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

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-treated (ABX) 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 VEGF and FGF-2. 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, ß-lactamase-mediated antibiotic resistance establishes microbial dominance, while metabolically, sphingolipid-driven spatiotemporal signaling remodels the regenerative microenvironment. This paradigm shifts the pathocentric view of wound microbiota, proposing a synergistic strategy combining "functional microbiota enrichment" and "metabolic axis targeting". 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. Overall design: 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.