The gut microbiome and heart failure: A better gut for a better heart

  • Maxime Branchereau
  • Rémy Burcelin
  • Christophe HeymesEmail author


Despite the development of new drugs and therapeutic strategies, mortality and morbidity related to heart failure (HF) remains high. It is also the leading cause of global mortality. Several concepts have been proposed to explore the underlying pathogenesis of HF, but there is still a strong need for more specific and complementary therapeutic options. In recent years, accumulating evidence has demonstrated that changes in the composition of gut microbiota, referred to as dysbiosis, might play a pivotal role in the development of several diseases, including HF. HF-associated decreased cardiac output, resulting in bowell wall oedema and intestine ischaemia, can alter gut structure, peamibility and function. These changes would favour bacterial translocation, exacerbating HF pathogenesis at least partly through activation of systemic inflammation. Although our knowledge of the precise molecular mechanisms by which gut dysbiosis influance HF is still limited, a growing body of evidence has recently demonstrated the impact of a series of gut microbiome-derived metabolites, such as trimetylamine N-oxide, short-chain fatty acids or secondary bile acids, which have been shown to play critical roles in cardiac health and disease. This review will summarize the role of gut microbiota and its metabolites in the pathogenesis of HF. Current and future preventive and therapeutic strategies to prevent HF by an adequate modulation of the microbiome and its derived metabolites are also discussed.


Gut microbiota Dysbiosis Heart failure Microbiota-derived metabolites Treatment 


Funding information

This work was supported by INSERM. Rémy Burcelin has received grants from Fondation de France (grant number 201300038591).

Compliance with ethical standards

Conflict of interest

M. Branchereau declares that he has no conflict of interest. R. Burcelin declares that he has no conflict of interest. C. Heymes declares that he has no conflict of interest.

Human or animals participants

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the global burden of disease study 2015. Lancet. 2016;388(10053):1459–544.CrossRefGoogle Scholar
  2. 2.
    Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. American College of Cardiology Foundation/American Heart Association task force on practice guidelines. ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation. 2013;128(16):e240–327.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, et al. American Heart Association statistics committee and stroke statistics subcommittee. Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6–e245.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001;292(5519):1115–8.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014;157(1):121–41.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Buffie CG, Pamer EG. Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol. 2013;13(11):790–801.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17(4):219–32.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Nagatomo Y, Tang WH. Intersections between microbiome and heart failure: revisiting the gut hypothesis. J Card Fail. 2015;21(12):973–80.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Tang WH, Kitai T, Hazen SL. Gut microbiota in cardiovascular health and disease. Circ Res. 2017;120(7):1183–96.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Tang WHW, Li DY, Hazen SL. Dietary metabolism, the gut microbiome, and heart failure. Nat Rev Cardiol. 2019;16(3):137–54.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Sandek A, Bauditz J, Swidsinski A, Buhner S, Weber-Eibel J, et al. Altered intestinal function in patients with chronic heart failure. J Am Coll Cardiol. 2007;50(16):1561–9.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Sandek A, Swidsinski A, Schroedl W, Watson A, Valentova M, et al. Intestinal blood flow in patients with chronic heart failure: a link with bacterial growth, gastrointestinal symptoms, and cachexia. J Am Coll Cardiol. 2014;64(11):1092–102.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Pasini E, Aquilani R, Testa C, Baiardi P, Angioletti S, et al. Pathogenic gut Flora in patients with chronic heart failure. JACC Heart Fail. 2016;4(3):220–7.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Luedde M, Winkler T, Heinsen FA, Rühlemann MC, Spehlmann ME, et al. Heart failure is associated with depletion of core intestinal microbiota. ESC Heart Fail. 2017;4(3):282–90.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Jenq RR, Taur Y, Devlin SM, Ponce DM, Goldberg JD, et al. Intestinal Blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(8):1373–83.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Miquel S, Martín R, Rossi O, Bermúdez-Humarán LG, Chatel JM, et al. Faecalibacterium prausnitzii and human intestinal health. Curr Opin Microbiol. 2013;16(3):255–61.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Richard ML, Sokol H. The gut mycobiota: insights into analysis, environmental interactions and role in gastrointestinal diseases. Nat Rev Gastroenterol Hepatol. 2019;16(6):331–45.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Cui X, Ye L, Li J, Jin L, Wang W, et al. Metagenomic and metabolomic analyses unveil dysbiosis of gut microbiota in chronic heart failure patients. Sci Rep. 2018;8(1):635.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Kamo T, Akazawa H, Suda W, Saga-Kamo A, Shimizu Y, et al. Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. PLoS One. 2017;12(3):e0174099.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Kummen M, Mayerhofer CCK, Vestad B, Broch K, Awoyemi A, et al. Gut microbiota signature in heart failure defined from profiling of 2 independent cohorts. J Am Coll Cardiol. 2018;71(10):1184–6.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Pullen AB, Jadapalli JK, Rhourri-Frih B, Halade GV. Re-evaluating the causes and consequences of non-resolving inflammation in chronic cardiovascular disease. Heart Fail Rev. 2019; In press.Google Scholar
  22. 22.
    Sarhene M, Wang Y, Wei J, Huang Y, Li M, et al. Biomarkers in heart failure: the past, current and future. Heart Fail Rev. 2019; In press.Google Scholar
  23. 23.
    Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the randomized Etanercept worldwide evaluation (RENEWAL). Circulation. 2004;109(13):1594–602.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Sandek A, Anker SD, von Haehling S. The gut and intestinal bacteria in chronic heart failure. Curr Drug Metab. 2009;10(1):22–8.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Krack A, Richartz BM, Gastmann A, Greim K, Lotze U, et al. Studies on intragastric PCO2 at rest and during exercise as a marker of intestinal perfusion in patients with chronic heart failure. Eur J Heart Fail. 2004;6(4):403–7.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Arutyunov GP, Kostyukevich OI, Serov RA, Rylova NV, Bylova NA. Collagen accumulation and dysfunctional mucosal barrier of the small intestine in patients with chronic heart failure. Int J Cardiol. 2008;125(2):240–5.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Amar J, Lange C, Payros G, Garret C, Chabo C, et al. Blood microbiota dysbiosis is associated with the onset of cardiovascular events in a large general population: the D.E.S.I.R. study. PLoS One. 2013;8(1):e54461.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Dinakaran V, Rathinavel A, Pushpanathan M, Sivakumar R, Gunasekaran P, et al. Elevated levels of circulating DNA in cardiovascular disease patients: metagenomic profiling of microbiome in the circulation. PLoS One. 2014;9(8):e105221.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet. 1999;353(9167):1838–42.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Peschel T, Schönauer M, Thiele H, Anker SD, Schuler G, et al. Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure. Eur J Heart Fail. 2003;5(5):609–14.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Sandek A, Bjarnason I, Volk HD, Crane R, Meddings JB, et al. Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure. Int J Cardiol. 2012;157(1):80–5.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Conraads VM, Bosmans JM, Schuerwegh AJ, Goovaerts I, De Clerck LS. At al. Intracellular monocyte cytokine production and CD 14 expression are up-regulated in severe vs mild chronic heart failure. J Heart Lung Transplant. 2005;24(7):854–9.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014;11(5):255–65.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Yu L, Feng Z. The role of toll-like receptor signaling in the progression of heart failure. Mediat Inflamm. 2018;2018:9874109.Google Scholar
  35. 35.
    Hietbrink F, Besselink MG, Renooij W, de Smet MB, Draisma A, et al. Systemic inflammation increases intestinal permeability during experimental human endotoxemia. Shock. 2009;32(4):374–8.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Tang WH, Wang Z, Fan Y, Levison B, Hazen JE, et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol. 2014;64(18):1908–14.PubMedCrossRefGoogle Scholar
  37. 37.
    Tang WH, Wang Z, Shrestha K, Borowski AG, Wu Y, et al. Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J Card Fail. 2015;21(2):91–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Albert CL, Tang WHW. Metabolic biomarkers in heart failure. Heart Fail Clin. 2018;14(1):109–18.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Hayashi T, Yamashita T, Watanabe H, Kami K, Yoshida N, et al. Gut microbiome and plasma microbiome-related metabolites in patients with decompensated and compensated heart failure. Circ J. 2018;83(1):182–92.PubMedCrossRefGoogle Scholar
  40. 40.
    Suzuki T, Yazaki Y, Voors AA, Jones DJL, Chan DCS, et al. Association with outcomes and response to treatment of trimethylamine N-oxide in heart failure (from BIOSTAT-CHF). Eur J Heart Fail. 2018; In press.Google Scholar
  41. 41.
    Kanitsoraphan C, Rattanawong P, Charoensri S, Senthong V. Trimethylamine N-oxide and risk of cardiovascular disease and mortality. Curr Nutr Rep. 2018;7(4):207–13.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Organ CL, Otsuka H, Bhushan S, Wang Z, Bradley J, et al. Choline diet and its gut microbe-derived metabolite, trimethylamine N-oxide, exacerbate pressure overload-induced heart failure. Circ Heart Fail. 2016;9(1):e002314.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Li Z, Wu Z, Yan J, Liu H, Liu Q, et al. Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis. Lab Investig. 2019;99(3):346–57.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Li X, Sun Y, Zhang X, Wang J. Reductions in gut microbiota-derived metabolite trimethylamine N-oxide in the circulation may ameliorate myocardial infarction-induced heart failure in rats, possibly by inhibiting interleukin-8 secretion. Mol Med Rep. 2019; In press.Google Scholar
  45. 45.
    Blacher E, Levy M, Tatirovsky E, Elinav E. Microbiome-modulated metabolites at the Interface of host immunity. J Immunol. 2017;198(2):572–80.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Levy M, Blacher E, Elinav E. Microbiome, metabolites and host immunity. Curr Opin Microbiol. 2017;35:8–15.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Tang WHW, Bäckhed F, Landmesser U, Hazen SL. Intestinal microbiota in cardiovascular health and disease: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(16):2089–105.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Battson ML, Lee DM, Weir TL, Gentile CL. The gut microbiota as a novel regulator of cardiovascular function and disease. J Nutr Biochem. 2018;56:1–15.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Wang Z, Zhao Y. Gut microbiota derived metabolites in cardiovascular health and disease. Protein Cell. 2018;9(5):416–31.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Marques FZ, Nelson E, Chu PY, Horlock D. Fiedler et al. high-Fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice. Circulation. 2017;135(10):964–77.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89(1):147–91.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Wahlström A, Sayin SI, Marschall HU, Bäckhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24(1):41–50.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Hanafi NI, Mohamed AS, Sheikh Abdul Kadir SH, Othman MHD. Overview of bile acids signaling and perspective on the signal of Ursodeoxycholic acid, the most hydrophilic bile acid, in the heart. Biomolecules. 2018;8(4):e159.PubMedCentralCrossRefGoogle Scholar
  54. 54.
    Khurana S, Raufman JP, Pallone TL. Bile acids regulate cardiovascular function. Clin Transl Sci. 2011;4(3):210–8.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Vasavan T, Ferraro E, Ibrahim E, Dixon P, Gorelik J, et al. Heart and bile acids - clinical consequences of altered bile acid metabolism. Biochim Biophys Acta Mol basis Dis. 2018;1864(4 Pt B):1345–55.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Mayerhofer CCK, Ueland T, Broch K, Vincent RP, Cross GF, et al. Increased secondary/primary bile acid ratio in chronic heart failure. J Card Fail. 2017;23(9):666–71.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Gao J, Liu X, Wang B, Xu H, Xia Q, et al. Farnesoid X receptor deletion improves cardiac function, structure and remodeling following myocardial infarction in mice. Mol Med Rep. 2017;16(1):673–9.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Eblimit Z, Thevananther S, Karpen SJ, Taegtmeyer H, Moore DD, et al. TGR5 activation induces cytoprotective changes in the heart and improves myocardial adaptability to physiologic, inotropic, and pressure-induced stress in mice. Cardiovasc Ther. 2018;36(5):e12462.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Battson ML, Lee DM, Jarrell DK, Hou S, Ecton KE, et al. Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction. Am J Physiol Endocrinol Metab. 2018;314(5):E468–77.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576–85.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Koeth RA, Lam-Galvez BR, Kirsop J, Wang Z, Levison BS, et al. L-carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. J Clin Invest. 2019;129(1):373–87.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Lang JM, Pan C, Cantor RM, Tang WHW, Garcia-Garcia JC, Kurtz I, Hazen SL, Bergeron N, Krauss RM, Lusis AJ. Impact of individual traits, saturated fat, and protein source on the gut microbiome. MBio. 2018;9(6):e01604–18.Google Scholar
  63. 63.
    Lopez-Garcia E, Rodriguez-Artalejo F, Li TY, Fung TT, Li S, et al. The Mediterranean-style dietary pattern and mortality among men and women with cardiovascular disease. Am J Clin Nutr. 2014;99(1):172–80.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Bjarnason-Wehrens B, Nebel R, Jensen K, Hackbusch M, Grilli M, et al. German Society of Cardiovascular Prevention and Rehabilitation (DGPR). Exercise-based cardiac rehabilitation in patients with reduced left ventricular ejection fraction: the cardiac rehabilitation outcome study in heart failure (CROS-HF): a systematic review and meta-analysis. Eur J Prev Cardiol. 2019.
  65. 65.
    Mailing LJ, Allen JM, Buford TW, Fields CJ, Woods JA. Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and implications for human health. Exerc Sport Sci Rev. 2019;47(2):75–85.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Lambert JE, Myslicki JP, Bomhof MR, Belke DD, Shearer J, et al. Exercise training modifies gut microbiota in normal and diabetic mice. Appl Physiol Nutr Metab. 2015;40(7):749–52.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Zhao X, Zhang Z, Hu B, Huang W, Yuan C, Zou L. Response of gut microbiota to metabolite changes induced by endurance exercise. Front Microbiol. 2018;9:765.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Lam V, Su J, Koprowski S, Hsu A, Tweddell JS, et al. Intestinal microbiota determine severity of myocardial infarction in rats. FASEB J. 2012;26(4):1727–35.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Conraads VM, Jorens PG, De Clerck LS, Van Saene HK, et al. Selective intestinal decontamination in advanced chronic heart failure: a pilot trial. Eur J Heart Fail. 2004;6(4):483–91.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Cheng YJ, Nie XY, Chen XM, Lin XX, Tang K, et al. The role of macrolide antibiotics in increasing cardiovascular risk. J Am Coll Cardiol. 2015;66(20):2173–84.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Gorelik E, Masarwa R, Perlman A, Rotshild V, Muszkat M, et al. Systemic review, meta-analysis, and network meta-analysis of the cardiovascular safety of macrolides. Antimicrob Agents Chemother. 2018;62(6):e00438–18.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Ettinger G, MacDonald K, Reid G, Burton JP. The influence of the human microbiome and probiotics on cardiovascular health. Gut Microbes. 2014;5(6):719–28.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Gan XT, Ettinger G, Huang CX, Burton JP, Haist JV, et al. Probiotic administration attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat. Circ Heart Fail. 2014;7:491–9.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Costanza AC, Moscavitch SD, Faria Neto HC, Mesquita ET. Probiotic therapy with Saccharomyces boulardii for heart failure patients: a randomized, double-blind, placebo-controlled pilot trial. Int J Cardiol. 2015;179:348–50.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Mayerhofer CCK, Awoyemi AO, Moscavitch SD, Lappegård KT, Hov JR, et al. Design of the GutHeart-targeting gut microbiota to treat heart failure-trial: a phase II, randomized clinical trial. ESC Heart Fail. 2018;5(5):977–84.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Cammarota G, Ianiro G, Gasbarrini A. Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review. J Clin Gastroenterol. 2014;48(8):693–702.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Suez J, Zmora N, Zilberman-Schapira G, Mor U, Dori-Bachash M, et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell. 2018;174(6):1406–1423.e16.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Maxime Branchereau
    • 1
  • Rémy Burcelin
    • 1
  • Christophe Heymes
    • 1
    • 2
    Email author
  1. 1.Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048Université de Toulouse, UPSToulouseFrance
  2. 2.INSERM U1048 - Institute of Cardiovascular and Metabolic Diseases - I2MCToulouse Cedex 4France

Personalised recommendations