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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. [Display omitted] • A synthetic human skin microbiome community rescues barrier function in germ-free mice • Skin microbiome is capable of regulating tryptophan metabolism in skin • Microbially regulated tryptophan metabolites improve skin barrier through AHR The skin microbiome is a fundamental component of the skin barrier, consisting of unique microbial communities distinct from those of other barrier organs. Commensal microbes on the skin enhance epithelial barrier function by regulating differentiation via the aryl hydrocarbon receptor (AHR). In this study, we developed a gnotobiotic model by colonizing germ-free (GF) mice with a synthetic microbial community comprising fifty distinct microbes isolated from healthy human skin, designed to represent the human skin microbiome. Using this ecological framework, we identified tryptophan metabolites produced by this synthetic microbiome and demonstrated their role in improving epithelial barrier function through AHR regulation. This proof-of-concept study illustrates the potential to harness host-microbiome-mediated metabolism in stratified epithelia to enhance skin barrier defenses. A comprehensive understanding of the mechanisms driving interactions within the skin ecosystem could lead to innovative, personalized, and cost-effective therapies that leverage host-microbiome interactions. The mechanisms underlying skin microbiome regulation of epithelial barrier homeostasis are unclear. Uberoi et al. developed a humanized gnotobiotic mouse model colonized with a 50-species microbial consortium mimicking the human skin microbiome. They identified tryptophan metabolites that enhance barrier function, emphasizing host-microbe-mediated metabolism's role in epithelial barrier regulation. [ABSTRACT FROM AUTHOR]