Systematic Mendelian randomization study of the effect of gut microbiome and plasma metabolome on venous thromboembolism

AbstractBackground Although there is considerable evidence suggesting a link between gut microbiota (GM) composition and venous thromboembolism (VTE)/deep vein thrombosis (DVT)/pulmonary embolism (PE), population-level studies that can establish a causal relationship are currently lacking. Methods Using two-sample Mendelian randomization (MR) approach was used to examine the causal effects of 211 GM and 489 plasma metabolites on VTE/PE/DVT. We employed instrumental variables comprised of single nucleotide polymorphisms (SNPs) strongly associated with GM composition and plasma metabolite levels to determine whether these factors play a causal role in the development of VTE/DVT/PE. Additionally, we conducted mediation analysis to explore the potential associations between specific taxonomic groups and metabolites. Results The MR analysis revealed significant associations between 16 taxonomic units and 40 metabolites with VTE/DVT/PE as the causative factors. Among these,Firmicutes,Clostridia,Roseburia,Ruminococcaceae NK4A214, andIntestinimonaswere found to have a protective effect against VTE/DVT/PE. In contrast,Bacteroidetes,Anaerotruncus,Victivallales,Desulfovibrionaceae,Clostridium innocuum,Eubacterium oxidoreducens, andLachnoclostridiumhave been identified as risk factors for VTE/DVT/PE. Reverse MR analysis revealed 11 associations between VTE/DVT/PE and GM. Furthermore, no significant heterogeneity or horizontal pleiotropy was observed in any of the instrumental variables. Mediation analysis revealed 10 intermediate relationships, and metabolic pathway analysis identified 6 significant pathways. Conclusions Our study emphasizes the significant causal associations between the gut microbiota (GM), plasma metabolome, and VTE/DVT/PE. These interconnections have the potential to be used as clinical biomarkers for risk stratification and prognosis assessment in patients with VTE/DVT/PE.