Causal relationships among gut microbiota, plasma metabolites, and hepatocellular carcinoma: A mediation Mendelian randomization study

Observational studies have revealed an association between gut microbiota and hepatocellular carcinoma (HCC), but the causal relationship is unclear. This study investigated the causal relationship between gut microbiota and HCC and quantified the potential mediating role of plasma metabolites using Mendelian randomization (MR) analysis. Two-sample MR analysis was performed to investigate the relationship between 211 gut microbiota species, 1400 plasma metabolites, and HCC using summary data from genome-wide association studies. Furthermore, a 2-step approach quantified the mediating effect of the gut microbiota on HCC through plasma metabolites. Effect estimates were primarily obtained using the inverse variance weighting method, and the robustness of the causal relationships was further assessed using Bayesian weighted MR. Our MR analysis revealed that the Coprococcus2 genus reduces the risk of HCC by increasing the plasma phosphate-to-ethylenediaminetetraacetic acid ratio (phosphate-to-EDTA ratio). Specifically, this ratio mediates 7.77% (95% CI: 2.20%-8.72%) of the causal relationship between Coprococcus2 and HCC. Conversely, the Ruminococcus2 genus significantly elevates the risk of HCC by lowering the plasma levels of 1-oleoyl-2-linoleoyl-glycero-3-phosphoethanolamine (1-oleoyl-2-linoleoyl-GPE) (18:1/18:2), with a mediating effect of 5.21% (95% CI: 0.94%-6.88%). No heterogeneity or pleiotropy was observed in any of the results, and both inverse variance weighting (IVW) and Bayesian weighted MR analyses confirmed the robustness of causal relationships. This study establishes a causal relationship between specific gut microbiota and HCC while also identifying the mediating role of plasma metabolites, which may influence the liver which may influence the development of liver cancer through bile metabolism or fat metabolism. These findings offer potential biomarkers and targeted strategies for early diagnosis and intervention of HCC.