Skip to main content

Advertisement

SpringerLink
Log in

Trimethylamine N-oxide facilitates the progression of atrial fibrillation in rats with type 2 diabetes by aggravating cardiac inflammation and connexin remodeling

  • Original Article
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

Diabetes is an independent risk factor for atrial fibrillation (AF). This study aimed to elucidate the pathophysiology of diabetes-related AF from the perspective of the gut microbial metabolite trimethylamine N-oxide (TMAO). In the present study, male rats received either a normal diet to serve as the control group or a high-fat diet/streptozotocin to induce type 2 diabetes mellitus. Then, diabetic rats were divided into two groups based on the presence or absence of 3,3-dimethyl-1-butanol (DMB, a specific TMAO inhibitor) in drinking water: the diabetic cardiomyopathy (DCM) group and the DCM + DMB group. Eight weeks later, compared with control rats, rats in the DCM group exhibited gut microbiota dysbiosis and systemic TMAO elevation. The inflammatory cytokines IL-1β, IL-6, and TNF-α were markedly increased in the atria of rats in the DCM group. Downregulated expression of connexin 40 and lateralized distribution of connexin 43 were also observed in the atria of DCM rats. AF inducibility was significantly higher in DCM rats than in control rats. Furthermore, DMB treatment effectively ameliorated atrial inflammation and connexin remodeling while markedly reducing plasma TMAO levels. DMB treatment also decreased the vulnerability of diabetic rats to AF. In conclusion, TMAO might promote atrial inflammation and connexin remodeling in the development of diabetes, which may play a key role in mediating diabetes-related AF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Bastin M, Andreelli F (2020) The gut microbiota and diabetic cardiomyopathy in humans. Diabetes Metab 46:197–202. https://doi.org/10.1016/j.diabet.2019.10.003

    Article  CAS  PubMed  Google Scholar 

  2. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, Wolf PA (1994) Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. Jama 271:840–844

    Article  CAS  PubMed  Google Scholar 

  3. Chen ML, Zhu XH, Ran L, Lang HD, Yi L, Mi MT (2017) Trimethylamine-N-oxide induces vascular inflammation by activating the NLRP3 inflammasome through the SIRT3-SOD2-mtROS signaling pathway. J Am Heart Assoc 6. https://doi.org/10.1161/jaha.117.006347

  4. Clemente JC, Manasson J, Scher JU (2018) The role of the gut microbiome in systemic inflammatory disease. BMJ 360:j5145. https://doi.org/10.1136/bmj.j5145

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dambrova M, Latkovskis G, Kuka J, Strele I, Konrade I, Grinberga S, Hartmane D, Pugovics O, Erglis A, Liepinsh E (2016) Diabetes is associated with higher trimethylamine n-oxide plasma levels. Exp Clin Endocrinol Diabetes 124:251–256. https://doi.org/10.1055/s-0035-1569330

    Article  CAS  PubMed  Google Scholar 

  6. Dang JK, Wu Y, Cao H, Meng B, Huang CC, Chen G, Li J, Song XJ, Lian QQ (2014) Establishment of a rat model of type II diabetic neuropathic pain. Pain Med 15(4):637–646. https://doi.org/10.1111/pme.12387_1

    Article  PubMed  Google Scholar 

  7. Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107. https://doi.org/10.1038/nri2925

    Article  CAS  PubMed  Google Scholar 

  8. Du X, Ninomiya T, de Galan B, Abadir E, Chalmers J, Pillai A, Woodward M, Cooper M, Harrap S, Hamet P, Poulter N, Lip GY, Patel A (2009) Risks of cardiovascular events and effects of routine blood pressure lowering among patients with type 2 diabetes and atrial fibrillation: results of the ADVANCE study. Eur Heart J 30:1128–1135. https://doi.org/10.1093/eurheartj/ehp055

    Article  PubMed  Google Scholar 

  9. Foster M, Petocz P, Samman S (2013) Inflammation markers predict zinc transporter gene expression in women with type 2 diabetes mellitus. J Nutr Biochem 24:1655–1661. https://doi.org/10.1016/j.jnutbio.2013.02.006

    Article  CAS  PubMed  Google Scholar 

  10. Fuentes-Antrás J, Ioan AM, Tuñón J, Egido J, Lorenzo O (2014) Activation of toll-like receptors and inflammasome complexes in the diabetic cardiomyopathy-associated inflammation. Int J Endocrinol 2014:847827. https://doi.org/10.1155/2014/847827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hartley A, Shalhoub J, Ng FS, Krahn AD, Laksman Z, Andrade JG, Deyell MW, Kanagaratnam P, Sikkel MB (2021) Size matters in atrial fibrillation: the underestimated importance of reduction of contiguous electrical mass underlying the effectiveness of catheter ablation. Europace 23(11):1698–1707. https://doi.org/10.1093/europace/euab078

    Article  PubMed  PubMed Central  Google Scholar 

  12. Heianza Y, Sun D, Li X, DiDonato JA, Bray GA, Sacks FM, Qi L (2019) Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial. Gut 68:263–270. https://doi.org/10.1136/gutjnl-2018-316155

    Article  CAS  PubMed  Google Scholar 

  13. Huxley RR, Filion KB, Konety S, Alonso A (2011) Meta-analysis of cohort and case-control studies of type 2 diabetes mellitus and risk of atrial fibrillation. Am J Cardiol 108:56–62. https://doi.org/10.1016/j.amjcard.2011.03.004

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hu YF, Chen YJ, Lin YJ, Chen SA (2015) Inflammation and the pathogenesis of atrial fibrillation. Nat Rev Cardiol 12:230–243. https://doi.org/10.1038/nrcardio.2015.2

    Article  CAS  PubMed  Google Scholar 

  15. Lazzerini PE, Capecchi PL, Laghi-Pasini F (2017) Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis. Eur Heart J 38:1717–1727. https://doi.org/10.1093/eurheartj/ehw208

    Article  CAS  PubMed  Google Scholar 

  16. Lazzerini PE, Laghi-Pasini F, Acampa M, Srivastava U, Bertolozzi I, Giabbani B, Finizola F, Vanni F, Dokollari A, Natale M, Cevenini G, Selvi E, Migliacci N et al (2019) systemic inflammation rapidly induces reversible atrial electrical remodeling: the role of interleukin-6-mediated changes in connexin expression. J Am Heart Assoc 8:e011006. https://doi.org/10.1161/jaha.118.011006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Leger T, He B, Azarnoush K, Jouve C, Rigaudiere JP, Joffre F, Bouvier D, Sapin V, Pereira B, Demaison L (2019) Dietary EPA increases rat mortality in diabetes mellitus, a phenomenon which is compensated by green tea extract. Antioxidants (Basel) 8(11):526. https://doi.org/10.3390/antiox8110526

    Article  CAS  PubMed  Google Scholar 

  18. Martínez-del Campo A, Bodea S, Hamer HA, Marks JA, Haiser HJ, Turnbaugh PJ, Balskus EP (2015) Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria. mBio 6. https://doi.org/10.1128/mBio.00042-15

  19. Murtaza G, Virk HUH, Khalid M, Lavie CJ, Ventura H, Mukherjee D, Ramu V, Bhogal S, Kumar G, Shanmugasundaram M, Paul TK (2019) Diabetic cardiomyopathy - a comprehensive updated review. Prog Cardiovasc Dis. 62(4):315–326. https://doi.org/10.1016/j.pcad.2019.03.003

    Article  PubMed  Google Scholar 

  20. Phang RJ, Ritchie RH, Hausenloy DJ, Lees JG, Lim SY (2022) Cellular interplay between cardiomyocytes and non-myocytes in diabetic cardiomyopathy. Cardiovasc Res cvac049 https://doi.org/10.1093/cvr/cvac049

  21. Plitt A, McGuire DK, Giugliano RP (2017) Atrial fibrillation, type 2 diabetes, and non-vitamin K antagonist oral anticoagulants: a review. JAMA Cardiol 2:442–448. https://doi.org/10.1001/jamacardio.2016.5224

    Article  PubMed  Google Scholar 

  22. Rohrmann S, Linseisen J, Allenspach M, von Eckardstein A, Müller D (2016) Plasma concentrations of trimethylamine-N-oxide are directly associated with dairy food consumption and low-grade inflammation in a German adult population. J Nutr 146:283–289. https://doi.org/10.3945/jn.115.220103

    Article  CAS  PubMed  Google Scholar 

  23. Romano KA, Vivas EI, Amador-Noguez D, Rey FE (2015) Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. mBio 6:e02481. https://doi.org/10.1128/mBio.02481-14

  24. Ryu K, Li L, Khrestian CM, Matsumoto N, Sahadevan J, Ruehr ML, Van Wagoner DR, Efimov IR, Waldo AL (2007) Effects of sterile pericarditis on connexins 40 and 43 in the atria: correlation with abnormal conduction and atrial arrhythmias. Am J Physiol Heart Circ Physiol 293:H1231–H1241. https://doi.org/10.1152/ajpheart.00607.2006

    Article  CAS  PubMed  Google Scholar 

  25. Sawaya SE, Rajawat YS, Rami TG, Szalai G, Price RL, Sivasubramanian N, Mann DL, Khoury DS (2007) Downregulation of connexin40 and increased prevalence of atrial arrhythmias in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor. Am J Physiol Heart Circ Physiol 292:H1561–H1567. https://doi.org/10.1152/ajpheart.00285.2006

    Article  CAS  PubMed  Google Scholar 

  26. Seldin MM, Meng Y, Qi H, Zhu W, Wang Z, Hazen SL, Lusis AJ, Shih DM (2016) Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-κB. J Am Heart Assoc 5. https://doi.org/10.1161/jaha.115.002767

  27. Sun Y, Shi H, Yin S, Ji C, Zhang X, Zhang B, Wu P, Shi Y, Mao F, Yan Y, Xu W, Qian H (2018) Human mesenchymal stem cell derived exosomes alleviate type 2 diabetes mellitus by reversing peripheral insulin resistance and relieving β-cell destruction. ACS Nano 12(8):7613–7628. https://doi.org/10.1021/acsnano.7b07643

    Article  CAS  PubMed  Google Scholar 

  28. Wang A, Green JB, Halperin JL, Piccini JP Sr (2019) Atrial fibrillation and diabetes mellitus: JACC review topic of the week. J Am Coll Cardiol 74:1107–1115. https://doi.org/10.1016/j.jacc.2019.07.020

    Article  PubMed  Google Scholar 

  29. Wang Z, Bergeron N, Levison BS, Li XS, Chiu S, Jia X, Koeth RA, Li L, Wu Y, Tang WHW, Krauss RM, Hazen SL (2019) Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. Eur Heart J 40:583–594. https://doi.org/10.1093/eurheartj/ehy799

    Article  CAS  PubMed  Google Scholar 

  30. Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, Gu X, Huang Y, Zamanian-Daryoush M, Culley MK, DiDonato AJ, Fu X, Hazen JE et al (2015) Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163:1585–1595. https://doi.org/10.1016/j.cell.2015.11.055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wiegerinck RF, van Veen TA, Belterman CN, Schumacher CA, Noorman M, de Bakker JM, Coronel R (2008) Transmural dispersion of refractoriness and conduction velocity is associated with heterogeneously reduced connexin43 in a rabbit model of heart failure. Heart Rhythm 5:1178–1185. https://doi.org/10.1016/j.hrthm.2008.04.026

    Article  PubMed  Google Scholar 

  32. Yoo W, Zieba JK (2021) High-fat diet-induced colonocyte dysfunction escalates microbiota-derived trimethylamine N-oxide. 373: 813–8.https://doi.org/10.1126/science.aba3683

  33. Zakkar M, Ascione R, James AF, Angelini GD, Suleiman MS (2015) Inflammation, oxidative stress and postoperative atrial fibrillation in cardiac surgery. Pharmacol Ther 154:13–20. https://doi.org/10.1016/j.pharmthera.2015.06.009

    Article  CAS  PubMed  Google Scholar 

  34. Zhang L, Xie F, Tang H, Zhang X, Hu J, Zhong X, Gong N, Lai Y, Zhou M, Tian J, Zhou Z, Xie L, Hu Z et al (2022) Gut microbial metabolite TMAO increases peritoneal inflammation and peritonitis risk in peritoneal dialysis patients. Transl Res 240:50–63. https://doi.org/10.1016/j.trsl.2021.10.001

    Article  CAS  PubMed  Google Scholar 

  35. Zhu Y, Jameson E, Crosatti M, Schäfer H, Rajakumar K, Bugg TD, Chen Y (2014) Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota. Proc Natl Acad Sci U S A 111:4268–4273. https://doi.org/10.1073/pnas.1316569111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (No. 81770333, No. 81800350).

Author information

Author notes

  1. Wan-Ying Jiang and Jun-Yu Huo contributed equally to this work and are considered to be co-first authors.

Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Wan-Ying Jiang, Jun-Yu Huo, Sheng-Chan Wang, Yan-Di Cheng, Yi-Ting Lyu, Zhi-Xin Jiang & Qi-Jun Shan

Authors
  1. Wan-Ying Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun-Yu Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sheng-Chan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan-Di Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi-Ting Lyu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhi-Xin Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qi-Jun Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors declare that all data were generated in-house and that no paper mill was used. WYJ and JYH designed this study and performed most of the experiments. SCW conducted the rest of the experiments. YTL, YDC, and ZXJ analyzed the data. WYJ and JYH wrote the manuscript. QJS was the corresponding author, and all the experiments were performed under his guidance. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Qi-Jun Shan.

Ethics declarations

Ethics approval

All study protocols were approved by the Animal Ethics Committee of Nanjing Medical University (IACUC-2011003) and fully complied with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health).

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Keypoints

• Diabetic rats showed disordered gut microbiota and increased TMAO levels.

• Elevated TMAO levels facilitated atrial inflammation and connexin remodeling.

• Elevated TMAO levels increased the susceptibility of diabetic rats to AF.

• DMB alleviated the progression of diabetes-related AF by reducing TMAO levels.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, WY., Huo, JY., Wang, SC. et al. Trimethylamine N-oxide facilitates the progression of atrial fibrillation in rats with type 2 diabetes by aggravating cardiac inflammation and connexin remodeling. J Physiol Biochem 78, 855–867 (2022). https://doi.org/10.1007/s13105-022-00908-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-022-00908-2

Keywords

Search

Navigation