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The epidermis forms a barrier that defends the body from desiccation and entry of harmful substances, while also sensing and integrating environmental signals. The tightly orchestrated cellular changes needed for the formation and maintenance of this epidermal barrier occur in the context of the skin microbiome. Using germ-free mice, we demonstrate the microbiota is necessary for proper differentiation and repair of the epidermal barrier. These effects are mediated by microbiota signaling through the aryl hydrocarbon receptor (AHR) in keratinocytes, a xenobiotic receptor also implicated in epidermal differentiation. Mice lacking keratinocyte AHR are more susceptible to barrier damage and infection, during steady-state and epicutaneous sensitization. Colonization with a defined consortium of human skin isolates restored barrier competence in an AHR-dependent manner. We reveal a fundamental mechanism whereby the microbiota regulates skin barrier formation and repair, which has far-reaching implications for the numerous skin disorders characterized by epidermal barrier dysfunction. [Display omitted] • Germ-free mice have abnormal skin barrier structure and function • Keratinocyte aryl hydrocarbon receptor (AHR) mediates barrier function and repair • Human skin commensal microbes activate keratinocyte AHR • Targeting the microbiota-AHR axis promotes skin barrier repair in disease models A self-renewing skin barrier is needed for terrestrial life. Uberoi et al. demonstrate that the skin microbiota regulates barrier repair and integrity by activating keratinocyte aryl hydrocarbon receptor (AHR). This microbiota-AHR axis was targeted with a defined consortium of human skin commensals to improve barrier repair in disease models. [ABSTRACT FROM AUTHOR]

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]