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ResearchIn-Press PreviewCardiologyCell biologyClinical Research Open Access | 10.1172/JCI201684

Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction

Selvam Arjunan,1 Isaiah Pemberton,1 Xinmin S. Li,1 Naseer Sangwan,1 Lydia Akino,2 Emmanuel Opoku,1 Dmitriy Verbovetskiy,1 Ina Nemet,1 Hyun Su Kim,1 Haruko Masumiya,1 Zeneng Wang,1 Joseph A. Lupica,1 Melissa Y. Tian,1 Karis Mao,1 Deepthi P. Mallela,1 Maradumane Mohan,1 Sarah Schumacher,1 Julie H. Rennison,1 Sathyamangla Prasad,1 Kenneth R. Laurita,2 Vamsi Chodisetty,1 Mina K. Chung,1 David R. Van Wagoner,1 John Barnard,1 Jonathan D. Smith,1 Oussama Wazni,1 Stanley L. Hazen,1 and Robert A. Koeth1

1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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1Department of Heart, Blood and Kidney Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, United States of America

2Department of Biomedical Engineering, Case School of Engineering School of Medicine, Case Western Reserve University, Cleveland, United States of America

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Published July 24, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI201684.
Copyright © 2026, Arjunan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 24, 2026 - Version history
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Abstract

Gut microbiota-derived trimethylamine N-oxide (TMAO) plays a role in the pathogenesis of cardiovascular disease. The role of TMAO in the pathogenesis of atrial fibrillation (AF) remains uncertain. TMAO levels were quantified in plasma from serial subjects undergoing elective cardiac catheterizations (N=5090) and shown to independently associate with prevalent AF following adjustment for risk factors (TMAO adjusted odds ratio 1.7 [95% confidence interval 1.3-2.1]; P<0.01). Human cAMP response element modulator isoform IbΔC-X transgenic mice (CREM-IbΔC-X), a spontaneous mouse model of AF, supplemented with a TMAO diet developed AF sooner. C57BL/6J mice on and off a TMAO had more inducible AF via a transesophageal pacing study compared to chow controls. Dietary choline supplementation increased circulating TMAO levels and significantly accelerated AF onset in CREM-IbΔC-X mice (P<0.01). Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that suppresses choline→TMA(O) metabolic transformation, reduced circulating TMAO levels (P<0.0001) and choline induced AF onset (P<0.01). Cecal metagenomic analyses showed that choline supplementation induced changes in microbial communities associated with AF, while many of these changes were attenuated by IMC. Choline supplementation promoted overall adverse atrial remodeling with left atrial dilation. Optical mapping studies showed that mice supplemented with choline exhibited reduced conduction velocity, shortened action potential duration at 80% repolarization, and decreased wavelength. TMAO inhibits muscarinic receptor 2 resulting in autonomic dysfunction that promotes AF. In summary, the gut microbial metabolite TMAO, independently associated with AF risk in subjects, enhances AF in multiple AF mouse models via autonomic dysfunction, and is a therapeutic target for prevention of AF.

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