BACKGROUND: Gut microbiota is associated with endometrial cancer (EC)
however, the causal relationship remains unexplored. This study attempted to explore the relationship between gut microbiota and EC using Mendelian randomization (MR) methods. METHODS: In this two-sample MR analysis, we used MiBioGen's gut microbiota data as the exposure and three datasets from European populations with EC as the outcome. The EC datasets included general EC, endometrioid histology, and non-endometrioid histology. Single nucleotide polymorphism (SNP) was used as the instrumental variable. Inverse variance weighted (IVW), multiplicative random effects IVW (MRE-IVW), Maximum likelihood (ML), MR Egger, MR-PRESSO, and the weighted median were used to perform MR analysis. Sensitivity analysis was conducted to assess the reliability of the results. RESULTS: In this MR analysis of three EC datasets, specific gut microbiota were identified as potentially associated with different pathological types of EC. For general EC (ID: ebi-a-GCST006464), Family.Acidaminococcaceae (OR = 1.23, 95%CI: 1.02-1.48) and genus.Butyrivibrio (OR = 1.08, 95%CI: 1.01-1.16) were identified as risk factors, while genus.Ruminococcaceae UCG014 (OR = 0.82, 95%CI: 0.69-0.98) and genus.Turicibacter (OR = 0.84, 95%CI: 0.73-0.97) appeared to have protective effects. For endometrioid histology EC (ID: ebi-a-GCST006465), Family.Acidaminococcaceae (OR = 1.27, 95%CI: 1.01-1.59) and genus.Butyrivibrio (OR = 1.10, 95%CI: 1.01-1.19) were identified as risk factors, while several microbiota, including Family.Lactobacillaceae, genus.Coprococcus3, genus.Dorea, genus.Flavonifractor, genus.Lactobacillus, genus.Paraprevotella, and genus.Turicibacter, were identified as protective factors. For non-endometrioid histology EC (ID: ebi-a-GCST006466), Family.Rhodospirillaceae (OR = 1.41, 95%CI: 1.01-1.96) and genus.Peptococcus (OR = 1.43, 95%CI: 1.07-1.91) were identified as risk factors, while no significant protective factors were identified. CONCLUSIONS: This two-sample MR study has identified gut microbiota with potential causal relationships with EC, varying by pathological type. These findings provide new insights into the pathogenesis of EC and suggest directions for future research on diagnosis and treatment strategies.