{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T18:20:57Z","timestamp":1786818057674,"version":"build-2736575974"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"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","award":["81870308"],"award-info":[{"award-number":["81870308"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEI\/ARB) are the first-line drugs for the treatment of essential hypertension (HTN), one of the most important risk factors for cardiovascular and cerebrovascular diseases. Intestinal flora and microbial metabolites have been demonstrated to play important roles in blood pressure (BP) regulation and HTN development. However, it remains elusive that intestinal bacteria and metabolites are associated with the protective effects of ACEI\/ARB anti-hypertensive drugs against HTN. In this study, we evaluated the effect of ACEI\/ARB on gut microbiome and metabolites in patients suffering from HTN. We performed 16S rRNA sequencing and fecal metabolomic analysis of 36 HTN patients placed on ACEI\/ARB therapy and 19 newly diagnosed HTN patients with no history of anti-hypertensive treatment. Patients under medication treatment were further classified into well-controlled (<jats:italic>n<\/jats:italic> = 24) and poor-controlled (<jats:italic>n<\/jats:italic> = 12) groups according to their BP levels. The ACEI\/ARB improved the intestinal microbiome of the HTN patients by reducing potentially pathogenic bacteria such as <jats:italic>Enterobacter<\/jats:italic> and <jats:italic>Klebsiella<\/jats:italic> and increasing beneficial bacteria such as <jats:italic>Odoribacter<\/jats:italic>. Moreover, ACEI\/ARB therapy was correlated with significant metabolomic changes in the HTN patients, including progressively enhanced inositol from poor-controlled to well-controlled groups. The profiles of gut bacteria were linked to the production of metabolites, and inositol was negatively correlated with <jats:italic>Klebsiella<\/jats:italic>, <jats:italic>Enterobacter<\/jats:italic>, and <jats:italic>Proteobacteria<\/jats:italic>. Our study suggests that ACEI\/ARB modulates gut microbial composition and functions and alters microbial metabolites in HTN patients.<\/jats:p>","DOI":"10.3389\/fcell.2022.861829","type":"journal-article","created":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T23:06:35Z","timestamp":1648508795000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Antihypertensive Therapy by ACEI\/ARB Is Associated With Intestinal Flora Alterations and Metabolomic Profiles in Hypertensive Patients"],"prefix":"10.3389","volume":"10","author":[{"given":"Ying","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinchun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mulei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1016\/j.chom.2015.04.004","article-title":"Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life","volume":"17","author":"B\u00e4ckhed","year":"2015","journal-title":"Cell Host & Microbe"},{"key":"B2","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/s41586-021-04091-0","article-title":"The Human Microbiome Encodes Resistance to the Antidiabetic Drug Acarbose","volume":"600","author":"Balaich","year":"2021","journal-title":"Nature"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1111\/bph.14905","article-title":"FK506 regulates Ca(2+) release evoked by inositol 1,4,5-trisphosphate independently of FK-binding protein in endothelial cells","volume":"177","author":"Buckley","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1042\/CS20191253","article-title":"Short-chain Fatty Acids Accompanying Changes in the Gut Microbiome Contribute to the Development of Hypertension in Patients with Preeclampsia","volume":"134","author":"Chang","year":"2020","journal-title":"Clin. Sci. (Lond)"},{"key":"B4","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1161\/hypertensionaha.120.15317","article-title":"ACE (Angiotensin-Converting Enzyme) Inhibitors\/Angiotensin Receptor Blockers Are Associated with Lower Colorectal Cancer Risk","volume":"76","author":"Cheung","year":"2020","journal-title":"Hypertension"},{"key":"B5","first-page":"105","article-title":"Metabolic and Hormonal Effects of Myo-Inositol in Women with Polycystic Ovary Syndrome: a Double-Blind Trial","volume":"13","author":"Costantino","year":"2009","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1530\/eje-11-0840","article-title":"Inositol Administration Reduces Oxidative Stress in Erythrocytes of Patients with Polycystic Ovary Syndrome","volume":"166","author":"Don\u00e0","year":"2012","journal-title":"Eur. J. Endocrinol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1038\/nrmicro.2017.64","article-title":"Klebsiella pneumoniae: when a Colonizer Turns Bad","volume":"15","author":"Dorman","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1007\/s10067-006-0391-2","article-title":"A Possible Link between Crohn's Disease and Ankylosing Spondylitis via Klebsiella Infections","volume":"26","author":"Ebringer","year":"2007","journal-title":"Clin. Rheumatol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.chom.2010.08.004","article-title":"Enterobacteriaceae Act in Concert with the Gut Microbiota to Induce Spontaneous and Maternally Transmitted Colitis","volume":"8","author":"Garrett","year":"2010","journal-title":"Cell Host & Microbe"},{"key":"B10","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1097\/gme.0b013e3181e8e1b1","article-title":"Effects of Myo-Inositol Supplementation in Postmenopausal Women with Metabolic Syndrome","volume":"18","author":"Giordano","year":"2011","journal-title":"Menopause"},{"key":"B11","doi-asserted-by":"publisher","first-page":"200","DOI":"10.4056\/sigs.1714269","article-title":"Complete Genome Sequence of Odoribacter Splanchnicus Type Strain (1651\/6T)","volume":"4","author":"G\u00f6ker","year":"2011","journal-title":"Stand. Genomic Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1161\/hypertensionaha.116.07910","article-title":"Increased Systolic and Diastolic Blood Pressure Is Associated with Altered Gut Microbiota Composition and Butyrate Production in Early Pregnancy","volume":"68","author":"Gomez-Arango","year":"2016","journal-title":"Hypertension"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.1161\/HYPERTENSIONAHA.120.15123","article-title":"Gut Microbiota Profile Identifies Transition from Compensated Cardiac Hypertrophy to Heart Failure in Hypertensive Rats","volume":"76","author":"Guti\u00e9rrez-Calabr\u00e9s","year":"2020","journal-title":"Hypertension"},{"key":"B14","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.clnesp.2021.06.017","article-title":"The Effect of Inositol Supplementation on Blood Pressure: A Systematic Review and Meta-Analysis of Randomized-Controlled Trials","volume":"44","author":"Hashemi Tari","year":"2021","journal-title":"Clin. Nutr. ESPEN"},{"key":"B15","doi-asserted-by":"publisher","first-page":"5778","DOI":"10.7150\/thno.55946","article-title":"Multi-omics Study Reveals that Statin Therapy Is Associated with Restoration of Gut Microbiota Homeostasis and Improvement in Outcomes in Patients with Acute Coronary Syndrome","volume":"11","author":"Hu","year":"2021","journal-title":"Theranostics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1161\/hypertensionaha.118.12588","article-title":"Gut Microbiota and Fecal Levels of Short-Chain Fatty Acids Differ upon 24-Hour Blood Pressure Levels in Men","volume":"74","author":"Huart","year":"2019","journal-title":"Hypertension"},{"key":"B17","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1136\/gutjnl-2015-310376","article-title":"Proton Pump Inhibitors Affect the Gut Microbiome","volume":"65","author":"Imhann","year":"2016","journal-title":"Gut"},{"key":"B18","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1136\/gutjnl-2015-310861","article-title":"Proton Pump Inhibitors Alter the Composition of the Gut Microbiota","volume":"65","author":"Jackson","year":"2016","journal-title":"Gut"},{"key":"B19","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1007\/s13238-020-00785-9","article-title":"Gut Microbes in Cardiovascular Diseases and Their Potential Therapeutic Applications","volume":"12","author":"Jin","year":"2021","journal-title":"Protein Cell"},{"key":"B20","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1038\/sj.ejcn.1602081","article-title":"Effects of Pinitol Isolated from Soybeans on Glycaemic Control and Cardiovascular Risk Factors in Korean Patients with Type II Diabetes Mellitus: a Randomized Controlled Study","volume":"59","author":"Kim","year":"2005","journal-title":"Eur. J. Clin. Nutr."},{"key":"B21","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/s41586-021-03891-8","article-title":"Bioaccumulation of Therapeutic Drugs by Human Gut Bacteria","volume":"597","author":"Kl\u00fcnemann","year":"2021","journal-title":"Nature"},{"key":"B22","doi-asserted-by":"publisher","first-page":"127","DOI":"10.3945\/ajcn.110.005447","article-title":"Erythrocyte Membrane Phospholipid Fatty Acids, Desaturase Activity, and Dietary Fatty Acids in Relation to Risk of Type 2 Diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study","volume":"93","author":"Kr\u00f6ger","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"B23","doi-asserted-by":"publisher","first-page":"399","DOI":"10.3390\/microorganisms7100399","article-title":"Characteristics of Gut Microbiota in Patients with Hypertension And\/or Hyperlipidemia: A Cross-Sectional Study on Rural Residents in Xinxiang County, Henan Province","volume":"7","author":"Li","year":"2019","journal-title":"Microorganisms"},{"key":"B24","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s40168-016-0222-x","article-title":"Gut Microbiota Dysbiosis Contributes to the Development of Hypertension","volume":"5","author":"Li","year":"2017","journal-title":"Microbiome"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.3389\/fmicb.2020.01256","article-title":"Colonization of Mice with Amoxicillin-Associated Klebsiella Variicola Drives Inflammation via Th1 Induction and Treg Inhibition","volume":"11","author":"Lin","year":"2020","journal-title":"Front. Microbiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e011704","DOI":"10.1161\/jaha.118.011704","article-title":"Inositol 1,4,5\u2010Trisphosphate Receptors in Endothelial Cells Play an Essential Role in Vasodilation and Blood Pressure Regulation","volume":"8","author":"Lin","year":"2019","journal-title":"Jaha"},{"key":"B27","first-page":"579","article-title":"Writing Group of 2010 Chinese Guidelines for the Management of Hypertension[2010 Chinese Guidelines for the Management of Hypertension]","volume":"39","author":"Liu","year":"2011","journal-title":"Zhonghua Xin Xue Guan Bing Za Zhi"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e74487","DOI":"10.1371\/journal.pone.0074487","article-title":"Comparative Genome Analysis of Enterobacter cloacae","volume":"8","author":"Liu","year":"2013","journal-title":"PLoS One"},{"key":"B29","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1152\/physiolgenomics.00136.2014","article-title":"Evidence for a Link between Gut Microbiota and Hypertension in the Dahl Rat","volume":"47","author":"Mell","year":"2015","journal-title":"Physiol. Genomics"},{"key":"B30","doi-asserted-by":"publisher","first-page":"R79","DOI":"10.1186\/gb-2012-13-9-r79","article-title":"Dysfunction of the Intestinal Microbiome in Inflammatory Bowel Disease and Treatment","volume":"13","author":"Morgan","year":"2012","journal-title":"Genome Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1099\/ijs.0.014571-0","article-title":"Alistipes Indistinctus Sp. Nov. And Odoribacter Laneus Sp. nov., Common Members of the Human Intestinal Microbiota Isolated from Faeces","volume":"60","author":"Nagai","year":"2010","journal-title":"Int. J. Syst. Evol. Microbiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1586\/eri.13.12","article-title":"Clinical Relevance of the ESKAPE Pathogens","volume":"11","author":"Pendleton","year":"2013","journal-title":"Expert Rev. Anti-infective Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"155932582110113","DOI":"10.1177\/15593258211011342","article-title":"An Insight into Intestinal Microbiota of Spontaneously Hypertensive Rats after Valsartan Administration","volume":"19","author":"Qi","year":"2021","journal-title":"Dose-Response"},{"key":"B34","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1079\/bjn2000279","article-title":"Dietary Fat Intake in Healthy Adolescents: Inverse Relationships between the Estimated Intake of Saturated Fatty Acids and Serum Cholesterol","volume":"85","author":"Samuelson","year":"2001","journal-title":"Br. J. Nutr."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.3945\/ajcn.114.092544","article-title":"Serum Pentadecanoic Acid (15:0), a Short-Term Marker of Dairy Food Intake, Is Inversely Associated with Incident Type 2 Diabetes and its Underlying Disorders","volume":"100","author":"Santaren","year":"2014","journal-title":"Am. J. Clin. Nutr."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.1053\/j.gastro.2020.05.034","article-title":"Associations between Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blocker Use, Gastrointestinal Symptoms, and Mortality Among Patients with COVID-19","volume":"159","author":"Tan","year":"2020","journal-title":"Gastroenterology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1038\/s41467-019-14177-z","article-title":"Impact of Commonly Used Drugs on the Composition and Metabolic Function of the Gut Microbiota","volume":"11","author":"Vich Vila","year":"2020","journal-title":"Nat. Commun."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2404","DOI":"10.1038\/oby.2011.234","article-title":"Obesity Modifies the Relations between Serum Markers of Dairy Fats and Inflammation and Oxidative Stress Among Adolescents","volume":"19","author":"Wang","year":"2011","journal-title":"Obesity (Silver Spring)"},{"key":"B39","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1161\/hypertensionaha.120.16154","article-title":"Gut Microbiota and Host Plasma Metabolites in Association with Blood Pressure in Chinese Adults","volume":"77","author":"Wang","year":"2021","journal-title":"Hypertension"},{"key":"B40","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1093\/ajh\/hpt186","article-title":"Hypertension Control in Community Health Centers across China: Analysis of Antihypertensive Drug Treatment Patterns","volume":"27","author":"Wang","year":"2014","journal-title":"Am. J. Hypertens."},{"key":"B41","doi-asserted-by":"publisher","first-page":"194","DOI":"10.3945\/ajcn.2009.29054","article-title":"Biomarkers of Milk Fat and the Risk of Myocardial Infarction in Men and Women: a Prospective, Matched Case-Control Study","volume":"92","author":"Warensj\u00f6","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"B42","doi-asserted-by":"publisher","first-page":"ajcn152702","DOI":"10.3945\/ajcn.117.152702","article-title":"Odd-chain Fatty Acids as a Biomarker for Dietary Fiber Intake: a Novel Pathway for Endogenous Production from Propionate","volume":"105","author":"Weitkunat","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"B43","doi-asserted-by":"publisher","first-page":"e426","DOI":"10.1161\/cir.0000000000000597","article-title":"2017 ACC\/AHA\/AAPA\/ABC\/ACPM\/AGS\/APhA\/ASH\/ASPC\/NMA\/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines","volume":"138","author":"Whelton","year":"2018","journal-title":"Circulation"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1953","DOI":"10.1097\/hjh.0000000000001940","article-title":"2018 ESC\/ESH Guidelines for the Management of Arterial Hypertension","volume":"36","author":"Williams","year":"2018","journal-title":"J. Hypertens."},{"key":"B45","year":"2021"},{"key":"B46","doi-asserted-by":"publisher","first-page":"109040","DOI":"10.1016\/j.biopha.2019.109040","article-title":"Candesartan Attenuates Hypertension-Associated Pathophysiological Alterations in the Gut","volume":"116","author":"Wu","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"B47","doi-asserted-by":"publisher","first-page":"116780","DOI":"10.1016\/j.carbpol.2020.116780","article-title":"Roles of Gut Microbiota and Metabolites in a Homogalacturonan-type Pectic Polysaccharide from Ficus Pumila Linn. Fruits Mediated Amelioration of Obesity","volume":"248","author":"Wu","year":"2020","journal-title":"Carbohydr. Polym."},{"key":"B48","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.bbi.2019.06.039","article-title":"Altered Gut Microbiota and Mucosal Immunity in Patients with Schizophrenia","volume":"85","author":"Xu","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"B49","doi-asserted-by":"publisher","first-page":"381","DOI":"10.3389\/fcimb.2017.00381","article-title":"Alterations of the Gut Microbiome in Hypertension","volume":"7","author":"Yan","year":"2017","journal-title":"Front. Cel. Infect. Microbiol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"719599","DOI":"10.3389\/fmicb.2021.719599","article-title":"Glycan Biosynthesis Ability of Gut Microbiota Increased in Primary Hypertension Patients Taking Antihypertension Medications and Potentially Promoted by Macrophage-Adenosine Monophosphate-Activated Protein Kinase","volume":"12","author":"Zheng","year":"2021","journal-title":"Front. Microbiol."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.861829\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T23:06:46Z","timestamp":1648508806000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.861829\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,23]]},"references-count":51,"alternative-id":["10.3389\/fcell.2022.861829"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2022.861829","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,23]]},"article-number":"861829"}}