Commensal yeast Malassezia produces tryptophan metabolites to promote tissue homeostasis via the aryl hydrocarbon receptor in mice

: As an abundant fungal colonizer of mammalian skin, Malassezia establishes mutualistic or pathogenic interactions with the host. Here we show that Malassezia furfur promotes skin homeostasis by maintaining epidermal integrity via tryptophan-derived metabolites that activate the aryl hydrocarbon receptor (AhR), a key regulator of keratinocyte differentiation and inflammation. M. furfur-derived tryptophan derivatives activated AhR in human epidermal equivalents and upregulated proteins important for skin structure and barrier activity in mouse epidermis. In a mouse model of atopic dermatitis, M. furfur colonization with tryptophan supplementation reduced inflammation and restored barrier function, while a fungal mutant defective in indole production was unable to do so. Mice lacking AhR specifically in keratinocytes failed to benefit from M. furfur-mediated barrier protection. These findings establish a previously unrecognized mutualistic role for Malassezia in skin physiology and expand our understanding of the skin microbiota's influence on barrier function and immune regulation.