Gut microbiota, immune cell traits, and colorectal cancer across populations: insights from integrated genetic analyses

The gut microbiota is closely linked to host immune regulation and may contribute to the development of colorectal cancer (CRC). Understanding how microbial features relate to immune cell phenotypes and CRC across different populations may provide biological and translational insights. We integrated large-scale genome-wide association (GWAS) datasets from European and East Asian populations to examine associations among gut microbiota, immune cell traits, and CRC risk using genetic instruments as proxies. Mediation was assessed via a stepwise framework: the exposure–mediator effect (β₁) was estimated by univariable MR (UVMR), and the mediator–outcome effect (β₂) by multivariable MR (MVMR) to avoid confounding by the upstream exposure. Mediation proportions were derived using the product method with delta-method standard errors. Key findings were externally validated using independent gut microbiota GWAS datasets. In European cohorts, we identified 16 microbial taxa and 33 immune traits showing genetically predicted associations with CRC risk. MVMR-based mediation analysis identified six microbiota–immune-CRC pathways, with the largest mediation proportions observed for effector-memory T-cell subsets within double-negative T cells linking Holdemania to CRC (8.68%, 95% CI: 0-19.47%) and CD19 expression on IgD⁺CD38⁻ B cells mediating the CAG-822 sp000432855 -CRC association (6.47%, 95% CI: 0-13.55%). Additional pathways involved CD4⁺ Treg counts ( Brachyspirales , 5.61%) and HLA-DR⁺⁺ monocytes ( Succinivibrionaceae , 0.25%). External validation confirmed the Holdemania -CRC association in the MiBioGen cohort (OR = 1.14, P = 5.11 × 10⁻⁴) and the Prevotella -CRC association in the Dutch Microbiome Project (OR = 1.16, P = 0.017). In East Asian cohorts, 12 and 21 microbial taxa were linked to colon and rectal cancer risk, respectively. Our findings highlight population-specific microbiota and immune phenotypes associated with CRC risk and provide MVMR-based evidence that immune traits may partially mediate microbiota-related CRC susceptibility. The implicated pathways may inform biomarker development for CRC risk stratification and generate hypotheses for future mechanistic research.