Abstract:Objective To investigate the potential association between 221 types of gut microbiota and hepatocellular carcinoma (HCC) using a two-sample Mendelian randomization approach, providing insights for the prevention and treatment of HCC. Methods The HCC data (n=197 611) from the IEU OpenGWAS database was used as outcome data, while gut microbiota data (n=18 340) obtained from a meta-analysis of a large-scale multi-ethnic genome-wide association study was used as exposure data. The analysis primarily employed the inverse variance weighting method, assessing the results based on the odds ratio (OR) and 95% confidence interval (CI). Quality control was conducted using leave-one-out analysis, heterogeneity tests, and the MR-PRESSO method. Results An increased abundance of the genus Oscillibacter was associated with a higher probability of developing HCC (OR=1.411, 95% CI: 1.049-1.899, P=0.025). Leave-one-out analysis indicated that the study results were stable and no instrumental variables had a strong impact on the results. This showed a positive causal relationship between gut microbiota and HCC, which could eliminate the effects of heterogeneity and horizontal gene pleiotropy on causal effect estimation. Conclusion An increased abundance of the genus Oscillibacter may raise the probability of developing HCC.