This prospective observational study evaluated whether targeted antifungal therapy could modify the intestinal fungal community and downstream microbiome, metabolome and clinical outcomes in patients with inflammatory bowel disease (IBD) who presented with mild oral thrush. The investigation leveraged the observation that Candida albicans strains can be shared between the oral cavity and gut in such patients to compare two antifungal strategies focused on different anatomical targets.
Fifty-three patients with mild-to-moderate ulcerative colitis or Crohn’s disease and mild oral thrush were enrolled. Participants received one of two antifungal regimens: an oral, swish-and-spit nystatin protocol termed oral nystatin fungal targeting (ORNT; n = 18), or systemic oral fluconazole intended to target both gastrointestinal and oral reservoirs, termed gastrointestinal and oral fluconazole fungal targeting (GIFT; n = 35). The study design and multi-omics sampling approach are summarized in the article’s figures and supplementary materials.
Treatment with fluconazole, but not nystatin, led to an effective reduction in intestinal Candida burden. Fluconazole also reshaped the broader gut mycobiome, producing measurable changes in fungal-community composition. The report emphasizes that the systemic antifungal reached and altered gastrointestinal fungal populations, whereas swish-and-spit nystatin did not produce comparable intestinal effects.
Fluconazole-treated patients showed increases in bacterial diversity relative to baseline and to the nystatin group. Notably, fluconazole treatment was accompanied by expansion of bacterial taxa known to produce short-chain fatty acids (SCFAs), including butyrate-producing organisms. These bacterial shifts are reported as a central link between antifungal therapy and restoration of beneficial microbial functions.
Metabolomics analysis identified metabolite modules that correlated with specific fungal taxa and with the antifungal treatment received. In participants treated with fluconazole, the metabolomic profile reflected restoration of anti-inflammatory microbial metabolites, consistent with expansion of SCFA-producing bacteria and overall improvement in microbial function.
Network analyses of cross-kingdom interactions revealed durable shifts after fluconazole therapy. The study reports changes in fungus–bacterium network architecture, suggesting that reducing intestinal Candida abundance can reconfigure interkingdom relationships within the gut ecosystem rather than producing only transient changes.
The microbiome and metabolomic changes observed with fluconazole coincided with clinical benefit: disease activity indices improved and the risk of disease progression was reduced during the 8-week follow-up period. The article contrasts these improvements with the lack of comparable microbiome, metabolomic or clinical changes in the nystatin-treated group.
Raw fungal ITS amplicon and shotgun metagenomic sequencing data from the study are deposited in the NCBI Sequence Read Archive under BioProject accession PRJNA1449485. Supplementary Tables provided with the paper include clinical characteristics and medication information (Supplementary Table 2), sequencing-sample information (Supplementary Table 3), metabolomics data (Supplementary Table 8) and bacterial abundance data (Supplementary Table 10). The authors note that additional individual-level clinical data that could enable re-identification remain restricted for privacy and IRB reasons; requests for de-identified data can be directed to the corresponding author per institutional requirements. The analysis code used for quality control, data processing, statistical analyses and visualization is publicly available on GitHub and an archived version is cited on Zenodo.
The findings demonstrate feasibility of mycobiome-based patient stratification in IBD and provide evidence that targeted antifungal therapy can reshape the intestinal microbiota, metabolome and clinical course in patients with fungal-associated disease manifestations. Specifically, systemic fluconazole that reduces intestinal Candida burden was associated with beneficial cross-kingdom microbiome reconfiguration, restoration of anti-inflammatory metabolites and short-term clinical improvement. The article establishes a framework for considering antifungal cotherapy in IBD patients who have fungal-associated presentations, while also making the underlying multi-omics data and code available for further study.
Note: The original article contains detailed figures, supplementary tables and methods that provide additional data and analyses. Specific numerical effect sizes, statistical tests and full methodological details are reported in the main paper and supplementary materials; those full details are not reproduced here but are available in the publication and associated data deposits.