The Causal Role of Gut Microbiota in Pulmonary Embolism and the Mediating Effects of Circulating Metabolites: A Mendelian Randomization Study.

The gut microbiota has been implicated in pulmonary vascular diseases, yet a direct causal link to pulmonary embolism (PE) remains unestablished. This study aimed to investigate the causal effects of gut microbiota on PE and to explore the mediating role of circulating metabolites in this relationship. We performed a two-sample Mendelian randomization (MR) analysis using summary statistics from large-scale genome-wide association studies. The gut microbiota data were sourced from the MiBioGen consortium, PE data from the FinnGen consortium (R10), and metabolite data from a meta-analysis of 136,016 participants. The inverse variance weighting method was used as the primary analytical approach, supplemented by sensitivity analyzes to ensure robustness. At the nominal level (p < 0.05), 12 gut microbial taxa showed suggestive associations with PE. Among these, genera LachnospiraceaeUCG010 and Defluviitaleaceae showed protective effects, while Subdoligranulum, Lentisphaerae, and Erysipelatoclostridium were associated with increased risk. In contrast, 26 circulating metabolites exhibited robust causal associations with PE, with several surviving Bonferroni correction. Mediation analyzes further revealed that specific metabolites, including histidine, triglycerides in small HDL, and docosahexaenoic acid ratio, significantly mediated the suggestive effects of nominal microbial taxa on PE risk, identifying potential metabolic pathways in the gut-vascular axis. This study generates hypothesis-generating evidence for the gut-pulmonary vascular axis, with identified metabolic mediators warranting further experimental validation. The potential effects of gut microbiota on PE provide exploratory leads for future mechanistic studies. These findings highlight the gut-pulmonary vascular axis as a potential target for novel preventive and therapeutic strategies against PE.