Abstract
BACKGROUND: Existing data suggests a potential link between human blood metabolites and sepsis, yet the precise cause-and-effect relationship remains elusive. By using a two-sample Mendelian randomization (MR) analysis, this study aims to establish a causal link between human blood metabolites and sepsis. METHODS: A two-sample MR analysis was employed to investigate the relationship between blood metabolites and sepsis. To assess the causal connection between sepsis and human blood metabolites, five different MR methods were employed, A variety of sensitivity analyses were conducted, including Cochrane's Q test, MR-Egger intercept test, MR-PRESSO and leave-one-out (LOO) analysis. In order to ensure the robustness of the causal association between exposure and outcome, the Bonferroni adjustment was employed. Additionally, we conducted analyses of the metabolic pathways of the identified metabolites using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Small Molecule Pathway Database (SMPDB) database. RESULTS: The MR analysis revealed a total of 27 metabolites (16 known and 11 unknown) causally linked to the development and progression of sepsis. After applying the Bonferroni correction, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) remained significant in relation to 28-day all-cause mortality in sepsis. By pathway enrichment analysis, we identified four significant metabolic pathways. Notably, the Alpha Linolenic Acid and Linoleic Acid metabolism pathway emerged as a pivotal contributor to the occurrence and progression of sepsis. CONCLUSION: This study provides preliminary evidence of causal associations between human blood metabolites and sepsis, as ascertained by MR analysis. The findings offer valuable insights into the pathogenesis of sepsis and may provide insight into preventive and therapeutic approaches.