Gut microbiota and risk of heart failure in European population-A comprehensive Mendelian randomization study

Gut dysbiosis is proven to be involved in the pathogenesis and progression of heart failure (HF). Hindering the detrimental effects of gut-heart axis is an emerging trend. Our goal is to investigate the causal relationship between gut microbiota and HF, with the aim of facilitating future exploration of microbiome-targeted approaches to prevent and delay the progression of HF.

Two-sample Mendelian randomization (MR) analysis was applied to investigate the causal association of the gut microbiome with HF among individuals of European ancestry. Genetic variants associated with the 196 bacterial taxa from MiBioGen consortium were used as exposure data, summary statistics for HF derived from Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) consortium were used as outcome data. Five MR methods were applied, including inverse variance weighted, maximum likelihood, MR-Egger, weighted median, and weighted mode. Reverse causality of instrumental variables (IVs) was tested by MR Steiger test of directionality. Strength of IVs was evaluated by F-statistics. Cochrane's Q test, MR-Egger regression analysis, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) tests were used to detect heterogeneity and pleiotropy. Leave-one-out method was used for testing the stability of results. Seven microbiomes were found to be associated with HF. Five of them were associated with higher risks of developing HF, these included Order_Selenomonadales (odds ratio [OR] = 1.11, P = 0.024), Family_Peptococcaceae (OR = 1.07, P = 0.045), Genus_Eubacterium eligens group (OR = 1.14, P = 0.022), Genus_Eubacterium oxidoreducens group (OR = 1.12, P = 0.011) and Genus_Flavonifractor (OR = 1.14, P = 0.012). Genus_Anaerostipes and Order_Bacillales were associated with lower risks of HF (OR = 0.90, P = 0.014; OR = 0.95, P = 0.042, respectively). Evidence of pleiotropy or heterogeneity was not observed.

We identified seven intestinal microbiomes that were causally associated with HF at the level of gene prediction. This study will help with the discovery of potential preventive and therapeutic targets for HF.