Integrated microbiome and metabolome profiling in prepubertal girls with vulvar lichen sclerosus

ABSTRACT Vulvar lichen sclerosus (VLS) is a chronic anogenital disease with long-term risks of genital disfigurement and squamous cell cancer. The involvement of the gut-skin axis in prepubertal VLS remains unclear. We conducted a cross-sectional study of 43 prepubertal VLS patients and 46 healthy controls, performing fecal 16S rRNA sequencing and serum LC-MS to characterize gut microbiome–metabolome associations and identify altered microbial and metabolic signatures. We further assessed their exploratory classification performance using random forest models. No significant differences in alpha or beta diversity were observed between groups. At the nominal significance level, an increase in Firmicutes_A (phylum; P = 0.021) and Streptococcus (genus; P = 0.046) and a decrease in Phocaeicola_A_858004 (genus; P = 0.004), Bacteroides_H (genus; P = 0.033), and Streptococcus (genus; P = 0.046) were observed in the VLS group. After multiple testing correction, only Phocaeicola_A_858004 remained significant (BH-adjusted q = 0.041). Linear discriminant analysis effect size identified 23 discriminant taxa, with 12 enriched in VLS patients and 11 enriched in controls. Functional prediction suggested perturbations in amino acid and lipid metabolism, aligning with host metabolic pathways. Metabolomic analysis identified 123 dysregulated metabolites, with integrative analysis showing correlations between key bacteria (e.g., s_Porphyromonas_A_859426_somerae ) and metabolites (e.g., 12,13-DHOME). Furthermore, serum metabolites showed strong discriminative performance (area under the curve [AUC] = 0.93), compared with microbial features alone (AUC = 0.83) or combined models (AUC = 0.87). These findings indicate modest but distinctive associations between gut microbiome and host serum metabolic profiles in girls with VLS and suggest that integrated microbial and metabolic signatures may serve as exploratory non-invasive biomarkers for this condition. IMPORTANCE Integrating gut microbiome and serum metabolome analyses, this study characterized gut-skin axis associations in prepubertal vulvar lichen sclerosus (VLS). Overall gut microbial diversity and community structure were preserved without statistically significant differences after multiple testing correction. However, linear discriminant analysis effect size identified discriminative taxa between groups, suggesting potential compositional differences at the feature level. In contrast, serum metabolomic profiles showed more robust alterations in VLS patients. The microbial and metabolic signatures demonstrated strong discriminative ability between VLS and control groups, supporting their potential as exploratory non-invasive biomarkers. These results indicate that modest gut microbiome–metabolome perturbations are early pathogenic events in VLS, preceding overt microbial structural remodeling, providing a reference for further exploration of early detection strategies in this condition. These findings suggest that VLS-related perturbations may be more evident at the metabolic than at the gut microbiome taxonomic level, providing a framework for future studies of gut-skin interactions and early disease characterization.