Abstract:

Objective To investigate the causal relationship between gut microbiota, T-cell function, and the risk of colorectal cancer. Methods Gut microbiota data from the MiBioGen database and T-cell and colorectal cancer data from publicly available GWAS datasets were obtained for analyzing the causality between gut microbiota, T-cell subsets, and the risk of colorectal cancer with two-sample Mendelian randomization (MR) analyses, using inverse variance weighting as the primary analytical method supplemented with MR-Egger, weighted median, simple mode, and weighted mode methods. Horizontal pleiotropy was assessed using MR-PRESSO and MR-Egger regression. Cochran's Q test was used to evaluate heterogeneity, and sensitivity analysis was performed using the leave-one-out method. Results In the Forward MR analysis of gut microbiota and T cells, 11 gut microbiota species showed causal relationships. Six of these species exhibited positive correlations with T cells, including Prevotella7 (P=0.003), Ruminococcaceae UCG011 (P=0.033), Ruminococcaceae UCG004 (0.010), Ebacterium brachy group (P=0.005), Lachnospiraceae FCS020 group (P=0.028), and Coprobacter (P=0.033), and the remaining 5 species showed negative correlations with T cells. Forward MR analysis of T cells and colorectal cancer suggested that CD25⁺⁺CD45RA^-CD4⁺ non-regulatory T cells were negatively correlated with colorectal cancer risk (IVW: OR=0.935, 95% CI: 0.878-0.995; P=0.035). The analysis of gut microbiota and colorectal cancer suggested that 11 gut microbiota species were causally associated with colorectal cancer, and 6 of them (Eubacterium xylanophilum group, P=0.039; Selenomonadales, P=0.014; Negativicutes, P=0.014; Bifidobacteriaceae, P=0.048; Bifidobacteriales, P=0.048; and Coprococcus1, P=0.033) showed positive correlations and the remaining 5 showed negative correlations. Conclusion Coprobacter spp. and Eubacterium xylanophilum group spp. are causally associated with both T cell activity and colorectal cancer risk, and the former bacteria induce inactivation of CD25⁺⁺CD45RA^-CD4⁺ non-regulatory T cells to promote colorectal cancer progression, whereas the latter bacteria promote CD25⁺⁺CD45RA^-CD4⁺ non-regulatory T cell activity to inhibit colorectal cancer development.

Key words: gut microbiota, T cells, colorectal cancer, Mendelian randomization, causal association