Factors Governing Gastrointestinal Colonization of Candida albicans

Candida albicans can colonize the human gastrointestinal tract (GI) and cause disseminated infections in immunocompromised hosts. Depletion of specific gut commensal microbiota is associated with or results in increased C. albicans burden in the gut and increased likelihood of dissemination in human patients and mice, respectively. The exact mechanisms by which gut microbiota mediate C. albicans colonization resistance in the gut, however, are unknown. Here, we show that gut microbiota-derived short chain fatty acids (SCFA) directly inhibit C. albicans growth in vitro. SCFA inhibit C. albicans hexose uptake and induce intracellular acidification. In contrast, SCFA promote C. albicans GI colonization resistance in vivo but only when an intact gut microbiome is present. SCFA induce gut microbiota composition changes that promote C. albicans colonization resistance. Commensal gut microbiota unable to produce SCFA have a diminished capacity to reduce C. albicans GI colonization. Prebiotic therapy results in increased GI SCFA levels which enhance C. albicans GI clearance. This work also describes two C. albicans isolates 529L and CHN1 that can stably colonize the murine GI tract without the use of antibiotics. These clinical isolates have a higher resistance to antimicrobial peptide CRAMP compared to the most commonly studied C. albicans laboratory strain SC5314. Thus, the work sheds light on mechanisms that might be critical in governing C. albicans gastrointestinal colonization levels. It provides mechanistic insights into the importance of gut microbiota-derived metabolites in maintaining C. albicans colonization resistance and may have therapeutic implications for modulating C. albicans gastrointestinal colonization levels in order to prevent invasive candidiasis in immunocompromised patients. Further, C. albicans strain-specific difference in colonization ability appears to depend on the sensitivity to these host immune effectors. The described isolates can further serve as valuable tools to probe the mechanisms of C. albicans gastrointestinal colonization without the intervention of any antibiotics.