Passage through the mammalian gut triggers a phenotypic switch that promotes Candida albicans commensalism

Among ~5,000,000 fungal species,(1) Candida albicans is exceptional in its lifelong association with humans, either within the gastrointestinal microbiome or as an invasive pathogen.(2) Opportunistic infections are generally ascribed to defective host immunity (3) but may require specific microbial programs. Here, we report that exposure of C. albicans to the mammalian gut triggers a developmental switch, driven by the Wor1 transcription factor, to a commensal cell type. Wor1 expression was previously observed only in rare genetic backgrounds,(4–6) where it controls a white-opaque switch for mating.(4–7) We show that passage of wild-type cells through the murine gastrointestinal tract triggers WOR1 expression and a novel phenotypic switch. The resulting GUT (Gastrointestinally-IndUced Transition) cells differ morphologically and functionally from previously defined cell types, including opaque, and express a transcriptome that is optimized for the digestive tract. The white-GUT switch illuminates how a microorganism utilizes distinct genetic programs to transition between commensalism and invasive pathogenesis.