Gut and skin microbiome-metabolome pathways in vitiligo: from dysbiosis to immune activation and melanocyte dysfunction.

Vitiligo is an autoimmune depigmenting disorder driven by genetic susceptibility, oxidative stress, immune dysregulation, and progressive melanocyte loss. Emerging microbiome-metabolome evidence suggests that gut and skin dysbiosis may contribute to disease progression through the gut-skin axis. This review integrates current evidence linking microbial imbalance with immune activation and melanocyte dysfunction in vitiligo. Studies in patients and experimental vitiligo models show altered gut and skin microbial diversity, enrichment of inflammation-associated taxa, depletion of commensal bacteria, impaired short-chain fatty acid biosynthesis, and disruption of tryptophan-indole, kynurenine, bile acid, taurine, riboflavin, and oxidative stress-related metabolic pathways. These alterations may weaken epithelial barrier integrity, impair immune tolerance, promote systemic low-grade inflammation, and increase melanocyte vulnerability to mitochondrial dysfunction, reactive oxygen species accumulation, impaired melanogenesis, apoptosis, and autoantigen exposure. Dysbiosis-associated metabolic remodeling may affect key immunometabolic pathways, including AhR-mediated tryptophan-kynurenine signaling, SCFA-dependent GPCR/HDAC regulation, IFN-γ-JAK/STAT-CXCL9/CXCL10 inflammatory amplification, and NF-κB/inflammasome-mediated innate immune priming. Together, these mechanisms may enhance dendritic cell activation, Th1/Th17 polarization, autoreactive CD8+ T-cell recruitment, and persistence of melanocyte-specific resident memory T cells. Current evidence supports a biologically plausible link between microbiome-metabolome disruption and autoimmune melanocyte loss in vitiligo. However, causality remains unproven. Longitudinal, multi-omics, and functional studies are required to define whether microbial and metabolic signatures act as biomarkers, mechanistic drivers, or therapeutic targets in vitiligo.