Microbiota-derived short-chain fatty acids mediate Candida albicans gastrointestinal colonization resistance

The gut microbiota plays critical roles in constraining Candida albicans colonization of the gastrointestinal (GI) tract, which is a key precursor to disseminated fungal infection in immunocompromised hosts. Depletion of commensal microbiota, such as by antibiotic treatment, increases C. albicans burden and promotes dissemination, yet the mechanisms of colonization resistance remain unclear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) directly inhibit C. albicans growth by inducing fungal metabolic reprogramming, impairing hexose uptake, and inducing intracellular acidification. In vivo, SCFAs enhance Candida colonization resistance only in the presence of an intact gut microbiome, which drives SCFA-induced taxonomic shifts that augment resistance. A Bacteroides thetaiotaomicron mutant unable to produce SCFAs exhibits diminished capacity to restrict C. albicans colonization, while prebiotic therapy that increases luminal SCFAs enhances C. albicans clearance. These findings define a critical microbiota-metabolite mechanism underlying Candida colonization resistance and suggest strategies to modulate GI fungal burden and prevent invasive disease.