Effect of gut microbiome and blood metabolites on colorectal cancer: A bidirectional Mendelian randomization and mediation analysis based on STROBE-MR guidelines

Previous studies have shown that gut microbiome as well as blood metabolites are involved in the development of colorectal cancer (CRC). Therefore, this study attempted to discover the causal effects of gut microbiome and blood metabolites on CRC. Using genetic data from published genome-wide association studies, the 2-sample Mendelian randomization (MR) and 2-step MR analyses were applied to evaluate the causal connections between gut microbiome (exposure) and CRC (outcome) with blood metabolites as the mediators, as well as between blood metabolites (exposure) and CRC (outcome) with gut microbiome as the mediators. Moreover, a reverse MR analysis was done to measure the impact of CRC on gut microbiome and blood metabolites. The inverse variance weighted method was primarily utilized to analyze causal effects, with the robustness of the findings further assessed by sensitivity analyses. The 2-sample MR analyses illustrated that 14 gut microbes, 23 gut bacterial pathways, and 96 blood metabolites exerted an evidence of causal effect on CRC. However, there were no causal relationships between CRC and gut microbes and blood metabolites. Additionally, mediation analyses revealed that 5 gut microbiome (three gut microbes and 2 gut bacterial pathway abundance) influenced CRC through 4 blood metabolites, and 9 blood metabolites influenced CRC through 7 gut microbiome (four gut microbes and 3 gut bacterial pathways). Sensitivity analyses indicated that all results were reliable. Our study further highlights the complex relationship among gut microbiome, blood metabolites, and CRC and provides insights into clinical interventions for CRC.