Genome-Wide Association Analysis of Gut Microbiome and Serum Metabolomics Identifies Heart Failure Therapeutic Targets

Download This Paper Open PDF in Browser Add Paper to My Library Share: Permalink Using these links will ensure access to this page indefinitely Copy URL Preprints with The Lancet is part of SSRN´s First Look, a place where journals identify content of interest prior to publication. Authors have opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed. The findings should not be used for clinical or public health decision making and should not be presented to a lay audience without highlighting that they are preliminary and have not been peer-reviewed. For more information on this collaboration, see the comments published in The Lancet about the trial period, and our decision to make this a permanent offering, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com. Genome-Wide Association Analysis of Gut Microbiome and Serum Metabolomics Identifies Heart Failure Therapeutic Targets 30 Pages Posted: 26 Feb 2024 See all articles by Xianbin LiXianbin LiKunming Medical UniversityYiming MaKunming Medical UniversityChaoyue ZhangKunming Medical UniversityChangzhi LiuKunming Medical UniversityZhao huKunming Medical UniversityYunke ShiKunming Medical UniversityMingqiang WangKunming Medical UniversityYushan XuKunming Medical UniversityKaixiong QingKunming Medical UniversityLixing ChenKunming Medical UniversityYan AngKunming Medical UniversityXingyu CaoKunming Medical UniversityXuejuan MaKunming Medical UniversityLiping LiuKunming Medical UniversityLi ShiKunming Medical UniversityJincheng WangKunming Medical UniversityFanru LinKunming Medical UniversityJinping LunKunming Medical UniversityJifa TaoKunming Medical UniversityXinyu LiKunming Medical UniversityXingying YuKunming Medical UniversityWei ZhangKunming Medical UniversityHaipeng GaoKunming Medical UniversityZhengyu LiKunming Medical UniversityHongbo CaiKunming Medical UniversityYunzhu PengKunming Medical UniversityHongyan CaiKunming Medical University More... 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.Findings: 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.Interpretation: Our study utilized MR to investigate the causal relationships between gut microbiota, serum metabolites, and heart failure. 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.Funding: This work was supported by the National Natural Science Foundation of China (Grant No. 82270372 and 82260087), the Program Innovative Research Team in Science and Technology(“Xingdian Talents” Support Project) of Yunnan Province(Grant No. 202305AS350024), the Yunnan Health Training Project of High Level Talents(Grant No. L-2019025 and H-2019052), the Famous Doctor Special Project of the Yunnan Health Training Project of High-Level Talents(Grant No RLMY20190006), the Special Foundation Projects of Joint Applied Basic Research of Yunnan Provincial Department of Science and Technology with Kunming Medical University(Grant No. 202301AS070071, 202301AT070199, 202301AY070001-119, 202201AY070001-041 and 202301AY070001-065), and the Program Innovative Research Team in Science and Technology in Kunming Medical University (Grant No. CXTD202202).Declaration of Interest: The authors declared no conficts of interest, financial, or otherwise. Keywords: Gut microbiome, Genetically determined metabolites, Heart failure, Mendelian randomization, Mediation analysis Suggested Citation: Suggested Citation Li, Xianbin and Ma, Yiming and Zhang, Chaoyue and Liu, Changzhi and hu, Zhao and Shi, Yunke and Wang, Mingqiang and Xu, Yushan and Qing, Kaixiong and Chen, Lixing and Ang, Yan and Cao, Xingyu and Ma, Xuejuan and Liu, Liping and Shi, Li and Wang, Jincheng and Lin, Fanru and Lun, Jinping and Tao, Jifa and Li, Xinyu and Yu, Xingying and Zhang, Wei and Gao, Haipeng and Li, Zhengyu and Cai, Hongbo and Peng, Yunzhu and Cai, Hongyan, Genome-Wide Association Analysis of Gut Microbiome and Serum Metabolomics Identifies Heart Failure Therapeutic Targets. Available at SSRN: https://ssrn.com/abstract=4738728 Xianbin Li Kunming Medical University ( email ) Yiming Ma Kunming Medical University ( email ) Chaoyue Zhang Kunming Medical University ( email ) Changzhi Liu Kunming Medical University ( email ) Zhao Hu Kunming Medical University ( email ) Yunke Shi Kunming Medical University ( email ) Mingqiang Wang Kunming Medical University ( email ) Yushan Xu Kunming Medical University ( email ) Kaixiong Qing Kunming Medical University ( email ) Lixing Chen Kunming Medical University ( email ) Yan Ang Kunming Medical University ( email ) Xingyu Cao Kunming Medical University ( email ) Xuejuan Ma Kunming Medical University ( email ) Liping Liu Kunming Medical University ( email ) Li Shi Kunming Medical University ( email ) Jincheng Wang Kunming Medical University ( email ) Fanru Lin Kunming Medical University ( email ) Jinping Lun Kunming Medical University ( email ) Jifa Tao Kunming Medical University ( email ) Xinyu Li Kunming Medical University ( email ) Xingying Yu Kunming Medical University ( email ) Wei Zhang Kunming Medical University ( email ) Haipeng Gao Kunming Medical University ( email ) Zhengyu Li Kunming Medical University ( email ) Hongbo Cai Kunming Medical University ( email ) Yunzhu Peng Kunming Medical University ( email ) Hongyan Cai (Contact Author) Kunming Medical University ( email ) Download This Paper Open PDF in Browser Please enable JavaScript to view the comments powered by Disqus. Click here to go to TheLancet.com Go to TheLancet.com Paper statistics Downloads 2 Abstract Views 17 PlumX Metrics Preprints with The Lancet Specialties All Journals (16541) Allergy & Immunology (1064) Anaesthesia & Analgesia (51) Cardiology & Vascular Medicine (1159) Child & Adoloscence Health (1297) Critical Care (577) Dermatology (104) Digital Health (805) Endocrinology (952) Gastroenterology (958) Genetics & Genomics (2200) Geriatrics (201) Global Health (1281) Haematology (652) Infectious Diseases (5577) Nephrology (340) Neurology (1463) Nutrition (496) Obstetrics & Gynaecology (767) Oncology (3344) Ophthalmology (228) Otolaryngology (112) Planetary Health (256) Primary Care (853) Psychiatry (1080) Public Health (3541) Radiology & Medical Imaging (451) Respiratory Medicine (696) Rheumatology & Orthopaedics (603) Surgery (398) Urology (97) Related eJournals Preprints with The Lancet Follow Preprints with The Lancet Subscribe to this free journal for more curated articles on this topic FOLLOWERS 256 PAPERS 16,541 Medical Genetics & Genomics eJournal Follow Medical Genetics & Genomics eJournal Subscribe to this fee journal for more curated articles on this topic FOLLOWERS 52 PAPERS 2,686 Gastroenterology eJournal Follow Gastroenterology eJournal Subscribe to this fee journal for more curated articles on this topic FOLLOWERS 42 PAPERS 1,344 Feedback Feedback to SSRN Feedback (required) Email (required) Submit If you need immediate assistance, call 877-SSRNHelp (877 777 6435) in the United States, or +1 212 448 2500 outside of the United States, 8:30AM to 6:00PM U.S. Eastern, Monday - Friday.