Metabolic reprogramming and taxonomic drivers in bacterial vaginosis: A large-scale metagenomic meta-analysis.
OBJECTIVE: Bacterial vaginosis (BV) represents a profound ecological shift from a Lactobacillus-dominated microbiota to a diverse polymicrobial biofilm associated with adverse outcomes. While taxonomic signatures are well-documented, the functional mechanisms driving this transition remain obscured. This study elucidates the genomic potential for metabolic reprogramming and the putative "functional handover" underpinning the stability of the dysbiotic state. METHODS: A computational meta-analysis of 3557 vaginal microbiomes from diverse global cohorts was performed using the standardized MGnify pipeline. A high-resolution subset of 187 whole-genome shotgun (WGS) metagenomes was stratified to compare functional potential across demographic groups. Taxon-function interaction networks were constructed, utilizing a dual-filter statistical approach (p < 0.05 and effect size ranking), to map the shift from homeostatic maintenance to dysbiotic metabolic potential. RESULTS: BV was characterized by a fundamental shift from "maintenance" pathways to high-turnover "growth-oriented" genomic repertoires. While ABC transporter-like domains were present in healthy communities, dysbiosis was marked by a quantitative expansion and diversification of these systems alongside P-loop NTPases. Network analysis revealed a putative "functional handover": while Gardnerella serves as the adherent structural scaffold, the metabolic burden appears to be associated with secondary anaerobes, specifically BVAB1 and Sneathia, which exhibit strong genomic correlations with nutrient transport and stress response pathways. Crucially, microbiomes from women of African ancestry (Black cohort) exhibited a distinct functional profile with genomic signatures consistent with functions previously associated with resistome expansion (e.g., tetracycline/macrolide resistance), contrasting with Asian cohorts. CONCLUSION: BV is a state of metabolic reprogramming where genomic functional dominance is transferred from Lactobacillus to a cooperative network of anaerobic opportunists. Identifying BVAB1 and Sneathia as candidate metabolic engines, supported by a Gardnerella scaffold, challenges current therapeutic paradigms and highlights the potential for precision medicine targeting specific functional drivers and resistome profiles across diverse populations.