Commensal-derived tryptophan metabolites fortify the skin barrier: Insights from a 50-species gnotobiotic model of human skin microbiome

The epidermal barrier defends the body against dehydration and harmful substances. The commensal microbiota is essential for proper differentiation and repair of the epidermal barrier, an effect mediated by the aryl hydrocarbon receptor (AHR). However, the microbial mechanisms of AHR activation in skin are less understood. Tryptophan metabolites are AHR ligands that can be products of microbial metabolism. To identify microbially regulated tryptophan metabolites in vivo, we established a gnotobiotic model colonized with fifty human skin commensals and performed targeted mass spectrometry on murine skin. Indole-related metabolites were enriched in colonized skin compared to germ-free skin. In reconstructed human epidermis and in murine models of atopic-like barrier damage, these metabolites improved barrier repair and function individually and as a cocktail. These results provide a framework for the identification of microbial metabolites that mediate specific host functions, which can guide the development of microbe-based therapies for skin disorders.