Causal associations of inflammatory proteins and plasma metabolites with Clostridium difficile colitis: A Mendelian randomization study

This Mendelian randomization (MR) study investigates the causal relationships between circulating inflammatory proteins, blood metabolites, and Clostridium difficile colitis (CDC), with a focus on potential metabolic mediation. Bidirectional and mediation MR analyses were performed using genome-wide association study (GWAS) summary statistics from 3384 CDC cases and 406,048 controls. The primary MR methods included inverse variance weighting (IVW) and MR-Egger regression, with MR-PRESSO applied to detect and correct horizontal pleiotropy. Sensitivity analyses, including leave-one-out tests, were conducted to ensure the robustness of the findings. Mediation analysis was performed using a two-step MR framework to estimate the causal effects of inflammatory proteins on metabolites and, subsequently, the impact of these metabolites on CDC risk. Bidirectional MR identified 2 inflammatory proteins associated with CDC risk. Higher IL-2 receptor subunit beta (IL-2RB) levels were protective against CDC (OR = 0.827, 95% CI = 0.718–0.953, P < .01), whereas increased IL-22 receptor subunit alpha-1 (IL-22RA1) levels elevated CDC risk (OR = 1.300, 95% CI = 1.078–1.570, P < .01). Unidirectional MR identified 11 plasma metabolites associated with CDC, including a positive correlation with spermidine-to-choline ratio. Mediation MR analysis suggested that 17.4% (−6.21%, 41%) of IL-2RB’s protective effect on CDC was mediated through this metabolite. Sensitivity analyses confirmed the robustness of these associations. Our findings suggest that higher IL-2RB levels were protective against CDC, while increased IL-22RA1 levels were associated with higher risk. The Spermidine-to-choline ratio partially mediated the protective effect of IL-2RB, suggesting a metabolic link between inflammation and CDC.