Dissecting Causal Links Between Gut Microbiota, Inflammatory Cytokines, and DLBCL: A Mendelian Randomization Study

Causal relationships between gut microbiota, inflammatory cytokines and diffuse large B-cell lymphoma (DLBCL) remain elusive. In addressing this gap, our Mendelian randomization (MR) study utilized data from the MiBioGen consortium encompassing 211 microbiota taxa (n= 18,340), genome-wide association study (GWAS) meta-analyses of 47 inflammatory cytokines, and DLBCL cases and controls from the FinnGen consortium (cases n = 1010, controls n = 287137). Through bidirectional MR analyses, we examined the causal links between gut microbiota and DLBCL, and employed mediation analyses, including two-step MR and multivariable MR (MVMR), to identify potential mediating inflammatory cytokines. Our findings revealed that four microbiota taxa were causally associated with DLBCL, and conversely, DLBCL influenced the abundance of 20 taxa. Specifically, in the two-step MR analysis, both the genus Ruminococcaceae UCG-002 (Odds Ratio [OR] = 1.427, 95% Confidence Interval [CI], 1.011-2.015, P = 0.043) and the inflammatory cytokine monokine induced by gamma (MIG) (OR = 1.244, 95% CI, 1.034-1.487, P = 0.020) were found to be causally associated with an increased risk of DLBCL. Additionally, a positive association was observed between genus Ruminococcaceae UCG-002 and MIG (OR = 1.275, 95% CI, 1.069-1.520, P = 0.007). Further, MVMR analysis indicated that the association between genus Ruminococcaceae UCG-002 and DLBCL was mediated by MIG, contributing to 14.9% of the effect (P = 0.005). In conclusion, our MR study provides evidence that supports the causal relationship between genus Ruminococcaceae UCG-002 and DLBCL, with a potential mediating role played by the inflammatory cytokine MIG.