Causal effects of oral microbiome traits on female reproductive diseases: a two-sample Mendelian randomization study

OBJECTIVE: Female reproductive diseases (FRDs) impose a substantial health burden. Observational studies suggest links between oral dysbiosis and systemic conditions, but whether oral microbial traits causally influence FRDs remains unclear. We used two-sample Mendelian randomization (MR) to evaluate potential causal effects of genetically predicted oral microbiome traits on FRDs. METHODS: Genome-wide association study (GWAS) summary statistics for 44 salivary microbial traits were obtained from a publicly available oral microbiome GWAS based on the Danish ADDITION-PRO cohort (16 S rRNA profiling; European ancestry; n = 610). Outcome GWAS summary statistics for six FRDs were obtained from FinnGen (R12). The inverse-variance weighted (IVW) method was the primary analysis, complemented by MR-Egger, weighted median, and weighted mode. Sensitivity analyses included Cochran's Q, MR-Egger intercept, MR-PRESSO, leave-one-out, and Steiger directionality tests. Multiple testing for primary IVW analyses was addressed using Benjamini-Hochberg false discovery rate (FDR) correction. RESULTS: In primary IVW analyses, several oral taxa showed nominal associations (P < 0.05) with uterine leiomyoma (class Bacilli: OR = 1.0303, 95% CI 1.0012-1.0602; genus Veillonella: OR = 1.0291, 95% CI 1.0075-1.0512) and tubal infertility (family Veillonellaceae: OR = 0.8640, 95% CI 0.7824-0.9541; genus Veillonella: OR = 0.8900, 95% CI 0.8167-0.9699). However, none of these associations remained statistically significant after Benjamini-Hochberg FDR correction for the primary IVW analyses (all q > 0.05). In sensitivity analyses, MR-PRESSO outlier correction suggested a nominal association between Rothia mucilaginosa and uterine leiomyoma (OR = 1.0228, 95% CI 1.0069-1.0391; P = 0.0202). Overall, sensitivity analyses and Steiger directionality tests did not indicate that the main signals were driven by strong directional pleiotropy or reverse causation. CONCLUSION: This two-sample MR study provides suggestive, exploratory genetic evidence that specific oral microbiome traits may be linked to uterine leiomyoma and tubal infertility, but the evidence did not remain statistically significant after multiple-testing correction. Larger oral microbiome GWAS, independent outcome datasets, and functional studies are needed to validate these signals and clarify biological mechanisms.