Presented by: Aayushi Uberoi
Commensal microbes are critical in maintaining skin homeostasis. However, their mechanisms of crosstalk with host epithelia during barrier disruption and repair are not defined. Our goal is to understand mechanisms by which skin microbiome regulate skin barrier. Using germ free (GF) mice, we have recently demonstrated that microbiota is necessary and sufficient for proper differentiation and repair of the epidermal barrier (Uberoi et al., Cell Host & Microbe, 2021). 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 as downregulated in GF epidermis. As AHR is a regulator of epidermal differentiation, we hypothesized that skin microbiota promotes barrier repair by activating AHR. 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 in homeostasis as well as in models of atopic dermatitis. 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 microbe genomes within 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 found that several metabolites can improve skin barrier in vitro in primary keratinocytes and in models of 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.