<i>Prevotella copri</i> 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 (ABX)-treated murine model, we identified <i>Prevotella copri</i> as a core functional commensal in the wound microecosystem that orchestrates tissue regeneration through metabolite-host crosstalk. ABX-induced microbial remodeling significantly enriched <i>P. copri</i> relative abundance, accelerated wound closure, and upregulated pro-regenerative factors vascular endothelial growth factor and epidermal growth factor. Metabolomic profiling revealed that <i>P. copri</i>-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, <i>P. copri</i> 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 <i>P. copri</i> 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.IMPORTANCETraditional wound repair research often focuses on microbial diversity, neglecting the critical role of specific taxa in tissue regeneration. Our study challenges this by highlighting <i>Prevotella copri</i> as a key species in wound healing, operating through the <i>Prevotella copri</i>-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.