples, microbiome data, and disease activity measurements before treatment, immediately afterward, at the two-week follow-up mark, and again after eight weeks of treatment. Both treatments were well tolerated and successfully resolved oral thrush. However, only fluconazole substantially reduced the intestinal Candida burden.
Researchers found that patients had genetically related strains of Candida albicans in their mouths and gastrointestinal tracts.
The study builds on more than a decade of research from Dr. Iliev’s laboratory examining how fungal organisms in the gastrointestinal tract interact with the immune system and the overall gut microbiota in IBD patients, showing that some patients with Crohn’s disease and ulcerative colitis have an intestinal overgrowth of Candida albicans.
The fungus can produce candidalysin, a toxin that can damage intestinal epithelial cells and trigger inflammatory immune responses. In preclinical animal model studies, researchers also found that fungal overgrowth could impair responses to anti-inflammatory therapies. Those findings are what led investigators to ask whether reducing fungal burden might restore microbial balance and improve disease outcomes.
Restoring the Gut Ecosystem With Fluconazole
The researchers found that reducing intestinal fungal overgrowth yielded a broader-than-expected impact. Patients who received fluconazole experienced remodeling of their gut microbial communities, including increased bacterial diversity, recovery of beneficial bacteria, improved production of butyrate and other microbiome-derived metabolites, and durable changes in microbial network structure.
The antifungal therapy is the first step in understanding a microbiome-targeted approach to inflammatory bowel disease.
— Dr. Ellen Scherl
The restoration of bacterial diversity was particularly noteworthy because “one of the problems with IBD is that there is not a diverse microbiome,” says Dr. Scherl. “By controlling the overabundance of fungi, the diversity returns to the microbiome.”
“What’s particularly interesting is that we only targeted fungal overgrowth, and by removing fungus, we saw the microbial community begin to shift toward a state that more closely resembled what we see in healthy individuals,” Dr. Iliev adds.
Notably, microbiome changes persisted during the study’s eight-week follow-up period, several weeks after antifungal therapy ended, suggesting the intervention may have durable effects on the intestinal ecosystem.
Toward Microbiome-Guided Therapy
The prospective observational study was not designed to establish efficacy, but researchers say the findings provide a framework for future clinical trials. The next step will be larger, multicenter placebo-controlled studies designed to determine whether antifungal therapy can improve outcomes in carefully selected patients with fungal dysbiosis. Investigators also hope to determine whether patients with intestinal fungal overgrowth but no visible oral thrush may benefit from similar treatment approaches.
Future studies will investigate not only whether antifungal treatment improves clinical outcomes in larger patient populations, but also how long microbiome changes persist post treatment and whether repeated or maintenance treatment might be beneficial for some patients.
Additionally, the findings point toward the possibility of microbiome-guided treatment strategies that identify and target specific microbial drivers of disease to ultimately help prevent disease progression and possibly reduce the need for immune-suppressing medications, which contribute to infection and cancer risk.
"The antifungal therapy is the first step in understanding a microbiome-targeted approach to inflammatory bowel disease,” says Dr. Scherl. “If we can modulate immune-mediated inflammation by understanding and targeting gut fungal regulators, we may be able to favorably impact natural progression of both Crohn’s disease and ulcerative colitis.”
