{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T18:48:45Z","timestamp":1791830925035,"version":"4.3.4"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100016350","name":"Sichuan Provincial Administration of Traditional Chinese Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100016350","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Previous observational studies have indicated that gut microbiota and metabolites may contribute to heart failure and its risk factors. However, with the limitation of reverse causality and confounder in observational studies, such relationship remains unclear. This study aims to reveal the causal effect of gut microbiota and metabolites on heart failure and its risk factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study collected summary statistics regarding gut microbiota and metabolites, heart failure, diabetes, hypertension, chronic kidney disease, myocardial infarction, atrial fibrillation, hypertrophic cardiomyopathy, dilated cardiomyopathy, coronary heart disease, valvular heart disease, and myocarditis. Two-sample Mendelian randomization analysis was performed using MR-Egger, inverse variance weighted (IVW), MR-PRESSO, maximum likelihood, and weighted median.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Results from gene prediction showed that among all gut microbiota, <jats:italic>candida, shigella<\/jats:italic>, and <jats:italic>campylobacter<\/jats:italic> were not associated with higher incidence of heart failure. However, genetic prediction suggested that for every 1 unit increase in <jats:italic>shigella<\/jats:italic> concentration, the relative risk increased by 38.1% for myocarditis and 13.3% for hypertrophic cardiomyopathy. Besides, for every 1 unit increased in <jats:italic>candida<\/jats:italic> concentration, the relative risk of chronic kidney disease increased by 7.1%. As for intestinal metabolites, genetic prediction results suggested that for every 1 unit increase in betaine, the relative risk of heart failure and myocardial infarction increased by 1.4% and 1.7%, separately.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study suggested new evidence of the relationship between gut microbiota and heart failure and its risk factors, which may shed light on designing microbiome- and microbiome-dependent metabolite interventions on heart failure and its risk factors in clinical trials in the future.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnut.2022.899746","type":"journal-article","created":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T13:57:22Z","timestamp":1655733442000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":77,"title":["Effects of Gut Microbiota and Metabolites on Heart Failure and Its Risk Factors: A Two-Sample Mendelian Randomization Study"],"prefix":"10.3389","volume":"9","author":[{"given":"Qiang","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.5603\/KP.2016.0141","article-title":"2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure","volume":"74","author":"Ponikowski","year":"2016","journal-title":"Kardiol Pol."},{"key":"B2","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1093\/eurheartj\/ehs104","article-title":"ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. developed in collaboration with the heart failure association (hfa) of the ESC","volume":"33","author":"McMurray","year":"2012","journal-title":"Eur Heart J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1136\/hrt.2003.025270","article-title":"Clinical epidemiology of heart failure","volume":"93","author":"Mosterd","year":"2007","journal-title":"Heart."},{"key":"B4","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1038\/nrcardio.2016.25","article-title":"Epidemiology and aetiology of heart failure","volume":"13","author":"Ziaeian","year":"2016","journal-title":"Nat Rev Cardiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1007\/s10741-016-9571-6","article-title":"Cardiac contractility modulation: a novel approach for the treatment of heart failure","volume":"21","author":"Abi-Samra","year":"2016","journal-title":"Heart Fail Rev."},{"key":"B6","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1056\/NEJMoa1409077","article-title":"Angiotensin-neprilysin inhibition versus enalapril in heart failure","volume":"371","author":"McMurray","year":"2014","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"S108","DOI":"10.1097\/MCG.0b013e3182309276","article-title":"Intestinal microecology in health and wellness","volume":"45","author":"Floch","year":"2011","journal-title":"J Clin Gastroenterol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.jchf.2015.10.009","article-title":"Pathogenic gut flora in patients with chronic heart failure","volume":"4","author":"Pasini","year":"2016","journal-title":"JACC Heart Fail."},{"key":"B9","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1111\/joim.12328","article-title":"Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure","volume":"277","author":"Tr\u00f8seid","year":"2015","journal-title":"J Intern Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e004947","DOI":"10.1161\/JAHA.116.004947","article-title":"Gut microbiota metabolites and risk of major adverse cardiovascular disease events and death: a systematic review and meta-analysis of prospective studies","volume":"6","author":"Heianza","year":"2017","journal-title":"J Am Heart Assoc."},{"key":"B11","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/s41569-018-0108-7","article-title":"Dietary metabolism, the gut microbiome, and heart failure","volume":"16","author":"Tang WHW Li","year":"2019","journal-title":"Nat Rev Cardiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ije\/dyg070","article-title":"'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?","volume":"32","author":"Smith","year":"2003","journal-title":"Int J Epidemiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"k601","DOI":"10.1136\/bmj.k601","article-title":"Reading mendelian randomisation studies: a guide, glossary, and checklist for clinicians","volume":"362","author":"Davies","year":"2018","journal-title":"BMJ."},{"key":"B14","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.cmet.2013.06.013","article-title":"A genome-wide association study of the human metabolome in a community-based cohort","volume":"18","author":"Rhee","year":"2013","journal-title":"Cell Metab."},{"key":"B15","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/s41588-020-00763-1","article-title":"Large-scale association analyses identify host factors influencing human gut microbiome composition","volume":"53","author":"Kurilshikov","year":"2021","journal-title":"Nat Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1371\/journal.pone.0236193","article-title":"Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure","volume":"11","author":"Shah","year":"2020","journal-title":"Nat Commun."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2941","DOI":"10.1038\/s41467-018-04951-w","article-title":"Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes","volume":"9","author":"Xue","year":"2018","journal-title":"Nat Commun."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1038\/s41588-018-0171-3","article-title":"Biobank-driven genomic discovery yields new insight into atrial fibrillation biology","volume":"50","author":"Nielsen","year":"2018","journal-title":"Nat Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1161\/CIRCRESAHA.117.312086","article-title":"Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease","volume":"122","author":"van der Harst","year":"2018","journal-title":"Circ Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"10023","DOI":"10.1038\/ncomms10023","article-title":"Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function","volume":"7","author":"Pattaro","year":"2016","journal-title":"Nat Commun."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1038\/s41588-018-0205-x","article-title":"Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits","volume":"50","author":"Evangelou","year":"2018","journal-title":"Nat Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1038\/s41588-021-00931-x","article-title":"A cross-population atlas of genetic associations for 220 human phenotypes","volume":"53","author":"Sakaue","year":"2021","journal-title":"Nat Genet."},{"key":"B23","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1177\/0962280210394459","article-title":"Using multiple genetic variants as instrumental variables for modifiable risk factors","volume":"21","author":"Palmer","year":"2012","journal-title":"Stat Methods Med Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1002\/sim.3034","article-title":"Mendelian randomization: using genes as instruments for making causal inferences in epidemiology","volume":"27","author":"Lawlor","year":"2008","journal-title":"Stat Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1038\/ng.2213","article-title":"Genetic investigation of ANthropometric Traits (GIANT) Consortium; DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium, et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits","volume":"44","author":"Yang","year":"2012","journal-title":"Nat Genet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1093\/aje\/kwt084","article-title":"Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators","volume":"178","author":"Pierce","year":"2013","journal-title":"Am J Epidemiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int J Epidemiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet Epidemiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat Genet."},{"key":"B30","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1007\/s10654-017-0255-x","article-title":"Interpreting findings from Mendelian randomization using the MR-Egger method","volume":"32","author":"Burgess","year":"2017","journal-title":"Eur J Epidemiol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.1136\/bmj.315.7121.1533","article-title":"Meta-analysis: principles and procedures","volume":"315","author":"Egger","year":"1997","journal-title":"BMJ."},{"key":"B32","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nature09922","article-title":"Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease","volume":"472","author":"Wang","year":"2011","journal-title":"Nature."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e37883","DOI":"10.1371\/journal.pone.0037883","article-title":"Betaine and secondary events in an acute coronary syndrome cohort","volume":"7","author":"Lever","year":"2012","journal-title":"PLoS ONE."},{"key":"B34","doi-asserted-by":"publisher","first-page":"e114969","DOI":"10.1371\/journal.pone.0114969","article-title":"Betaine and trimethylamine-N-oxide as predictors of cardiovascular outcomes show different patterns in diabetes mellitus: an observational study","volume":"9","author":"Lever","year":"2014","journal-title":"PLoS ONE."},{"key":"B35","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1093\/clinchem\/hvaa224","article-title":"Choline metabolism and risk of atrial fibrillation and heart failure in the PREDIMED study","volume":"67","author":"Papandreou","year":"2021","journal-title":"Clin Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.cardfail.2014.11.006","article-title":"Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure","volume":"21","author":"Tang","year":"2015","journal-title":"J Card Fail."},{"key":"B37","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1002\/prot.22266","article-title":"The osmolyte betaine promotes protein misfolding and disruption of protein aggregates","volume":"75","author":"Natalello","year":"2009","journal-title":"Proteins."},{"key":"B38","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1093\/advances\/nmz064","article-title":"The gut microbial metabolite trimethylamine N-oxide and hypertension risk: a systematic review and dose-response meta-analysis","volume":"11","author":"Ge","year":"2020","journal-title":"Adv Nutr."},{"key":"B39","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1161\/HYPERTENSIONAHA.120.14759","article-title":"Trimethylamine-N-oxide promotes age-related vascular oxidative stress and endothelial dysfunction in mice and healthy humans","volume":"76","author":"Brunt","year":"2020","journal-title":"Hypertension."},{"key":"B40","doi-asserted-by":"publisher","first-page":"437","DOI":"10.3390\/metabo10110437","article-title":"Characteristic of metabolic status in heart failure and its impact in outcome perspective","volume":"10","author":"Tang","year":"2020","journal-title":"Metabolites."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1093\/ajcn\/nqab238","article-title":"Metabolomics of the tryptophan-kynurenine degradation pathway and risk of atrial fibrillation and heart failure: potential modification effect of Mediterranean diet","volume":"114","author":"Razquin","year":"2021","journal-title":"Am J Clin Nutr."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1016\/j.jacc.2015.02.018","article-title":"Metabolic disturbances identified in plasma are associated with outcomes in patients with heart failure: diagnostic and prognostic value of metabolomics","volume":"65","author":"Cheng","year":"2015","journal-title":"J Am Coll Cardiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1002\/ejhf.1076","article-title":"Nuclear magnetic resonance-based metabolomics identifies phenylalanine as a novel predictor of incident heart failure hospitalization: results from PROSPER and FINRISK 1997","volume":"20","author":"Delles","year":"2018","journal-title":"Eur J Heart Fail."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2884","DOI":"10.1002\/ehf2.12896","article-title":"Elevated plasma phenylalanine predicts mortality in critical patients with heart failure","volume":"7","author":"Chen","year":"2020","journal-title":"ESC Heart Fail."}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2022.899746\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T13:57:28Z","timestamp":1655733448000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2022.899746\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,20]]},"references-count":44,"alternative-id":["10.3389\/fnut.2022.899746"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2022.899746","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,20]]},"article-number":"899746"}}