Advertisement

Targeting the Microbiome in Heart Failure

  • Allyson Zabell
  • W. H. Wilson TangEmail author
Heart Failure (W Tang, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Heart Failure

Opinion statement

Heart failure is the leading cause of mortality and morbidity in the world today. While there have been major advances in our understanding of the pathophysiology of heart failure over the past decades, disease progression remains inevitable in the majority of patients and effective therapies to prevent heart failure are still lacking. Research has turned to better understand the gut microbiome because alterations in their ecosystems have been associated with various downstream chronic conditions including cardiovascular diseases. The gut microbiome is complex and diverse in nature, making it difficult to generalize to specific populations or individual patients. Nevertheless, current evidence has found links between heart failure and alterations in microbial composition and function, since heart failure has long been associated with impaired intestinal barrier function and bacterial translocation leading to inflammatory and immune responses. Recent studies have also shed light on the contributions of gut microbiota-derived metabolites from dietary nutrients that can promote adverse effects in the setting of cardiorenal diseases. In this review, we will discuss the role of gut microbiome in the setting of heart failure and potential interventional approaches that may potentially lower the risk of disease progression in heart failure.

Keywords

Heart failure Microbiome Cardiovascular disease Gut microbiome 

Notes

Compliance with Ethical Standards

Conflict of Interest

Wilson Tang is supported by grants from the National Institutes of Health (NIH) and the Office of Dietary Supplements (R01HL103866, P20HL113452, R01DK106000, R01HL126827). Dr. Tang is a section editor for Current Treatment Options in Cardiovascular Medicine.

Allyson Zabell declares no potential conflicts of interest.

Human and Animal Rights and Informed Consent

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

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Green ED, Watson JD, Collins FS. Human Genome Project: twenty-five years of big biology. Nature. 2015;526(7571):29–31.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Neish AS. Microbes in gastrointestinal health and disease. Gastroenterology. 2009;136(1):65–80.CrossRefPubMedGoogle Scholar
  3. 3.
    Levy M, Blacher E, Elinav E. Microbiome, metabolites and host immunity. Curr Opin Microbiol. 2016;35:8–15.CrossRefPubMedGoogle Scholar
  4. 4.
    Ding T, Schloss PD. Dynamics and associations of microbial community types across the human body. Nature. 2014;509(7500):357–60.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest. 2014;124(10):4204–11.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Falony G, Joossens M, Vieira-Silva S, et al. Population-level analysis of gut microbiome variation. Science. 2016;352(6285):560–4.CrossRefPubMedGoogle Scholar
  7. 7.
    Yadav D, Ghosh TS, Mande SS. Global investigation of composition and interaction networks in gut microbiomes of individuals belonging to diverse geographies and age-groups. Gut Pathog. 2016;8:17.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Tang WH, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368(17):1575–84.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    •• Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57–63. Seminal paper describing the contributory role of trimethylamine N-oxide in atherogenesis and the obligatory participation of gut microbiome.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Albenberg LG, Wu GD. Diet and the intestinal microbiome: associations, functions, and implications for health and disease. Gastroenterology. 2014;146(6):1564–72.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Lawson-Yuen A, Levy HL. The use of betaine in the treatment of elevated homocysteine. Mol Genet Metab. 2006;88(3):201–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Ufnal M, Zadlo A, Ostaszewski R. TMAO: a small molecule of great expectations. Nutrition. 2015;31(11-12):1317–23.CrossRefPubMedGoogle Scholar
  13. 13.
    Velasquez MT, Ramezani A, Manal A, Raj DS. Trimethylamine N-oxide: the good, the bad and the unknown. Toxins (Basel). 2016;8(11):326.CrossRefGoogle Scholar
  14. 14.
    Senthong V, Li XS, Hudec T, et al. Plasma trimethylamine N-oxide, a gut microbe-generated phosphatidylcholine metabolite, is associated with atherosclerotic burden. J Am Coll Cardiol. 2016;67(22):2620–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Hai X, Landeras V, Dobre MA, DeOreo P, Meyer TW, Hostetter TH. Mechanism of prominent trimethylamine oxide (TMAO) accumulation in hemodialysis patients. PLoS One. 2015;10(12):e0143731.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Missailidis C, Hallqvist J, Qureshi AR, et al. Serum trimethylamine-N-oxide is strongly related to renal function and predicts outcome in chronic kidney disease. PLoS One. 2016;11(1):e0141738.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Shafi T, Powe NR, Meyer TW, et al. Trimethylamine N-oxide and cardiovascular events in hemodialysis patients. J Am Soc Nephrol. 2016;28(1):321–31.CrossRefPubMedGoogle Scholar
  18. 18.
    Stubbs JR, House JA, Ocque AJ, et al. Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden. J Am Soc Nephrol. 2016;27(1):305–13.CrossRefPubMedGoogle Scholar
  19. 19.
    Tang WH, Wang Z, Kennedy DJ, et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res. 2015;116(3):448–55.CrossRefPubMedGoogle Scholar
  20. 20.
    •• Niebauer J, Volk HD, Kemp M, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet. 1999;353(9167):1838–42. Prospective demonstration of endotoxin and immune activation in heart failure.CrossRefPubMedGoogle Scholar
  21. 21.
    • Sandek A, Bauditz J, Swidsinski A, et al. Altered intestinal function in patients with chronic heart failure. J Am Coll Cardiol. 2007;50(16):1561–9. Key demonstration of the contributions of altered intestinal function in heart failure.CrossRefPubMedGoogle Scholar
  22. 22.
    Sharma R, Bolger AP, Rauchhaus M, et al. Cellular endotoxin desensitization in patients with severe chronic heart failure. Eur J Heart Fail. 2005;7(5):865–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Sharma R, von Haehling S, Rauchhaus M, et al. Whole blood endotoxin responsiveness in patients with chronic heart failure: the importance of serum lipoproteins. Eur J Heart Fail. 2005;7(4):479–84.CrossRefPubMedGoogle Scholar
  24. 24.
    Sandek A, Bjarnason I, Volk HD, et al. Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure. Int J Cardiol. 2012;157(1):80–5.CrossRefPubMedGoogle Scholar
  25. 25.
    • Peschel T, Schonauer M, Thiele H, Anker SD, Schuler G, Niebauer J. Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure. Eur J Heart Fail. 2003;5(5):609–14. Early work demonstrating the presence of bacterial endotoxin and inflammatory cytokines in acute heart failure.CrossRefPubMedGoogle Scholar
  26. 26.
    von Haehling S, Genth-Zotz S, Bolger AP, et al. Effect of noradrenaline and isoproterenol on lipopolysaccharide-induced tumor necrosis factor-alpha production in whole blood from patients with chronic heart failure and the role of beta-adrenergic receptors. Am J Cardiol. 2005;95(7):885–9.CrossRefGoogle Scholar
  27. 27.
    Pasini E, Aquilani R, Testa C, et al. Pathogenic gut flora in patients with chronic heart failure. JACC Heart Fail. 2016;4(3):220–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Phillips Campbell RB, Duffourc MM, Schoborg RV, et al. Aberrant fecal flora observed in guinea pigs with pressure overload is mitigated in animals receiving vagus nerve stimulation therapy. Am J Physiol Gastrointest Liver Physiol. 2016;311(4):G754–62.CrossRefPubMedGoogle Scholar
  29. 29.
    • Tang WH, Wang Z, Fan Y, 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. First demonstration of association between elevated TMAO and prognosis in heart failure.CrossRefPubMedGoogle Scholar
  30. 30.
    Tang WH, Wang Z, Shrestha K, 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.CrossRefPubMedGoogle Scholar
  31. 31.
    Troseid M, Ueland T, Hov JR, et al. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med. 2015;277(6):717–26.CrossRefPubMedGoogle Scholar
  32. 32.
    Gabe SM, Bjarnason I, Tolou-Ghamari Z, et al. The effect of tacrolimus (FK506) on intestinal barrier function and cellular energy production in humans. Gastroenterology. 1998;115(1):67–74.CrossRefPubMedGoogle Scholar
  33. 33.
    Dickson RP, Erb-Downward JR, Freeman CM, et al. Changes in the lung microbiome following lung transplantation include the emergence of two distinct Pseudomonas species with distinct clinical associations. PLoS One. 2014;9(5):e97214.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kitai T, Kirsop J, Tang WH. Exploring the microbiome in heart failure. Curr Heart Fail Rep. 2016;13(2):103–9.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    • Organ CL, Otsuka H, Bhushan S, 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. Animal studies demonstrating the contribution of dietary-induced TMAO production and cardiac remodeling in mouse model.CrossRefPubMedGoogle Scholar
  36. 36.
    Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368(14):1279–90.CrossRefPubMedGoogle Scholar
  37. 37.
    De Filippis F, Pellegrini N, Vannini L, et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut. 2015;28:gutjnl-2015.Google Scholar
  38. 38.
    Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576–85.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Miller MJ, Bostwick BL, Kennedy AD, et al. Chronic oral L-carnitine supplementation drives marked plasma TMAO elevations in patients with organic acidemias despite dietary meat restrictions. JIMD Rep. 2016;30:39–44.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    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.CrossRefPubMedGoogle Scholar
  41. 41.
    • Gan XT, Ettinger G, Huang CX, et al. Probiotic administration attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat. Circ Heart Fail. 2014;7(3):491–9. Probiotics intervention with signals of attenuating cardiac remodeling in a rat heart failure model.CrossRefPubMedGoogle Scholar
  42. 42.
    Ranganathan N, Friedman EA, Tam P, Rao V, Ranganathan P, Dheer R. Probiotic dietary supplementation in patients with stage 3 and 4 chronic kidney disease: a 6-month pilot scale trial in Canada. Curr Med Res Opin. 2009;25(8):1919–30.CrossRefPubMedGoogle Scholar
  43. 43.
    Fujii H, Nishijima F, Goto S, et al. Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress. Nephrol Dial Transplant. 2009;24(7):2089–95.CrossRefPubMedGoogle Scholar
  44. 44.
    Bennett BJ, de Aguiar Vallim TQ, Wang Z, et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013;17(1):49–60.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Gregory JC, Buffa JA, Org E, et al. Transmission of atherosclerosis susceptibility with gut microbial transplantation. J Biol Chem. 2015;290(9):5647–60.CrossRefPubMedGoogle Scholar
  46. 46.
    Shih DM, Wang Z, Lee R, et al. Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis. J Lipid Res. 2015;56(1):22–37.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Tang WH, Wang Z, Li XS, et al. Increased trimethylamine N-oxide portends high mortality risk independent of glycemic control in patients with type 2 diabetes mellitus. Clin Chem. 2016;63(1):297–306.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.ClevelandUSA

Personalised recommendations