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

Abstract

The gut microbiota plays a critical role in constraining Candida albicans (Ca) colonization of the gastrointestinal (GI) tract, a key precursor to disseminated fungal infection in immunocompromised hosts. Depletion of commensal microbiota increases Ca burden and promotes dissemination, yet the mechanisms of microbiota-mediated Ca colonization resistance remain poorly defined. Here, we show that gut microbiota-derived short-chain fatty acids (SCFAs) directly inhibit Ca growth by impairing hexose uptake, disrupting central carbon metabolism, and inducing intracellular acidification. In vivo, SCFAs enhance Ca colonization resistance only in the presence of an intact gut microbiome, which is required to drive SCFA-induced taxonomic shifts that further augment resistance. Commensal microbiota lacking SCFA production exhibit diminished capacity to restrict Ca colonization, while prebiotic therapy that increases luminal SCFA levels enhances Ca clearance. These findings define a critical microbiota-metabolite mechanism underlying Ca colonization resistance and suggest strategies to modulate GI fungal burden and prevent invasive disease.