Genetic Evidence for Metabolites Mediated Causal Inference Between Gut Microbiota and Venous Thromboembolism

Background: More efficient and safe preventive treatments for venous thromboembolism (VTE) are warranted to decrease the incidence of hemorrhage. Emerging evidence has highlighted the pivotal role of the intestinal microbiota alterations and their metabolites in the pathophysiology of VTE process. However, the specific species involved the VTE process and the potential underlying mechanisms remain unclear. Methods: The causal relationships between 82 species and VTE were assessed using two-sample Mendelian Randomization (MR) analyses. Instrumental variables (F > 10) without horizontal pleiotropy were selected using the PhenoScanner and MR PRESSO global test. Subsequently, causal estimates were primarily derived using the inverse variance weighted method. The reliability of the results was further examined utilizing various sensitivity analyses, reverse MR analysis and multivariate MR analysis. Additionally, the potential mediated effects of gut microbiota-related metabolites were explored and replicated using the mediation MR analysis. Moreover, genome annotation and pathway enrichment analysis were conducted to investigate the role of CAG-81 sp000435795 in the related metabolites metabolism. Results: We identified independent and positive causal effects of CAG-81 sp000435795 and CAG-877 sp000433455 on VTE, which remained robust across multiple sensitivity analyses. Mediation analysis further revealed that the causal effect of CAG-81 sp000435795 on VTE risk was partially mediated by albumin, Omega-3 fatty acids and polyunsaturated fatty acids (PUFA), which were all validated in the replicated cohorts. Furthermore, CAG-81 sp000435795 might participate in the metabolism of albumin and fatty acids. Conclusions: Our findings provide evidence supporting a causal role of CAG-81 sp000435795 in the VTE pathogenesis and implicate microbes associated metabolites, albumin and Omega-3, as potential mediators.