The stone-degrading metabolic potential of the urinary microbiome: Sexual dimorphism and dysbiosis in urolithiasis.

Urolithiasis is a prevalent global health burden characterized by high recurrence rates and marked sexual dimorphism. While the gut microbiome's role in oxalate degradation is established, the functional capacity of the local urinary microbiome remains largely unexplored. This study investigated the composition and function of the urinary microbiome in 40 healthy volunteers and 61 urolithiasis patients using 16S rRNA amplicon sequencing, alongside a retrospective analysis of stone composition in 2027 patients. We identified a diverse, ecologically structured microbiome in healthy urine dominated by genera such as Lactobacillus, Streptococcus, and Gardnerella. Significant sex-dependent differences were observed: While males exhibited higher microbial α-diversity, females demonstrated a distinct compositional structure with superior predicted functional capacity for stone degradation. Specifically, the female microbiome was enriched with enzymes including oxalyl-CoA decarboxylase, formyl-CoA transferase, urate oxidase, and purine nucleosidase. Correlation analysis identified Lactobacillus, Enterococcus, and Gardnerella as key contributors to this litholytic potential. Conversely, urolithiasis patients displayed significant dysbiosis, characterized by disrupted microbial networks and a marked reduction in these stone-degrading enzymes. Clinical data supported these findings, revealing a significantly higher prevalence of uric acid stones in males, consistent with their lower microbial degradation capacity. These findings suggest that the healthy urinary microbiome functions as a metabolically active defense system against stone formation. The observed sex-specific variations in microbial composition and enzymatic function provide a novel mechanistic explanation for the epidemiological sex disparities in urolithiasis, highlighting the urinary-kidney axis as a potential therapeutic target.