Genetic evidence for potential causal associations between gut microbiota and site-specific urolithiasis risk: a...

Urolithiasis is a common and recurrent condition with substantial clinical burden. Although observational studies have linked the gut microbiome to stone formation, causal inference is limited by confounding and reverse causation. We applied two-sample Mendelian randomization (MR), a genetic epidemiological approach that uses germline genetic variants as instrumental variables to minimize confounding and reverse causation bias, to evaluate the potential causal associations between gut microbial taxa and site-specific urolithiasis subtypes. Genetic association estimates for gut microbiota were obtained from the MiBioGen consortium. Summary statistics for urolithiasis subtypes were sourced from two independent European-ancestry GWAS datasets. Instrumental variables were selected per taxon at P < 5 × 10⁻⁶, LD-clumped (r²<0.01, 1000 kb), harmonized across datasets, and screened via PhenoScanner to remove variants associated with potential confounders at genome-wide significance. Weak instruments were excluded (F < 10). Primary causal estimates were obtained using inverse-variance weighted (IVW), with complementary analyses using weighted median, MR-Egger, simple mode, and weighted mode. Sensitivity analyses included Cochran's Q, MR-Egger intercept, MR presso analysis, leave-one-out analyses, and reverse MR. After applying multiple testing correction and sensitivity filtering, three taxa showed evidence of potential causal associations with specific urolithiasis subtypes. Genetically predicted higher abundance of family Prevotellaceae (id.960) was associated with decreased risk of bladder calculus (OR = 0.88, 95% CI 0.79-0.97, p = 8.85 × 10⁻³). Higher abundance of class Bacilli (id.1673) was associated with decreased risk of ureter calculus (OR = 0.59, 95% CI 0.42-0.84, p = 2.72 × 10⁻³). Higher abundance of genus Coprobacter (id.949) was associated with increased risk of renal calculus (OR = 1.37, 95% CI 1.14-1.66, p = 9.79 × 10 ⁻⁴). Sensitivity analyses indicated no evidence of heterogeneity, directional pleiotropy, or horizontal pleiotropy. Leave-one-out and reverse MR analyses supported robustness and directionality. Our study provides genetic evidence supporting potential causal associations within the gut-stone axis, suggesting that specific gut microbial taxa may influence the risk of site‑specific urolithiasis.