Dietary exposure modulates cutaneous immunity and microbiota to facilitate wound healing 2308096
Nutrition influences all host physiological processes, yet its role in regulating tissue repair remains poorly understood. Although both the immune system and the microbiota have been implicated in tissue repair, how diet reshapes host physiology, microbial function, or host—microbe interactions to promote regeneration has not been investigated. To test this, we manipulated the nutritional status of mice using either dietary restriction or nutrient-enriched diets and assessed wound closure following injury. Here, we show that the ketogenic diet (KD), a diet enriched in fats and low in carbohydrates, feeding reshapes the metabolic environment of the skin and enhances both the abundance and metabolic output of the commensal Staphylococcus epidermidis. In vivo metatranscriptomics revealed KD-induced increases in microbial glycolysis, nucleotide synthesis, and riboflavin-pathway activity. Lipidomic profiling further showed that KD elevated bacterial sphingomyelinase-dependent ceramides in the epidermis. These diet-responsive microbial metabolites amplified cutaneous γδ T cell and mucosal-associated invariant T (MAIT) cell responses and directly promoted keratinocyte activation, collectively accelerating wound repair. Genetic disruption of microbial ribD or sphingomyelinase impaired these effects, demonstrating that host nutritional status drives tissue regeneration by rewiring commensal metabolic programs. Together, our findings reveal a diet-sensitive metabolic axis through which skin microbes coordinate tissue regeneration. Supported by NIAID; 1ZIA-AI001115 and 1ZIA-AI001132; JSPS CPD Reseach Fellowship for Young Scientist Mucosal and Regional Immunology (MUC)