Microbiota-derived butyrate promotes dermal collagen production through epidermal-dermal crosstalk

Abstract

The commensal microbiota actively shapes skin homeostasis by regulating immune responses and barrier function, yet interactions with the dermis and dermal fibroblasts remain poorly defined. Here, we show that the commensal microbiota regulates dermal collagen homeostasis through epidermal-mediated signaling. Transcriptomic analysis revealed enrichment of extracellular matrix (ECM)-associated gene programs in the dermis of conventionally raised (CR) mice compared with germ-free (GF) counterparts. CR skin exhibited increased collagen content, a thicker dermis, and thicker collagen fibers, indicative of a structurally robust dermal ECM. Similar microbiota-dependent collagen regulation was observed in additional tissues and during embryonic skin development, suggesting contributions from microbiota-derived signals beyond directly colonized sites. Mechanistically, short chain fatty acid butyrate robustly induced epidermal platelet-derived growth factor B (PDGFB) expression in vitro through a histone acetylation-dependent transcriptional program. Conditioned media from butyrate-treated human epidermal equivalents promoted collagen production in primary human dermal fibroblasts, an effect that was attenuated by inhibition of PDGF receptor signaling or histone acetyltransferase activity. Moreover, topical butyrate treatment of explants derived from aged human skin induced epidermal PDGFB and dermal collagen expression. Together, these findings identify a microbiota-epidermis-dermis signaling axis in which the commensal microbiota regulates dermal collagen through metabolite-enhanced epidermal signaling, highlighting a previously underappreciated role for the microbiota in maintaining dermal homeostasis.