Commensal microbes can regulate skin barrier through the control of tryptophan-aryl hydrocarbon receptor signaling cascade

Commensal microbes are critical in maintaining skin homeostasis. However, their mechanisms of crosstalk with host epithelia during barrier disruption and repair are not defined. Using germ free (GF) mice, we have recently demonstrated that microbiota is necessary and sufficient for proper differentiation and repair of the epidermal barrier. By comparing epithelial transcriptomes of GF mice to specific pathogen free (SPF) mice we found that microbiota regulate genes involved in epithelial development and differentiation. GF mice were impaired in barrier repair compared to SPF mice following tape-stripping, as measured by transepidermal water loss. We identified the aryl hydrocarbon receptor (AHR) pathway, a regulator of epidermal differentiation, as downregulated in GF epidermis. Activating AHR in GF mouse skin through a topical AHR-activator rescued impaired barrier repair function of GF skin. We found that colonization with a defined consortium of human skin commensals curated from healthy human skin restored barrier competence in AHR-dependent manner. Tryptophan (Trp) metabolites are potent AHR ligands and cornified skin envelope is a rich source of substrates for Trp metabolism by microbes. We constructed Trp metabolic enzyme profiles and mined them against healthy human skin metagenomes and microbial genomes in the defined consortium. We found motif enrichment for enzymes that metabolize Trp to indole and its derivatives, e.g., indole-3-acetaldehyde, indole propionic acid. We tested 14 indole-derived metabolites and identified n=4 therapeutic candidates that improve skin barrier in vitro in primary keratinocytes and in reconstructed human epidermis. We reveal a fundamental mechanism whereby the microbiota regulates skin barrier formation and repair through Trp metabolism, with far-reaching implications for the numerous skin disorders characterized by epidermal barrier dysfunction.