Abstract
Tissue injury induces metabolic changes in stem cells, which likely modulate regeneration. Using a model of organ regeneration called Wound-Induced Hair Follicle Neogenesis (WIHN), we identify skin-resident bacteria as key modulators of keratinocyte metabolism, demonstrating a positive correlation between bacterial load, glutamine metabolism, and regeneration. Specifically, through comprehensive multi-omic analysis and single-cell RNA sequencing in murine skin, we show that bacterially-induced hypoxia drives increased glutamine metabolism in keratinocytes with attendant enhancement of skin and hair follicle regeneration. In human skin wounds, topical broad-spectrum antibiotics inhibit glutamine production and are partially responsible for reduced healing. These findings reveal a conserved mechanism by which bacterially-induced metabolic changes improve the tolerance of stem cells to damage and enhance regenerative capacity. This surprising, pro-regenerative function of the skin microbiome affords novel approaches to wound healing, and suggests a refinement of the role of cutaneous antimicrobials.
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