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Vagal signaling may foster neuroinflammation and cerebral injury, which then compromises cardiac performance, while reduced cerebral perfusion amplifies the bidirectional loop. Trimethylamine-N-oxide (TMAO), generated from dietary choline and L-carnitine through microbial conversion and hepatic oxidation, emerges as a central mediator. Elevated TMAO associates with atherosclerosis and heart failure by activating NLRP3 inflammasome, impairing SIRT3-SOD2 signaling, and increasing platelet hyperreactivity, alongside modulating the autonomic nervous system and promoting arrhythmias. Clinical findings indicate TMAO predicts HF mortality and could complement or extend current beta-blocker and ACE-inhibitor strategies by enabling microbiota- and TMAO-targeted, personalized interventions.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/interplay-among-gut-microbiota-derived-tmao-autonomic-nervous-system-dysfunction-and-heart-failure-progression/465467/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/interplay-among-gut-microbiota-derived-tmao-autonomic-nervous-system-dysfunction-and-heart-failure-progression/465467.png","ImageObject",300,407,{"name":92,"@type":93},"Connor ","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-04","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does gut dysbiosis connect to heart failure progression?","Question",{"text":112,"@type":113},"Dysbiosis disrupts the gut–brain–heart axis: vagal signaling can trigger neuroinflammation and cerebral damage, which then impairs cardiac function, with reduced cerebral perfusion further worsening the cycle.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What role does TMAO play in the proposed mechanism?",{"text":117,"@type":113},"TMAO acts as a key mediator. It is produced from dietary choline and L-carnitine via microbial conversion and hepatic oxidation, and it is linked to atherosclerosis and heart failure through inflammatory and metabolic pathways.",{"name":119,"@type":110,"acceptedAnswer":120},"Why is TMAO considered a potential therapeutic target in heart failure?",{"text":121,"@type":113},"Current HF therapies mainly target end-organ response or humoral pathways, whereas directly modulating microbiota and TMAO offers a new therapeutic direction. The review also emphasizes integrating TMAO into risk models and developing gut–brain models for personalized interventions.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},465467,1791118063,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},687207022233,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Review  \nInterplay Among Gut Microbiota-Derived TMAO, Autonomic Nervous System Dysfunction, and Heart Failure Progression  \nLaura Calvillo 1, *,†, Emilio Vanoli 2,†, Fulvio Ferrara 3 and Eugenio Caradonna 4  \n1 Istituto Auxologico Italiano IRCCS, 20145 Milan, Italy  \n2 School of Nursing, University of Pavia, 27100 Pavia, Italy; [emilio.vanoli@unipv.it](emilio.vanoli@unipv.it)  \n3 Servizio Integrato di Medicina di Laboratorio, Centro Diagnostico Italiano—CDI, 20147 Milan, Italy; [fulvio.ferrara@cdi.it](fulvio.ferrara@cdi.it)  \n4 Dipartimento Patologia Medica e Anatomia Patologica, Centro Diagnostico Italiano—CDI, 20147 Milan, Italy; [eugenio.caradonna@cdi.it](eugenio.caradonna@cdi.it)  \n* Correspondence: [l.calvillo@auxologico.it](l.calvillo@auxologico.it)[ ](l.calvillo@auxologico.it)† These authors contributed equally to this work.  \nAbstract  \nThe gut microbiota is crucial for metabolic homeostasis and cardiovascular health. Dysbiosis triggers a gut–brain–heart axis dysfunction: vagal signaling promotes neuroinflammation and cerebral damage, which in turn impairs cardiac function. This bidirectional cycle is further exacerbated by reduced cerebral perfusion. Trimethylamine-N-oxide (TMAO), ametabolite of dietary choline and L-carnitine, acts as a primary mediator in this network. Elevated TMAO levels—resulting from bacterial conversion and hepatic oxidation—are linked to atherosclerosis and heart failure. Mechanistically, TMAO activates the NLRP3 inflammasome, inhibits the SIRT3-SOD2 pathway, and promotes platelet hyperreactivity. Furthermore, it modulates the autonomic nervous system, enhancing sympathetic activity and cardiac arrhythmias. Clinical evidence suggests TMAO is a potent predictor of mortality in HF. While current HF therapies focus on end-organ response (beta-blockers) or humoral pathways (ACE inhibitors), directly targeting the microbiota and TMAO offers a novel therapeutic frontier. Integrating TMAO assessment into risk models and utilizing advanced in vitro gut–brain models will be essential for developing personalized, groundbreaking cardiovascular interventions. Within this framework, the main aim of the present review is to describe how cardiac autonomic control can be directly modulated by the microbiota and its byproducts like TMAO. This latter is a leading target candidate for novel HF prevention and therapy interventions.  \nAcademic Editor: Anastasios Lymperopoulos  \nReceived: 10 November 2025  \nRevised: 17 December 2025  \nAccepted: 18 December 2025  \nPublished: 24 December 2025  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \nKeywords: trimethylamine-N-oxide (TMAO); microbiota; dysbiosis; cardiovascular disease; autonomic nervous system dysfunction  \n1. Introduction  \nHeart failure (HF) is a complex clinical syndrome involving not only hemodynamic and structural abnormalities but also systemic inflammatory, metabolic, and neurohumoral dysregulation. Among emerging factors involved in HF development and progression, the gut microbiota and its metabolite TMAO have gained considerable attention. TMAO, produced through microbial metabolism of dietary precursors and hepatic oxidation, has been linked to endothelial dysfunction, mitochondrial stress, and chronic low-grade inflammation [1,2] . As previously described, TMAO is also produced in the aorta cellular layer and in adipose tissue [3–5] . Recent evidence also implicates TMAO in modulating the  \nautonomic nervous system (ANS), contributing to sympathetic hyperactivity—a known driver of HF progression and arrhythmogenesis. Thus, a critical loop exists between gut microbiota ANS balance and function, inflammation, and cardiovascular diseases. Such a detrimental loop becomes strikingly manifest when considering the proactive interactions between these factors in favoring myocardial infarction occurr","cbCaihwptXXWgsWx","https://ap.wps.com/l/cbCaihwptXXWgsWx","pdf",1634638,18,"English","# 1. Introduction\n# 2. ANS in HF","[{\"question\":\"How does gut dysbiosis connect to heart failure progression?\",\"answer\":\"Dysbiosis disrupts the gut–brain–heart axis: vagal signaling can trigger neuroinflammation and cerebral damage, which then impairs cardiac function, with reduced cerebral perfusion further worsening the cycle.\"},{\"question\":\"What role does TMAO play in the proposed mechanism?\",\"answer\":\"TMAO acts as a key mediator. It is produced from dietary choline and L-carnitine via microbial conversion and hepatic oxidation, and it is linked to atherosclerosis and heart failure through inflammatory and metabolic pathways.\"},{\"question\":\"Why is TMAO considered a potential therapeutic target in heart failure?\",\"answer\":\"Current HF therapies mainly target end-organ response or humoral pathways, whereas directly modulating microbiota and TMAO offers a new therapeutic direction. The review also emphasizes integrating TMAO into risk models and developing gut–brain models for personalized interventions.\"}]","Interplay Among Gut Microbiota-Derived TMAO, Autonomic Nervous System Dysfunction, and Heart Failure Progression | PDF",1790769663,45]