Suggestive associations between genetically predicted gut microbiota and endometriosis: a two-sample Mendelian...

Introduction. Endometriosis affects 10-20% of reproductive-age women. Emerging evidence links the gut microbiota to endometriosis pathogenesis, but observational studies are limited by confounding, reverse causation and uncertainty about whether reported microbial signals represent reproducible aetiological associations.Hypothesis/Gap Statement. Whether genetically predicted gut microbial genera are associated with endometriosis risk remains unclear, and available observational evidence does not establish robust causal effects after accounting for multiple testing.Aim. This study aimed to explore potential Mendelian randomization (MR)-based associations between genetically predicted gut microbiota composition and endometriosis using a two-sample MR framework.Methodology. Genome-wide association study (GWAS) summary statistics for 119 bacterial genera (MiBioGen consortium: n=18,340) and endometriosis (FinnGen: 8,288 cases, 68,969 controls) were used. Single nucleotide polymorphisms (SNPs) associated with each genus (P<5×10⁻⁵) were selected as instrumental variables after linkage disequilibrium clumping and weak instrument exclusion. The primary method was inverse-variance weighting (IVW), supplemented by four complementary methods. Benjamini-Hochberg false discovery rate (FDR) correction was applied across all 119 genera.Results. Seven genera showed nominally significant IVW associations with endometriosis (P<0.05): Lactococcus, Olsenella, Senegalimassilia, Ruminococcaceae UCG-002, Holdemania, Eubacterium ruminantium group and Anaerotruncus. Olsenella, Ruminococcaceae UCG-002 and Anaerotruncus were directionally associated with increased risk, whereas the remaining four were directionally associated with reduced risk. However, none survived FDR correction (all FDR-adjusted P=0.731). No significant heterogeneity or horizontal pleiotropy was detected.Conclusion. These findings provide exploratory and suggestive MR evidence for potential associations between specific gut microbial genera and endometriosis, rather than definitive causal evidence. As no associations survived multiple testing correction, these results should be interpreted as hypothesis-generating and require replication in larger, ancestry-matched cohorts.