The causal relationship between gut microbiota and lipid metabolism in heart failure: A 2-sample Mendelian randomization study

Heart failure is a major global health burden with increasing incidence and mortality. Emerging evidence suggests that gut microbiota (GM) and lipid metabolism may play key roles in heart failure, but their causal relationships remain unclear. We performed a 2-sample Mendelian randomization (MR) analysis using genome-wide association study data from European cohorts to investigate the causal effects of GM on heart failure. To assess mediation, a 2-step MR and multivariable MR were applied to quantify the role of 179 lipid metabolites. Robustness of findings was evaluated through multiple sensitivity analyses. Significant causal associations were observed between several GM taxa (e.g., Bifidobacterium catenulatum, Lawsonibacter sp000492175) and heart failure. Multiple lipid metabolites, particularly phosphatidylcholine (PC) subtypes, were identified as mediators, with mediation proportions ranging from 7% to 13%. Sensitivity analyses supported the stability of the results. This study provides evidence for a causal pathway linking GM to heart failure through lipid metabolism. The findings highlight potential microbiota-based and metabolic intervention targets, offering new insights into heart failure pathogenesis and informing precision prevention strategies.