Association of 91 Inflammatory Factors and 1400 Metabolites with Sepsis: A Mendelian Randomization Analysis

Objective: Observational studies suggest links between inflammatory factors, metabolites, and sepsis, yet their causality is uncertain. This study employs Mendelian Randomization (MR) to investigate the causality between these factors and sepsis, aiming to uncover the precise relationship and identify novel treatment approaches. Methods: We used summary data from genome-wide association studies (GWAS) involving 91 inflammatory factors, 1400 metabolites as exposure, and STREPTO SEPSIS as outcome. Inverse variance weighting (IVW) and MR-Egger were used to evaluate the causal effect between exposure and outcome. Sensitivity analyses were performed using Cochrane's Q test, MR-Egger intercept method, MR-PRESSO method and leave-one-out method. Results: Thymic stromal lymphopoietin levels (TSLP) (OR = 1.269; 95%CI = 1.016-1.585; <i>P</i> = .036) and Interleukin 15 receptor subunit alpha levels (IL-15Rα) (OR = 0.894; 95%CI = 0.801-0.998; <i>P</i> = .046) had a significant causal relationship with sepsis. Forty-four metabolites were associated with sepsis, including Spermidine to choline ratio (OR = 1.447; 95%CI = 1.104-1.977; <i>P</i> = .009), 4-hydroxyhippurate levels (OR = 1.448; 95%CI = 1.117-1.877; <i>P</i> = .005), and Sphingomyelin (d18:1/20:1, d18:2/20:0) levels (OR = 1.371; 95%CI = 1.139-1.651; <i>P</i> < .001). TSLP was associated with 19 metabolites, and IL-15Rα was associated with 30 metabolites. Conclusions: This study uncovers the causal link between sepsis and two inflammatory factors, TSLP and IL-15Rα, and suggests metabolites' potential in intervention. It also identifies 44 metabolites associated with sepsis, indicating possible biomarkers or therapeutic targets. The findings offer new perspectives on sepsis pathogenesis and could inform future treatment strategies.