Gut Microbiome–Metabolite Interactions Contribute to Esophageal Cancer Risk: Evidence From Mendelian Randomization and Multiomics Integration

Background Growing evidence implicates gut microbiota (GM) in the pathogenesis of esophageal cancer (EC). However, the causal nature of this association—particularly the potential mediating role of circulating metabolites—remains insufficiently clarified, especially across EC subtypes. Methods We applied a two‐sample Mendelian randomization (MR) framework to investigate the causal associations of GM and blood metabolites with EC and esophageal adenocarcinoma (EAC). The primary analysis was conducted using the inverse‐variance weighted method, with complementary MR approaches and genetic risk score (GRS) validation to ensure robustness. Mediation analyses were further performed to assess whether metabolites mediate the effects of GM on EC and EAC. Results Twenty‐five GM taxa showed significant associations with EC, including 11 with risk‐promoting and 14 with protective effects. For EAC, 15 taxa were implicated, with 11 increasing and 4 decreasing disease risk. In addition, five metabolites were causally linked to EC (two risk‐related and three protective), and six to EAC (five risk‐related and one protective). Mediation analyses revealed that specific metabolites partially mediated the effects of GM on both EC and EAC. Conclusions Our findings provide genetic evidence for a causal GM–metabolite–cancer axis in EC pathogenesis. These results highlight the role of circulating metabolites as potential intermediaries linking GM to EC and EAC, and suggest new avenues for biomarker discovery and microbiome‐targeted interventions.