{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:30:05Z","timestamp":1786613405055,"version":"build-2736575974"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cardiac dysfunction and arrhythmias are serious complications of sepsis-induced cardiomyopathy and are closely associated with increased mortality. The gut microbial metabolite phenylacetylglutamine (PAGln) has been shown to be closely associated with the prognosis of patients with heart failure. However, it remains unclear whether PAGln plays a role in regulating sepsis-induced cardiac dysfunction and ventricular arrhythmias (VAs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective and methods<\/jats:title>\n                    <jats:p>The objective of this study is to evaluate the effects of PAGln on ventricular remodeling and VAs in mice with sepsis. In this study, we administered intraperitoneal injections of PAGln to mice for 14 days as a pretreatment, followed by stimulation with lipopolysaccharide (LPS) to establish a sepsis model, which was then evaluated using histopathology, molecular biology, cardiac electrophysiology, and echocardiography.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that PAGln pretreatment exacerbated LPS-induced cardiac dysfunction and LPS-mediated inflammatory responses. Furthermore, PAGln exacerbated cardiac electrical remodeling and increased susceptibility to VAs in LPS-treated mice. Mechanistically, PAGln may participate in mediating sepsis-induced inflammation, cardiac dysfunction, and susceptibility to VAs by regulating the ferroptosis and TLR4\/NF-\u03baB signaling pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study preliminarily demonstrates that the gut microbial metabolite PAGln exacerbates LPS-induced cardiac dysfunction and inflammation and increases susceptibility to VAs, a mechanism that may be associated with the activation of ferroptosis and the TLR4\/NF-\u03baB signaling pathway.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1870510","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:10:15Z","timestamp":1786612215000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Phenylacetylglutamine exacerbates sepsis-induced cardiac dysfunction and left ventricular remodeling via the ferroptosis and TLR4\/NF-\u03baB pathway"],"prefix":"10.3389","volume":"13","author":[{"given":"Xin","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianhua","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Renmin Hospital of Wuhan University","place":["Wuhan, Hubei, China"]},{"name":"Cardiovascular Research Institute of Wuhan University","place":["Wuhan, China"]},{"name":"Hubei Key Laboratory of Cardiology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangji","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/S0140-6736(18)30696-2","article-title":"Sepsis and septic shock","volume":"392","author":"Cecconi","year":"2018","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1186\/s13054-024-05221-6","article-title":"Megakaryocyte in sepsis: the trinity of coagulation, inflammation and immunity","volume":"28","author":"Hua","year":"2024","journal-title":"Crit Care"},{"key":"B3","doi-asserted-by":"publisher","first-page":"3339","DOI":"10.1093\/eurheartj\/ehaf340","article-title":"Sepsis-induced cardiomyopathy","volume":"46","author":"Aissaoui","year":"2025","journal-title":"Eur Heart J"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2643","DOI":"10.3390\/biomedicines13112643","article-title":"Sepsis-Induced cardiomyopathy and cardiac arrhythmias. Pathophysiology and implications for novel therapeutic approaches","volume":"13","author":"Pamporis","year":"2025","journal-title":"Biomedicines"},{"key":"B5","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s13073-025-01493-x","article-title":"Microbiome-based therapeutics towards healthier aging and longevity","volume":"17","author":"Kadyan","year":"2025","journal-title":"Genome Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"107806","DOI":"10.1016\/j.phrs.2025.107806","article-title":"Interaction between gut-heart axis in sepsis-induced cardiomyopathy","volume":"217","author":"Zhou","year":"2025","journal-title":"Pharmacol Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1015386","DOI":"10.3389\/fcimb.2022.1015386","article-title":"Gut microbiota-derived indole 3-propionic acid partially activates aryl hydrocarbon receptor to promote macrophage phagocytosis and attenuate septic injury","volume":"12","author":"Huang","year":"2022","journal-title":"Front Cell Infect Microbiol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.molimm.2025.05.024","article-title":"Gut microbiota-derived proline-leucine dipeptide aggravated sepsis-induced acute lung injury via activating Nod2\/NF-kappa B signaling pathway","volume":"184","author":"Yang","year":"2025","journal-title":"Mol Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1161\/CIRCRESAHA.120.316242","article-title":"Gut Microbiota and cardiovascular disease","volume":"127","author":"Witkowski","year":"2020","journal-title":"Circ Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e009972","DOI":"10.1161\/CIRCHEARTFAILURE.122.009972","article-title":"Gut microbiota-generated phenylacetylglutamine and heart failure","volume":"16","author":"Romano","year":"2023","journal-title":"Circ Heart Fail"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e038175","DOI":"10.1161\/JAHA.124.038175","article-title":"Association of circulating phenylacetylglutamine with multi-vessel coronary disease severity and outcomes in ST-segment-elevation myocardial infarction","volume":"14","author":"Zhao","year":"2025","journal-title":"J Am Heart Assoc"},{"key":"B12","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.cell.2020.02.016","article-title":"A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors","volume":"180","author":"Nemet","year":"2020","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1147687","DOI":"10.3389\/fcimb.2023.1147687","article-title":"Gut microbiota and cardiac arrhythmia","volume":"13","author":"Fan","year":"2023","journal-title":"Front Cell Infect Microbiol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1007\/s10495-024-02046-0","article-title":"The gut microbial metabolite phenylacetylglutamine increases susceptibility to atrial fibrillation after myocardial infarction through ferroptosis and NLRP3 inflammasome","volume":"30","author":"Wang","year":"2025","journal-title":"Apoptosis"},{"key":"B15","doi-asserted-by":"publisher","first-page":"3532","DOI":"10.7150\/thno.103809","article-title":"The m6A modification of SOX18 leads to increased PTX3 and cardiomyocyte pyroptosis in sepsis-induced cardiomyopathy","volume":"15","author":"Sun","year":"2025","journal-title":"Theranostics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1038\/s43587-024-00795-w","article-title":"Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence","volume":"5","author":"Yang","year":"2025","journal-title":"Nat Aging"},{"key":"B17","doi-asserted-by":"publisher","first-page":"108341","DOI":"10.1016\/j.jnutbio.2020.108341","article-title":"3,3-Dimethyl-1-butanol attenuates cardiac remodeling in pressure-overload-induced heart failure mice","volume":"78","author":"Wang","year":"2020","journal-title":"J Nutr Biochem"},{"key":"B18","doi-asserted-by":"publisher","first-page":"103576","DOI":"10.1016\/j.redox.2025.103576","article-title":"Succinate predisposes mice to atrial fibrillation by impairing mitochondrial function via SUCNR1\/AMPK axis","volume":"81","author":"Zhang","year":"2025","journal-title":"Redox Biol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"175930","DOI":"10.1016\/j.ejphar.2023.175930","article-title":"Dapagliflozin ameliorates sepsis-induced heart injury by inhibiting cardiomyocyte apoptosis and electrical remodeling through the PI3\u2005K\/akt pathway","volume":"955","author":"Han","year":"2023","journal-title":"Eur J Pharmacol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.jare.2023.10.011","article-title":"Ceria nanozyme coordination with curcumin for treatment of sepsis-induced cardiac injury by inhibiting ferroptosis and inflammation","volume":"63","author":"Jiang","year":"2024","journal-title":"J Adv Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1002\/ptr.8093","article-title":"Astilbin protects from sepsis-induced cardiac injury through the NRF2\/HO-1 and TLR4\/NF-kappa B pathway","volume":"38","author":"Fang","year":"2024","journal-title":"Phytother Res"},{"key":"B22","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1007\/s00281-017-0639-8","article-title":"Cytokine storm and sepsis disease pathogenesis","volume":"39","author":"Chousterman","year":"2017","journal-title":"Semin Immunopathol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1038\/s41467-023-36865-7","article-title":"N(6)-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice","volume":"14","author":"Wang","year":"2023","journal-title":"Nat Commun"},{"key":"B24","doi-asserted-by":"publisher","first-page":"108357","DOI":"10.1016\/j.jstrokecerebrovasdis.2025.108357","article-title":"Gut microbiota-derived phenylacetylglutamine mitigates neuroinflammation induced by intracerebral hemorrhage in mice","volume":"34","author":"Zhang","year":"2025","journal-title":"J Stroke Cerebrovasc Dis"},{"key":"B25","doi-asserted-by":"publisher","first-page":"109795","DOI":"10.1016\/j.intimp.2023.109795","article-title":"Phenylacetylglutamine increases the susceptibility of ventricular arrhythmias in heart failure mice by exacerbated activation of the TLR4\/AKT\/mTOR signaling pathway","volume":"116","author":"Fu","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.ceca.2010.02.002","article-title":"TNF-alpha and IL-1beta increase Ca2\u2009+\u2009leak from the sarcoplasmic reticulum and susceptibility to arrhythmia in rat ventricular myocytes","volume":"47","author":"Duncan","year":"2010","journal-title":"Cell Calcium"},{"key":"B27","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1186\/s13054-024-04879-2","article-title":"Characteristics, predictors and outcomes of new-onset QT prolongation in sepsis: a multicenter retrospective study","volume":"28","author":"Liu","year":"2024","journal-title":"Crit Care"},{"key":"B28","doi-asserted-by":"publisher","first-page":"0165","DOI":"10.34133\/research.0165","article-title":"Cardiac Piezo1 exacerbates lethal ventricular arrhythmogenesis by linking mechanical stress with ca (2+) handling after myocardial infarction","volume":"6","author":"Su","year":"2023","journal-title":"Research (Wash D C)"},{"key":"B29","doi-asserted-by":"publisher","first-page":"4516","DOI":"10.1111\/bph.70090","article-title":"A potential therapeutic target at Connexin 43 serine phosphorylation against ischaemia\/reperfusion arrhythmia","volume":"182","author":"Fu","year":"2025","journal-title":"Br J Pharmacol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1253\/circj.cj-09-1019","article-title":"Connexin-43 redistribution and gap junction activation during forced restraint protects against sudden arrhythmic death in rats","volume":"74","author":"Unuma","year":"2010","journal-title":"Circ J"},{"key":"B31","doi-asserted-by":"publisher","first-page":"euaf083","DOI":"10.1093\/europace\/euaf083","article-title":"GSTP1 Inhibits angiotensin II-induced atrial fibrillation by regulating ferroptosis","volume":"27","author":"Li","year":"2025","journal-title":"Europace"},{"key":"B32","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1016\/j.freeradbiomed.2024.12.005","article-title":"Puerarin reduces susceptibility to ventricular arrhythmias and inhibits ferroptosis via Sirt1\/Nrf2 signaling in high-fat-diet rats","volume":"227","author":"Jiang","year":"2025","journal-title":"Free Radic Biol Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"106473","DOI":"10.1016\/j.phrs.2022.106473","article-title":"Losartan attenuates sepsis-induced cardiomyopathy by regulating macrophage polarization via TLR4-mediated NF-kappa B and MAPK signaling","volume":"185","author":"Chen","year":"2022","journal-title":"Pharmacol Res"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1016\/j.ymthe.2023.01.018","article-title":"Gut microbial metabolite hyodeoxycholic acid targets the TLR4\/MD2 complex to attenuate inflammation and protect against sepsis","volume":"31","author":"Li","year":"2023","journal-title":"Mol Ther"},{"key":"B35","doi-asserted-by":"publisher","first-page":"4954","DOI":"10.1038\/s44318-024-00237-8","article-title":"Acetylation of TIR domains in the TLR4-mal-MyD88 complex regulates immune responses in sepsis","volume":"43","author":"Li","year":"2024","journal-title":"EMBO J"},{"key":"B36","doi-asserted-by":"publisher","first-page":"110311","DOI":"10.1016\/j.intimp.2023.110311","article-title":"Tirzepatide attenuates lipopolysaccharide-induced left ventricular remodeling and dysfunction by inhibiting the TLR4\/NF-kB\/NLRP3 pathway","volume":"120","author":"Liu","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.ejphar.2018.11.025","article-title":"Loss of MD1 exacerbates myocardial ischemia\/reperfusion injury and susceptibility to ventricular arrhythmia","volume":"844","author":"Jiang","year":"2019","journal-title":"Eur J Pharmacol"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1870510\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:10:15Z","timestamp":1786612215000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1870510\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":37,"alternative-id":["10.3389\/fcvm.2026.1870510"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2026.1870510","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]},"article-number":"1870510"}}