Prevotella copri facilitates wound healing in mice through the sphingosine-CerS1-ceramide metabolic pathway

ABSTRACT Skin wound repair constitutes a sophisticated biological process involving spatiotemporally coordinated molecular cascades, with emerging evidence highlighting the dynamic regulatory role of skin microbiota. Utilizing a broad-spectrum antibiotic (ABX)-treated murine model, we identified Prevotella copri as a core functional commensal in the wound microecosystem that orchestrates tissue regeneration through metabolite-host crosstalk. ABX-induced microbial remodeling significantly enriched P. copri relative abundance, accelerated wound closure, and upregulated pro-regenerative factors vascular endothelial growth factor and epidermal growth factor. Metabolomic profiling revealed that P. copri -secreted sphingosine undergoes bioconversion to C18-ceramide via the non-canonical CerS1 pathway, driving keratinocyte hyperproliferation and neoangiogenesis. Pharmacological inhibition of CerS1 with P053 suppressed ceramide synthesis and delayed healing, mechanistically validating the sphingosine-CerS1-ceramide axis. Crucially, P. copri exhibits dual regulatory modalities: ecologically, β-lactamase-mediated antibiotic resistance establishes microbial dominance, while metabolically, sphingolipid-driven spatiotemporal signaling remodels the regenerative microenvironment. These findings align with and extend the evolving perspective of a functional wound microbiota and propose a potential synergistic strategy that combines targeted enrichment of beneficial commensals like P. copri with metabolic axis modulation to promote healing. Our findings elucidate a microecology-metabolism circuit that transitions wound management from passive anti-infection to precision intervention, providing a molecular blueprint for developing microbiome-reprogramming therapies in regenerative medicine. IMPORTANCE Traditional wound repair research often focuses on microbial diversity, neglecting the critical role of specific taxa in tissue regeneration. Our study challenges this by highlighting Prevotella copri as a key species in wound healing, operating through the Prevotella copri -sphingosine-CerS1-ceramide signaling pathway. This discovery reshapes the understanding of microbiome-host interactions and paves the way for precision microbial therapies. By showing that a single bacterium can replace complex community dynamics, we connect ecological theory with regenerative applications, offering a strategy to use microbial metabolism for precise wound healing.