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Canadian Journal of Cardiology

Gut Microbiota Dysbiosis Induced by a High-Fat Diet Increases Susceptibility to Atrial Fibrillation

  • Author Footnotes
    ‡ These authors contributed equally to this article.
    Bin Kong
    Footnotes
    ‡ These authors contributed equally to this article.
    Affiliations
    Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. of China

    Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei, P.R. of China

    Hubei Key Laboratory of Cardiology, Wuhan, Hubei, P.R. of China
    Search for articles by this author
  • Author Footnotes
    ‡ These authors contributed equally to this article.
    Hui Fu
    Footnotes
    ‡ These authors contributed equally to this article.
    Affiliations
    Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. of China

    Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei, P.R. of China

    Hubei Key Laboratory of Cardiology, Wuhan, Hubei, P.R. of China
    Search for articles by this author
  • Author Footnotes
    ‡ These authors contributed equally to this article.
    Zheng Xiao
    Footnotes
    ‡ These authors contributed equally to this article.
    Affiliations
    Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. of China

    Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei, P.R. of China

    Hubei Key Laboratory of Cardiology, Wuhan, Hubei, P.R. of China
    Search for articles by this author
  • Yanxiang Zhou
    Affiliations
    Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. of China
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  • Wei Shuai
    Correspondence
    Corresponding author: Dr Wei Shuai, Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei, P.R. of China.
    Affiliations
    Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. of China

    Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei, P.R. of China

    Hubei Key Laboratory of Cardiology, Wuhan, Hubei, P.R. of China
    Search for articles by this author
  • He Huang
    Correspondence
    Corresponding author: Dr He Huang, Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei, P.R. of China.
    Affiliations
    Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. of China

    Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei, P.R. of China

    Hubei Key Laboratory of Cardiology, Wuhan, Hubei, P.R. of China
    Search for articles by this author
  • Author Footnotes
    ‡ These authors contributed equally to this article.
Published:September 06, 2022DOI:https://doi.org/10.1016/j.cjca.2022.08.231

      Abstract

      Background

      Obesity is a significant risk factor for atrial fibrillation (AF), and the gut microbiota is closely related to obesity-induced diseases. However, whether the gut microbiota is involved in regulating obesity-induced AF has not been studied. This study investigated whether gut microbiota dysbiosis affects obesity-related AF.

      Methods

      Fecal microbes derived from normal diet (ND)-fed and high-fat diet (HD)-fed mice were transplanted into those fed normally. Morphologic, biochemical, functional, histologic, electrophysiological studies, molecular analysis, 16S rRNA gene amplicon sequencing, and RNA-sequencing were performed.

      Results

      Transplantation of the HD gut microbes in ND-maintained (THD) mice led to a significant increase in the susceptibility to AF. Gut microbiota analysis showed a significant increase in Desulfovibrionaceae, which generated metabolic endotoxemia in THD mice. Transplantation with HD microbes also resulted in significantly increased levels of circulating lipopolysaccharide (LPS), significant disruption in the histologic architecture of the intestinal tissue, and significantly increased proinflammatory cytokines in the left atrium, indicating that atrial inflammation likely contributed to AF susceptibility. RNA-sequencing showed that the THD group had enhanced activation of ferroptosis and TLR4/NF-κB/NLRP3 inflammasome signalling pathway. Inhibiting the ferroptosis or NLRP3 inflammasome signalling pathway significantly improved atrial fibrosis and reduced susceptibility to obesity-related gut dysbiosis-induced AF.

      Conclusions

      This study provides evidence showing an original causal role of gut microbiota dysbiosis in the pathogenesis of obesity-related AF, which showed elevated LPS and dysregulation of atrial pathologic remodelling by activating ferroptosis and the TLR4/NF-κB/NLRP3 inflammasome signalling pathway.

      Résumé

      Contexte

      L’obésité est un facteur de risque important de la fibrillation auriculaire (FA), et il existe un lien étroit entre le microbiote du tractus digestif et les maladies causées par l’obésité. Toutefois, le rôle du microbiote du tractus digestif dans la régulation de la FA liée à l’obésité n’a pas été étudié. Dans cette étude, nous avons examiné la possibilité d’une incidence de la dysbiose du microbiote du tractus digestif sur la FA liée à l’obésité.

      Méthodologie

      Une transplantation de microbes fécaux obtenus à partir de souris ayant reçu une alimentation normale (AN) ou une alimentation riche en graisses (ARG) a été effectuée sur des souris ayant été nourries normalement. Des analyses morphologiques, biochimiques, fonctionnelles, histologiques, électrophysiologiques et moléculaires, ainsi qu’un séquençage des amplicons de l’ARNr 16S et un séquençage de l’ARN ont été réalisés.

      Résultats

      La transplantation de microbes du tractus digestif provenant de souris ayant une ARG chez les souris dont l’alimentation normale a été maintenue (TARG) a entraîné une augmentation significative de la susceptibilité à la FA. Des analyses du microbiote du tractus digestif ont révélé une augmentation significative de la présence de Desulfovibrionaceae, ce qui a entraîné une endotoxémie métabolique chez les souris de ce groupe. La transplantation de microbes provenant de souris ayant une ARG a également mené à une augmentation significative des taux de lipopolysaccharides (LPS) circulants, à une perturbation importante de l’architecture histologique des tissus intestinaux, et à une augmentation significative des cytokines pro-inflammatoires dans l’atrium gauche, ce qui semble indiquer que l’inflammation auriculaire a probablement contribué à la susceptibilité à la FA. Le séquençage de l’ARN a permis de montrer que le groupe TARG présentait une plus grande activation de la ferroptose et de la voie de signalisation TLR4/NF-κB/inflammasome NLRP3. Une inhibition de la ferroptose ou de la voie de signalisation de l’inflammasome NLRP3 entraînait une réduction significative de la fibrose auriculaire et de la susceptibilité à la FA entraînée par la dysbiose du tractus digestif et liée à l’obésité.

      Conclusions

      Notre étude montre le lien causal de la dysbiose du microbiote du tractus digestif dans la pathogenèse de la FA liée à l’obésité, caractérisée par une élévation des taux de LPS et un dérèglement pathologique du remodelage auriculaire par l’activation de la ferroptose et de la voie de signalisation TLR4/NF-κB/inflammasome NLRP3.

      Graphical abstract

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