Microbiota‐Derived Butyrate Preserves Epithelial Integrity Through <scp>SIRT1</scp> ‐Mediated Metabolic‐Epigenetic Crosstalk in Vulvar Lichen Sclerosus

Vulvar lichen sclerosus (VLS) is increasingly understood as a disorder shaped by systemic immune-metabolic disturbances and microbiome dysregulation. This study investigated how temporal changes in the gut and reproductive tract microbiota influence gene expression, metabolic status, and therapeutic responses in VLS. Fecal and vaginal samples from 20 VLS patients and 20 healthy women were collected at baseline and four follow-up time points and analyzed using multi-omics profiling. VLS patients exhibited consistently reduced microbial diversity, with increased abundances of Prevotella and Gardnerella and decreased Bifidobacterium and Lactobacillus. These microbial shifts were accompanied by significant upregulation of inflammatory genes (IL-6 and TNF-α) and downregulation of metabolic regulators (FOXO3 and SIRT1), with dynamic changes closely paralleling clinical progression. Metabolomic analysis further revealed marked disruptions in lipid and carbohydrate metabolism, particularly reduced levels of short-chain fatty acids (SCFAs). Functional assays demonstrated that patient-derived microbiota impaired cellular homeostasis by suppressing proliferation, enhancing apoptosis, and amplifying inflammatory signaling in vulvar epithelial and fibroblast models. In vivo, SCFA supplementation most effectively restored SIRT1 expression, reduced inflammatory cytokines, and improved metabolic balance in a DMBA-induced VLS mouse model. Together, these findings highlight a mechanistic link between microbiome dysbiosis, inflammatory activation, and metabolic dysfunction in VLS. They also underscore the therapeutic potential of targeting microbial and metabolic pathways, providing a foundation for microbiome-informed and personalized interventions for VLS.