Genome-wide association analysis of gut microbiome and serum metabolomics identifies heart failure therapeutic targets
Authors: Li Xianbin , Ma Yiming , Zhang Chaoyue , Liu Changzhi , hu Zhao , Shi Yunke , Wang Mingqiang , Xu Yushan , Qing Kaixiong , Chen Lixing , Ang Yan , Cao Xingyu , Ma Xuejuan , Liu Liping , Shi Li , Wang Jincheng , Lin Fanru , Lun Jinping , Tao Jifa , Li Xinyu , Yu Xingying , Zhang Wei , Gao Haipeng , Li Zhengyu , Cai Hongbo , Peng Yunzhu , Cai Hongyan 
Published: March 2024

Abstract
Background
Previous investigations have established a correlation between the gut microbiota and heart failure (HF). Nevertheless, the causal relationship and potential mediators between these two factors remain elusive. In this study, we aim to elucidate the causal relationship and identify potential serum metabolites that regulate the gut microbiota and HF from a genetic perspective. Our ultimate goal is to uncover potential targets for the prevention and treatment of heart failure.
Methods
Two-sample bidirectional Mendelian randomization (MR) and mediated Mendelian randomization studies were conducted using pooled statistics from genome-wide association studies of 211 gut microbial taxa (MiBioGen, n = 18340), 486 serum metabolites (n = 7824), and heart failure (47,309 cases and 93,0014 controls). Inverse variance weighted estimation (IVW) was used as the primary analysis method, with Weighted median (WM), MR-Egger, Simple mode, and Weighted mode as complementary analyses. Pleiotropy and heterogeneity were assessed using MR-PRESSO, MR-Egger intercept, and Cochran's Q statistical analysis. A multivariate MR method based on Bayesian model averaging (MR-BMA) was used to prioritize the most likely causal serum metabolites, and metabolic pathway analyses were performed using MetbraAnalyst 5.0 software.
Results
Among the 211 gut microbiota categories, 10 were causally associated with heart failure risk, including Genus Eubacterium eligens group (OR = 1.126, 95% CI = 1.017–1.247, P = 0.023). Of the 486 human circulating metabolites, 13 with known structure such as Isoleucine (OR = 1.978, 95% CI = 1.191–3.287, P = 0.008) were causally associated with heart failure risk. The top three serum metabolites with the strongest causal association with heart failure were pyroglutamine (marginal inclusion probability(MIP) = 0.609, model averaged causal effect(MACE) = 0.141), isoleucin (MIP = 0.591, MACE = 0.354), and cholesterol (MIP = 0.59, MACE = 0.266). Mediator MR analysis indicated that Isoleucine may mediate 23.86% of the causal effect of Genus Eubacterium eligens group on heart failure. Further metabolic pathway analysis revealed that the "Valine, leucine and isoleucine biosynthesis" pathway may be involved in the development of heart failure.
Conclusions
Our findings suggest that specific gut microbial taxa and serum metabolites are independently associated with heart failure risk. Notably, Isoleucine emerged as a significant determinant of heart failure, potentially mediating the relationship between gut microbiota and heart failure. Furthermore, our results indicate that the "Valine, leucine and isoleucine biosynthesis" pathway may play a role in the development of heart failure. In summary, our research provides novel insights into the potential targets for prevention and treatment of heart failure, focusing on the interplay between intestinal flora and circulating metabolites in the human body.