Mendelian randomization analysis on the dissecting causal relationships between gut microbiota, circulating metabolites, and colorectal cancer: Insights from the latest evidence

The gut microbiota (GM) plays a direct role in colorectal cancer (CRC), but much of the epidemiological evidence linking the gut microbiome to CRC risk stems from observational studies. It remains unclear whether the observed microbial changes are causes or consequences of CRC development, and the role of metabolites as potential mediators is also uncertain. We conducted bidirectional Mendelian randomization (MR) using aggregated GWAS data on GM and circulating metabolites to explore causal relationships with CRC. Additionally, mediation analyses, 2-step MR, and multivariate MR were conducted to identify potential mediating factors of circulating metabolites in this relationship. We identified 12 positive and 15 negative causal effects between GM and CRC, and 4 positive and 3 negative causal effects between circulating metabolites and CRC. Notably, Succinivibrionaceae protected against CRC by increasing the CLA/FA ratio (CLA/FA; odds ratio [OR]: 1.045, 95% confidence interval [CI]: 1.006-1.086, P = .025), while Peptococcus increased CRC risk by raising the cholesterol esters to total lipids ratio in chylomicrons and extremely large VLDL (XXL-VLDL-CE_percent; OR: 1.098, 95% CI: 1.004-1.201, P = .04). This MR study provides new evidence supporting causal relationships between specific GM and CRC, along with potential new mediating metabolites.