Causal links between gut microbiota, metabolites, and diffuse large B-cell lymphoma: Evidence from a Mendelian...

The precise causal relationship between alterations in the gut microbiota, microbiota-derived metabolites, and the development of diffuse large B-cell lymphoma (DLBCL) remains unclear.

To investigate the potential causal relationships between gut microbiota, microbiota-derived metabolites, and DLBCL.

Genetic data on gut microbiota were obtained from the MiBioGen consortium, while data on microbiota-derived metabolites were sourced from the TwinsUK and KORA studies.Statistics for DLBCL were retrieved from FinnGen. Mendelian randomization (MR) analysis was performed, with inverse-variance weighting (IVW) used as the primary analytical method. Sensitivity analyses included Cochran's Q test, the MR-Egger intercept test, and MR-PRESSO. Reverse MR analysis was conducted to assess potential bidirectional causal relationships between gut microbiota and DLBCL. Bayesian weighted MR (BWMR) was applied for additional validation to enhance the robustness of the findings.

Among 196 gut microbial taxa analyzed, Bilophila (odds ratio (OR) = 1.777, 95% confidence interval (95% CI): 1.053-3.000, p = 0.031) was associated with an increased risk of DLBCL. In contrast, Alistipes (OR = 0.521, 95% CI: 0.311-0.873, p = 0.013) and Ruminococcaceae UCG011 (OR = 0.749, 95% CI: 0.574-0.978, p = 0.034) were associated with a reduced risk. Reverse MR analysis demonstrated a positive association between DLBCL risk and the abundance of Anaerofilum (OR = 1.087, 95% CI: 1.008-1.173, p = 0.031). Negative associations were observed between DLBCL risk and the abundance of Deltaproteobacteria (OR = 0.959, 95% CI: 0.922-0.997, p = 0.037), Desulfovibrionales (OR = 0.959, 95% CI: 0.922-0.998, p = 0.041), Oxalobacteraceae (OR = 0.914, 95% CI: 0.843-0.992, p = 0.031), and Oxalobacter (OR = 0.909, 95% CI: 0.837-0.988, p = 0.024). Analysis of microbiota-derived metabolites identified a causal association between indolepropionate (OR = 0.296, 95% CI: 0.131-0.669, p = 0.003) and reduced DLBCL risk, whereas 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-HOCA) (OR = 9.561, 95% CI: 1.426-64.088, p = 0.020) was associated with an increased risk. No evidence of directional pleiotropy or heterogeneity was detected.

This MR study provides evidence that specific gut microbial taxa and microbiota-derived metabolites may causally influence the risk of DLBCL.