Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Dietary metabolism, the gut microbiome, and heart failure

Nature Reviews Cardiology volume 16, pages 137–154 (2019)Cite this article

Subjects

Abstract

Advances in our understanding of how the gut microbiota contributes to human health and diseases have expanded our insight into how microbial composition and function affect the human host. Heart failure is associated with splanchnic circulation congestion, leading to bowel wall oedema and impaired intestinal barrier function. This situation is thought to heighten the overall inflammatory state via increased bacterial translocation and the presence of bacterial products in the systemic blood circulation. Several metabolites produced by gut microorganisms from dietary metabolism have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. These findings suggest that the gut microbiome functions like an endocrine organ by generating bioactive metabolites that can directly or indirectly affect host physiology. In this Review, we discuss several newly discovered gut microbial metabolic pathways, including the production of trimethylamine and trimethylamine N-oxide, short-chain fatty acids, and secondary bile acids, that seem to participate in the development and progression of cardiovascular diseases, including heart failure. We also discuss the gut microbiome as a novel therapeutic target for the treatment of cardiovascular disease, and potential strategies for targeting intestinal microbial processes.

Key points

  • The gut hypothesis of heart failure (HF) postulates that bowel wall oedema and impaired intestinal barrier function in HF can promote bacterial translocation and inflammation.

  • Changes in the composition and diversity of the gut microbiota have been observed in patients with HF.

  • Microbial metabolites, especially those derived from dietary nutrients, can generate paracrine and endocrine effects that can lead to an increased susceptibility to HF.

  • Novel therapeutic strategies targeting gut microbial metabolic pathways and/or metabolites, as well as altering gut microbial composition, have the potential to modulate cardiovascular disease susceptibility and prevent progression to HF.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Microbial–host meta-organismal pathway linking dietary metabolism, the gut microbiota, and cardiorenal disease progression.
Fig. 2: Downstream effects of gut microbiota-generated short-chain fatty acids in the cardiovascular system.
Fig. 3: Microbial generation of dietary-induced trimethylamine and trimethylamine N-oxide.
Fig. 4: Relationship between plasma levels of trimethylamine N-oxide and 5-year risk of death in patients with chronic heart failure.
Fig. 5: Microbial metabolic pathways as potential druggable targets.

Similar content being viewed by others

References

  1. Yancy, C. W. et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 128, 1810–1852 (2013).

    PubMed  Google Scholar 

  2. Yancy, C. W. et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines and the Heart Failure Society of America. J. Am. Coll. Cardiol. 70, 776–803 (2017).

    PubMed  Google Scholar 

  3. Anker, S. D. et al. Elevated soluble CD14 receptors and altered cytokines in chronic heart failure. Am. J. Cardiol. 79, 1426–1430 (1997).

    CAS  PubMed  Google Scholar 

  4. Krack, A., Sharma, R., Figulla, H. R. & Anker, S. D. The importance of the gastrointestinal system in the pathogenesis of heart failure. Eur. Heart J. 26, 2368–2374 (2005).

    CAS  PubMed  Google Scholar 

  5. Sender, R., Fuchs, S. & Milo, R. Revised estimates for the number of human and bacteria cells in the body. PLOS Biol. 14, e1002533 (2016).

    PubMed  PubMed Central  Google Scholar 

  6. Turnbaugh, P. J. et al. The human microbiome project. Nature 449, 804–810 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Dethlefsen, L., Eckburg, P. B., Bik, E. M. & Relman, D. A. Assembly of the human intestinal microbiota. Trends Ecol. Evol. 21, 517–523 (2006).

    PubMed  Google Scholar 

  8. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

    Google Scholar 

  9. Booijink, C. C., Zoetendal, E. G., Kleerebezem, M. & de Vos, W. M. Microbial communities in the human small intestine: coupling diversity to metagenomics. Future Microbiol. 2, 285–295 (2007).

    CAS  PubMed  Google Scholar 

  10. Gorbach, S. L. in Medical Microbiology 4th edn (ed. Baron, S.) (Univ. of Texas Medical Branch, 1996).

  11. Hooper, L. V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001).

    CAS  PubMed  Google Scholar 

  12. Marcobal, A. et al. Consumption of human milk oligosaccharides by gut-related microbes. J. Agr. Food Chem. 58, 5334–5340 (2010).

    CAS  Google Scholar 

  13. Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Fujiya, M. et al. The Bacillus subtilis quorum-sensing molecule CSF contributes to intestinal homeostasis via OCTN2, a host cell membrane transporter. Cell Host Microbe 1, 299–308 (2007).

    CAS  PubMed  Google Scholar 

  15. Buffie, C. G. & Pamer, E. G. Microbiota-mediated colonization resistance against intestinal pathogens. Nat. Rev. Immunol. 13, 790–801 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Corr, S. C. et al. Bacteriocin production as a mechanism for the antiinfective activity of Lactobacillus salivarius UCC118. Proc. Natl Acad. Sci. USA 104, 7617–7621 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Rajilic-Stojanovic, M., Smidt, H. & de Vos, W. M. Diversity of the human gastrointestinal tract microbiota revisited. Environ. Microbiol. 9, 2125–2136 (2007).

    PubMed  Google Scholar 

  18. Yang, X., Xie, L., Li, Y. & Wei, C. More than 9,000,000 unique genes in human gut bacterial community: estimating gene numbers inside a human body. PLOS ONE 4, e6074 (2009).

    PubMed  PubMed Central  Google Scholar 

  19. Palmer, C., Bik, E. M., DiGiulio, D. B., Relman, D. A. & Brown, P. O. Development of the human infant intestinal microbiota. PLOS Biol. 5, e177 (2007).

    PubMed  PubMed Central  Google Scholar 

  20. Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).

    PubMed  PubMed Central  Google Scholar 

  21. Chu, D. M. et al. Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery. Nat. Med. 23, 314–326 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Hall, A. B., Tolonen, A. C. & Xavier, R. J. Human genetic variation and the gut microbiome in disease. Nat. Rev. Genet. 18, 690–699 (2017).

    CAS  PubMed  Google Scholar 

  23. Koppel, N., Maini Rekdal, V. & Balskus, E. P. Chemical transformation of xenobiotics by the human gut microbiota. Science 356, eaag2770 (2017).

    PubMed  Google Scholar 

  24. Sonnenburg, J. L. & Backhed, F. Diet-microbiota interactions as moderators of human metabolism. Nature 535, 56–64 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Brown, J. M. & Hazen, S. L. Targeting of microbe-derived metabolites to improve human health: the next frontier for drug discovery. J. Biol. Chem. 292, 8560–8568 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Saitta, K. S. et al. Bacterial beta-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: mode of action and pharmacokinetics. Xenobiotica 44, 28–35 (2014).

    CAS  PubMed  Google Scholar 

  27. Wallace, B. D. et al. Structure and inhibition of microbiome β-glucuronidases essential to the alleviation of cancer drug toxicity. Chem. Biol. 22, 1238–1249 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Hermiston, M. L. & Gordon, J. I. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science 270, 1203–1207 (1995).

    CAS  PubMed  Google Scholar 

  29. Sandek, A. et al. Altered intestinal function in patients with chronic heart failure. J. Am. Coll. Cardiol. 50, 1561–1569 (2007).

    CAS  PubMed  Google Scholar 

  30. Fink, M. P., Kaups, K. L., Wang, H. L. & Rothschild, H. R. Maintenance of superior mesenteric arterial perfusion prevents increased intestinal mucosal permeability in endotoxic pigs. Surgery 110, 154–160 (1991).

    CAS  PubMed  Google Scholar 

  31. Triposkiadis, F. et al. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J. Am. Coll. Cardiol. 54, 1747–1762 (2009).

    CAS  PubMed  Google Scholar 

  32. Jodal, M. & Lundgren, O. Countercurrent mechanisms in the mammalian gastrointestinal tract. Gastroenterology 91, 225–241 (1986).

    CAS  PubMed  Google Scholar 

  33. Maynard, N. et al. Assessment of splanchnic oxygenation by gastric tonometry in patients with acute circulatory failure. JAMA 270, 1203–1210 (1993).

    CAS  PubMed  Google Scholar 

  34. Krack, A. 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. 6, 403–407 (2004).

    PubMed  Google Scholar 

  35. Arutyunov, G. P., Kostyukevich, O. I., Serov, R. A., Rylova, N. V. & Bylova, N. A. Collagen accumulation and dysfunctional mucosal barrier of the small intestine in patients with chronic heart failure. Int. J. Cardiol. 125, 240–245 (2008).

    PubMed  Google Scholar 

  36. Lu, Y. C., Yeh, W. C. & Ohashi, P. S. LPS/TLR4 signal transduction pathway. Cytokine 42, 145–151 (2008).

    CAS  PubMed  Google Scholar 

  37. Frangogiannis, N. G. The inflammatory response in myocardial injury, repair, and remodelling. Nat. Rev. Cardiol. 11, 255–265 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Niebauer, J. et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 353, 1838–1842 (1999).

    CAS  PubMed  Google Scholar 

  39. Peschel, T. et al. Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure. Eur. J. Heart Fail. 5, 609–614 (2003).

    CAS  PubMed  Google Scholar 

  40. Hietbrink, F. et al. Systemic inflammation increases intestinal permeability during experimental human endotoxemia. Shock 32, 374–378 (2009).

    CAS  PubMed  Google Scholar 

  41. Munger, M. A., Johnson, B., Amber, I. J., Callahan, K. S. & Gilbert, E. M. Circulating concentrations of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am. J. Cardiol. 77, 723–727 (1996).

    CAS  PubMed  Google Scholar 

  42. Paulus, W. J. How are cytokines activated in heart failure? Eur. J. Heart Fail. 1, 309–312 (1999).

    CAS  PubMed  Google Scholar 

  43. Deswal, A. et al. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 103, 2055–2059 (2001).

    CAS  PubMed  Google Scholar 

  44. Rauchhaus, M. et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 102, 3060–3067 (2000).

    CAS  PubMed  Google Scholar 

  45. Ferrari, R. et al. Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation 92, 1479–1486 (1995).

    CAS  PubMed  Google Scholar 

  46. Conraads, V. M. et al. Selective intestinal decontamination in advanced chronic heart failure: a pilot trial. Eur. J. Heart Fail. 6, 483–491 (2004).

    CAS  PubMed  Google Scholar 

  47. Mann, D. L. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ. Res. 116, 1254–1268 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Bozkurt, B. et al. Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 97, 1382–1391 (1998).

    CAS  PubMed  Google Scholar 

  49. Kubota, T. et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ. Res. 81, 627–635 (1997).

    CAS  PubMed  Google Scholar 

  50. Al-Sadi, R. et al. Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene. PLOS ONE 9, e85345 (2014).

    PubMed  PubMed Central  Google Scholar 

  51. Al-Sadi, R. M. & Ma, T. Y. IL-1beta causes an increase in intestinal epithelial tight junction permeability. J. Immunol. 178, 4641–4649 (2007).

    CAS  PubMed  Google Scholar 

  52. Ma, T. Y., Boivin, M. A., Ye, D., Pedram, A. & Said, H. M. Mechanism of TNF-{alpha} modulation of Caco-2 intestinal epithelial tight junction barrier: role of myosin light-chain kinase protein expression. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G422–G430 (2005).

    CAS  PubMed  Google Scholar 

  53. Al-Sadi, R., Guo, S., Ye, D. & Ma, T. Y. TNF-alpha modulation of intestinal epithelial tight junction barrier is regulated by ERK1/2 activation of Elk-1. Am. J. Pathol. 183, 1871–1884 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Chung, E. S. et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 107, 3133–3140 (2003).

    CAS  PubMed  Google Scholar 

  55. Mann, D. L. et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109, 1594–1602 (2004).

    CAS  PubMed  Google Scholar 

  56. Torre-Amione, G. et al. Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): a placebo-controlled randomised trial. Lancet 371, 228–236 (2008).

    CAS  PubMed  Google Scholar 

  57. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    CAS  PubMed  Google Scholar 

  58. Abbate, A. et al. Interleukin-1beta modulation using a genetically engineered antibody prevents adverse cardiac remodelling following acute myocardial infarction in the mouse. Eur. J. Heart Fail. 12, 319–322 (2010).

    CAS  PubMed  Google Scholar 

  59. Abbate, A. et al. Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation 117, 2670–2683 (2008).

    CAS  PubMed  Google Scholar 

  60. Van Tassell, B. W. et al. Interleukin-1 trap attenuates cardiac remodeling after experimental acute myocardial infarction in mice. J. Cardiovasc. Pharmacol. 55, 117–122 (2010).

    PubMed  Google Scholar 

  61. Van Tassell, B. W. et al. Interleukin-1 blockade in recently decompensated systolic heart failure: results from REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ. Heart Fail. 10, e004373 (2017).

    PubMed  PubMed Central  Google Scholar 

  62. Van Tassell, B. W. et al. Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2). Clin. Cardiol. 40, 626–632 (2017).

    PubMed  PubMed Central  Google Scholar 

  63. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01900600 (2017).

  64. Gullestad, L. et al. Inflammatory cytokines in heart failure: mediators and markers. Cardiology 122, 23–35 (2012).

    CAS  PubMed  Google Scholar 

  65. Dick, S. A. & Epelman, S. Chronic heart failure and inflammation: what do we really know? Circ. Res. 119, 159–176 (2016).

    CAS  PubMed  Google Scholar 

  66. Jakobsson, H. E. et al. The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep. 16, 164–177 (2015).

    CAS  PubMed  Google Scholar 

  67. Tlaskalova-Hogenova, H. et al. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cell. Mol. Immunol. 8, 110–120 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).

    CAS  PubMed  Google Scholar 

  69. Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

    PubMed  Google Scholar 

  70. Morgan, X. C. et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 13, R79 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Wen, L. et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109–1113 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).

    CAS  PubMed  Google Scholar 

  73. Kummen, M. et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut 66, 611–619 (2017).

    PubMed  Google Scholar 

  74. Sears, C. L. & Garrett, W. S. Microbes, microbiota, and colon cancer. Cell Host Microbe 15, 317–328 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Arthur, J. C. et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338, 120–123 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Le Roy, T. et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 62, 1787–1794 (2013).

    PubMed  Google Scholar 

  77. Dumas, M. E. et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc. Natl Acad. Sci. USA 103, 12511–12516 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Foster, J. A. & McVey Neufeld, K. A. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 36, 305–312 (2013).

    CAS  PubMed  Google Scholar 

  80. Naseribafrouei, A. et al. Correlation between the human fecal microbiota and depression. Neurogastroenterol. Motil. 26, 1155–1162 (2014).

    CAS  PubMed  Google Scholar 

  81. Gregory, J. C. et al. Transmission of atherosclerosis susceptibility with gut microbial transplantation. J. Biol. Chem. 290, 5647–5660 (2015).

    CAS  PubMed  Google Scholar 

  82. Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Pluznick, J. L. et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc. Natl Acad. Sci. USA 110, 4410–4415 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Mell, B. et al. Evidence for a link between gut microbiota and hypertension in the Dahl rat. Physiol. Genom. 47, 187–197 (2015).

    CAS  Google Scholar 

  85. Durgan, D. J. et al. Role of the gut microbiome in obstructive sleep apnea-induced hypertension. Hypertension 67, 469–474 (2016).

    CAS  PubMed  Google Scholar 

  86. Lam, V. et al. Intestinal microbiota determine severity of myocardial infarction in rats. FASEB J. 26, 1727–1735 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Sandek, A. et al. Intestinal blood flow in patients with chronic heart failure: a link with bacterial growth, gastrointestinal symptoms, and cachexia. J. Am. Coll. Cardiol. 64, 1092–1102 (2014).

    PubMed  Google Scholar 

  88. Pasini, E. et al. Pathogenic gut flora in patients with chronic heart failure. JACC Heart Fail. 4, 220–227 (2016).

    PubMed  Google Scholar 

  89. Mamic, P., Heidenreich, P. A., Hedlin, H., Tennakoon, L. & Staudenmayer, K. L. Hospitalized patients with heart failure and common bacterial infections: a nationwide analysis of concomitant Clostridium difficile infection rates and in-hospital mortality. J. Card. Fail. 22, 891–900 (2016).

    PubMed  Google Scholar 

  90. Luedde, M. et al. Heart failure is associated with depletion of core intestinal microbiota. ESC Heart Fail. 4, 282–290 (2017).

    PubMed  PubMed Central  Google Scholar 

  91. Cui, X. et al. Metagenomic and metabolomic analyses unveil dysbiosis of gut microbiota in chronic heart failure patients. Sci. Rep. 8, 635 (2018).

    PubMed  PubMed Central  Google Scholar 

  92. Kamo, T. et al. Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. PLOS ONE 12, e0174099 (2017).

    PubMed  PubMed Central  Google Scholar 

  93. Kummen, M. et al. Gut microbiota signature in heart failure defined from profiling of 2 independent cohorts. J. Am. Coll. Cardiol. 71, 1184–1186 (2018).

    PubMed  Google Scholar 

  94. Engels, C., Ruscheweyh, H. J., Beerenwinkel, N., Lacroix, C. & Schwab, C. The common gut microbe Eubacterium hallii also contributes to intestinal propionate formation. Front. Microbiol. 7, 713 (2016).

    PubMed  PubMed Central  Google Scholar 

  95. Karlsson, F. H. et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat. Commun. 3, 1245 (2012).

    PubMed  Google Scholar 

  96. Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Rothschild, D. et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215 (2018).

    CAS  PubMed  Google Scholar 

  98. Maier, L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Caparros-Martin, J. A. et al. Statin therapy causes gut dysbiosis in mice through a PXR-dependent mechanism. Microbiome 5, 95 (2017).

    PubMed  PubMed Central  Google Scholar 

  100. Wu, H. et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858 (2017).

    CAS  PubMed  Google Scholar 

  101. Haiser, H. J. et al. Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science 341, 295–298 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhernakova, A. et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352, 565–569 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Selwyn, F. P., Cui, J. Y. & Klaassen, C. D. RNA-seq quantification of hepatic drug processing genes in germ-free mice. Drug Metab. Dispos. 43, 1572–1580 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Bjorkholm, B. et al. Intestinal microbiota regulate xenobiotic metabolism in the liver. PLOS ONE 4, e6958 (2009).

    PubMed  PubMed Central  Google Scholar 

  105. Claus, S. P. et al. Colonization-induced host-gut microbial metabolic interaction. MBio 2, e00271 (2011).

    PubMed  PubMed Central  Google Scholar 

  106. Spanogiannopoulos, P., Bess, E. N., Carmody, R. N. & Turnbaugh, P. J. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat. Rev. Microbiol. 14, 273–287 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Topping, D. L. & Clifton, P. M. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol. Rev. 81, 1031–1064 (2001).

    CAS  PubMed  Google Scholar 

  108. Hadjiagapiou, C., Schmidt, L., Dudeja, P. K., Layden, T. J. & Ramaswamy, K. Mechanism(s) of butyrate transport in Caco-2 cells: role of monocarboxylate transporter 1. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G775–G780 (2000).

    CAS  PubMed  Google Scholar 

  109. Mascolo, N., Rajendran, V. M. & Binder, H. J. Mechanism of short-chain fatty acid uptake by apical membrane vesicles of rat distal colon. Gastroenterology 101, 331–338 (1991).

    CAS  PubMed  Google Scholar 

  110. Vidyasagar, S., Barmeyer, C., Geibel, J., Binder, H. J. & Rajendran, V. M. Role of short-chain fatty acids in colonic HCO(3) secretion. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G1217–G1226 (2005).

    CAS  PubMed  Google Scholar 

  111. den Besten, G. et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 54, 2325–2340 (2013).

    Google Scholar 

  112. Sellin, J. H. SCFAs: the enigma of weak electrolyte transport in the colon. News Physiol. Sci. 14, 58–64 (1999).

    CAS  PubMed  Google Scholar 

  113. Duncan, S. H., Louis, P., Thomson, J. M. & Flint, H. J. The role of pH in determining the species composition of the human colonic microbiota. Environ. Microbiol. 11, 2112–2122 (2009).

    PubMed  Google Scholar 

  114. Cherrington, C. A., Hinton, M., Pearson, G. R. & Chopra, I. Short-chain organic acids at ph 5.0 kill Escherichia coli and Salmonella spp. without causing membrane perturbation. J. Appl. Bacteriol. 70, 161–165 (1991).

    CAS  PubMed  Google Scholar 

  115. Pouteau, E., Meirim, I., Metairon, S. & Fay, L. B. Acetate, propionate and butyrate in plasma: determination of the concentration and isotopic enrichment by gas chromatography/mass spectrometry with positive chemical ionization. J. Mass Spectrom. 36, 798–805 (2001).

    CAS  PubMed  Google Scholar 

  116. Yang, T. et al. Gut dysbiosis is linked to hypertension. Hypertension 65, 1331–1340 (2015).

    CAS  PubMed  Google Scholar 

  117. Pluznick, J. A novel SCFA receptor, the microbiota, and blood pressure regulation. Gut Microbes 5, 202–207 (2014).

    PubMed  Google Scholar 

  118. Marques, F. Z. 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 135, 964–977 (2017).

    CAS  PubMed  Google Scholar 

  119. Pouteau, E., Nguyen, P., Ballevre, O. & Krempf, M. Production rates and metabolism of short-chain fatty acids in the colon and whole body using stable isotopes. Proc. Nutr. Soc. 62, 87–93 (2003).

    CAS  PubMed  Google Scholar 

  120. Lefebvre, P., Cariou, B., Lien, F., Kuipers, F. & Staels, B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol. Rev. 89, 147–191 (2009).

    CAS  PubMed  Google Scholar 

  121. Dawson, P. A., Lan, T. & Rao, A. Bile acid transporters. J. Lipid Res. 50, 2340–2357 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Devlin, A. S. & Fischbach, M. A. A biosynthetic pathway for a prominent class of microbiota-derived bile acids. Nat. Chem. Biol. 11, 685–690 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Ridlon, J. M., Kang, D. J. & Hylemon, P. B. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 47, 241–259 (2006).

    CAS  PubMed  Google Scholar 

  124. Hamilton, J. P. et al. Human cecal bile acids: concentration and spectrum. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G256–G263 (2007).

    CAS  PubMed  Google Scholar 

  125. Mayerhofer, C. C. K. et al. Increased secondary/primary bile acid ratio in chronic heart failure. J. Card. Fail. 23, 666–671 (2017).

    CAS  PubMed  Google Scholar 

  126. Binah, O., Rubinstein, I., Bomzon, A. & Better, O. S. Effects of bile acids on ventricular muscle contraction and electrophysiological properties: studies in rat papillary muscle and isolated ventricular myocytes. Naunyn Schmiedebergs Arch. Pharmacol. 335, 160–165 (1987).

    CAS  PubMed  Google Scholar 

  127. Joubert, P. An in vivo investigation of the negative chronotropic effect of cholic acid in the rat. Clin. Exp. Pharmacol. Physiol. 5, 1–8 (1978).

    CAS  PubMed  Google Scholar 

  128. Gazawi, H. et al. The effects of bile acids on beta-adrenoceptors, fluidity, and the extent of lipid peroxidation in rat cardiac membranes. Biochem. Pharmacol. 59, 1623–1628 (2000).

    CAS  PubMed  Google Scholar 

  129. Wang, H., Chen, J., Hollister, K., Sowers, L. C. & Forman, B. M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol. Cell 3, 543–553 (1999).

    CAS  PubMed  Google Scholar 

  130. Forman, B. M. et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81, 687–693 (1995).

    CAS  PubMed  Google Scholar 

  131. Kawamata, Y. et al. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278, 9435–9440 (2003).

    CAS  PubMed  Google Scholar 

  132. Rosen, H., Gonzalez-Cabrera, P. J., Sanna, M. G. & Brown, S. Sphingosine 1-phosphate receptor signaling. Annu. Rev. Biochem. 78, 743–768 (2009).

    CAS  PubMed  Google Scholar 

  133. Raufman, J. P., Chen, Y., Zimniak, P. & Cheng, K. Deoxycholic acid conjugates are muscarinic cholinergic receptor antagonists. Pharmacology 65, 215–221 (2002).

    CAS  PubMed  Google Scholar 

  134. Calkin, A. C. & Tontonoz, P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat. Rev. Mol. Cell Biol. 13, 213–224 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Sayin, S. I. et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235 (2013).

    CAS  PubMed  Google Scholar 

  136. Wang, Y. D. et al. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48, 1632–1643 (2008).

    CAS  PubMed  Google Scholar 

  137. Li, Y. T., Swales, K. E., Thomas, G. J., Warner, T. D. & Bishop-Bailey, D. Farnesoid x receptor ligands inhibit vascular smooth muscle cell inflammation and migration. Arterioscler. Thromb. Vasc. Biol. 27, 2606–2611 (2007).

    PubMed  Google Scholar 

  138. Purcell, N. H. et al. Activation of NF-kappa B is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes. Proc. Natl Acad. Sci. USA 98, 6668–6673 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Gordon, J. W., Shaw, J. A. & Kirshenbaum, L. A. Multiple facets of NF-kappaB in the heart: to be or not to NF-kappaB. Circ. Res. 108, 1122–1132 (2011).

    CAS  PubMed  Google Scholar 

  140. Pu, J. et al. Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury. Eur. Heart J. 34, 1834–1845 (2013).

    CAS  PubMed  Google Scholar 

  141. Ali, A. H., Carey, E. J. & Lindor, K. D. Recent advances in the development of farnesoid X receptor agonists. Ann. Transl Med. 3, 5 (2015).

    PubMed  PubMed Central  Google Scholar 

  142. Pellicciari, R. et al. 6α-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J. Med. Chem. 45, 3569–3572 (2002).

    CAS  PubMed  Google Scholar 

  143. Nevens, F. et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N. Engl. J. Med. 375, 631–643 (2016).

    CAS  PubMed  Google Scholar 

  144. Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).

    CAS  PubMed  Google Scholar 

  145. Mudaliar, S. et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145, 574–582 (2013).

    CAS  PubMed  Google Scholar 

  146. Xu, Y. et al. Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice. Hepatology 64, 1072–1085 (2016).

    CAS  PubMed  Google Scholar 

  147. Cipriani, S., Mencarelli, A., Palladino, G. & Fiorucci, S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J. Lipid Res. 51, 771–784 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. von Haehling, S. et al. Ursodeoxycholic acid in patients with chronic heart failure: a double-blind, randomized, placebo-controlled, crossover trial. J. Am. Coll. Cardiol. 59, 585–592 (2012).

    Google Scholar 

  149. Aouad, K. et al. Immunosuppressive effects of endotoxins and bile acids in vivo in the rat. Eur. J. Clin. Invest. 26, 45–48 (1996).

    CAS  PubMed  Google Scholar 

  150. Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Tang, W. H. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Zhao, Y. et al. The effect of different L-carnitine administration routes on the development of atherosclerosis in ApoE knockout mice. Mol. Nutr. Food Res. 62, 1700299 (2018).

    Google Scholar 

  154. Organ, C. L. et al. Choline diet and its gut microbe-derived metabolite, trimethylamine N-oxide, exacerbate pressure overload-induced heart failure. Circ. Heart Fail. 9, e002314 (2016).

    CAS  PubMed  Google Scholar 

  155. Seibel, B. A. & Walsh, P. J. Trimethylamine oxide accumulation in marine animals: relationship to acylglycerol storage. J. Exp. Biol. 205, 297–306 (2002).

    CAS  PubMed  Google Scholar 

  156. Parab, S. N. & Rao, S. B. Distribution of trimethylamine oxie in some marine and freshwater fish. Curr. Sci. 53, 307–309 (1984).

    CAS  Google Scholar 

  157. Cladis, D. P., Kleiner, A. C., Freiser, H. H. & Santerre, C. R. Fatty acid profiles of commercially available finfish fillets in the United States. Lipids 49, 1005–1018 (2014).

    CAS  PubMed  Google Scholar 

  158. Weaver, K. L. et al. The content of favorable and unfavorable polyunsaturated fatty acids found in commonly eaten fish. J. Am. Diet. Assoc. 108, 1178–1185 (2008).

    CAS  PubMed  Google Scholar 

  159. Svensson, B. G., Akesson, B., Nilsson, A. & Paulsson, K. Urinary excretion of methylamines in men with varying intake of fish from the Baltic Sea. J. Toxicol. Environ. Health 41, 411–420 (1994).

    CAS  PubMed  Google Scholar 

  160. Yazdekhasti, N. et al. Fish protein increases circulating levels of trimethylamine-N-oxide and accelerates aortic lesion formation in apoE null mice. Mol. Nutr. Food Res. 60, 358–368 (2016).

    CAS  PubMed  Google Scholar 

  161. Gao, X. et al. Fish oil ameliorates trimethylamine N-oxide-exacerbated glucose intolerance in high-fat diet-fed mice. Food Funct. 6, 1117–1125 (2015).

    CAS  PubMed  Google Scholar 

  162. Kasiske, B. L., Lakatua, J. D., Ma, J. Z. & Louis, T. A. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function. Am. J. Kidney Dis. 31, 954–961 (1998).

    CAS  PubMed  Google Scholar 

  163. Pedrini, M. T., Levey, A. S., Lau, J., Chalmers, T. C. & Wang, P. H. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis. Ann. Intern. Med. 124, 627–632 (1996).

    CAS  PubMed  Google Scholar 

  164. Collins, H. L. et al. L-carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE −/− transgenic mice expressing CETP. Atherosclerosis 244, 29–37 (2016).

    CAS  PubMed  Google Scholar 

  165. Bennett, B. J. et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 17, 49–60 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Zhu, W., Wang, Z., Tang, W. H. W. & Hazen, S. L. Gut microbe-generated trimethylamine N-oxide from dietary choline is prothrombotic in subjects. Circulation 135, 1671–1673 (2017).

    PubMed  PubMed Central  Google Scholar 

  167. Seldin, M. M. et al. Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-kappaB. J. Am. Heart Assoc. 5, e002767 (2016).

    PubMed  PubMed Central  Google Scholar 

  168. Sun, X. et al. Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome. Biochem. Biophys. Res. Commun. 481, 63–70 (2016).

    CAS  PubMed  Google Scholar 

  169. Ma, G. et al. Trimethylamine N-oxide in atherogenesis: impairing endothelial self-repair capacity and enhancing monocyte adhesion. Biosci. Rep. 37, BSR20160244 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Bennion, B. J. & Daggett, V. Counteraction of urea-induced protein denaturation by trimethylamine N-oxide: a chemical chaperone at atomic resolution. Proc. Natl Acad. Sci. USA 101, 6433–6438 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Liberles, S. D. & Buck, L. B. A second class of chemosensory receptors in the olfactory epithelium. Nature 442, 645–650 (2006).

    CAS  PubMed  Google Scholar 

  172. Ufnal, M. et al. Trimethylamine-N-oxide: a carnitine-derived metabolite that prolongs the hypertensive effect of angiotensin II in rats. Can. J. Cardiol. 30, 1700–1705 (2014).

    PubMed  Google Scholar 

  173. Organ, C. L. et al. Removal of dietary trimethylamine N-oxide (TMAO) attenuates cardiac dysfunction in pressure overload induced heart failure [abstract]. Circulation 134 (Suppl. 1), 19293 (2016).

    Google Scholar 

  174. Chen, K., Zheng, X., Feng, M., Li, D. & Zhang, H. Gut microbiota-dependent metabolite trimethylamine N-oxide contributes to cardiac dysfunction in western diet-induced obese mice. Front. Physiol. 8, 139 (2017).

    PubMed  PubMed Central  Google Scholar 

  175. Tang, W. H. 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. 64, 1908–1914 (2014).

    CAS  PubMed  Google Scholar 

  176. Tang, W. H. et al. Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J. Card. Fail. 21, 91–96 (2015).

    CAS  PubMed  Google Scholar 

  177. Troseid, M. et al. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J. Intern. Med. 277, 717–726 (2015).

    CAS  PubMed  Google Scholar 

  178. Schuett, K. et al. Trimethylamine-N-oxide and heart failure with reduced versus preserved ejection fraction. J. Am. Coll. Cardiol. 70, 3202–3204 (2017).

    PubMed  Google Scholar 

  179. Suzuki, T., Heaney, L. M., Bhandari, S. S., Jones, D. J. & Ng, L. L. Trimethylamine N-oxide and prognosis in acute heart failure. Heart 102, 841–848 (2016).

    CAS  PubMed  Google Scholar 

  180. Savi, M. et al. Trimethylamine-N-oxide (TMAO)-induced impairment of cardiomyocyte function and the protective role of urolithin B-glucuronide. Molecules 23, E549 (2018).

    PubMed  Google Scholar 

  181. Oakley, C. et al. The uremic metabolite, trimethylamine-N-oxide (TMAO), directly alters cardiac contractile function [abstract]. FASEB J. 31 (Suppl. 1), 688.3 (2017).

    Google Scholar 

  182. Schefold, J. C., Filippatos, G., Hasenfuss, G., Anker, S. D. & von Haehling, S. Heart failure and kidney dysfunction: epidemiology, mechanisms and management. Nat. Rev. Nephrol. 12, 610–623 (2016).

    CAS  PubMed  Google Scholar 

  183. Hillege, H. L. et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 113, 671–678 (2006).

    PubMed  Google Scholar 

  184. van Deursen, V. M. et al. Co-morbidities in patients with heart failure: an analysis of the European Heart Failure Pilot Survey. Eur. J. Heart Fail. 16, 103–111 (2014).

    PubMed  Google Scholar 

  185. Cho, C. E. et al. Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: a randomized controlled trial. Mol. Nutr. Food Res. 61, 1600324 (2017).

    Google Scholar 

  186. Smith, J. L., Wishnok, J. S. & Deen, W. M. Metabolism and excretion of methylamines in rats. Toxicol. Appl. Pharmacol. 125, 296–308 (1994).

    CAS  PubMed  Google Scholar 

  187. Forster, R. P., Berglund, F. & Rennick, B. R. Tubular secretion of creatine, trimethylamine oxide, and other organic bases by the aglomerular kidney of Lophius americanus. J. Gen. Physiol. 42, 319–327 (1958).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Cohen, J. J., Krupp, M. A., Chidsey, C. A. 3rd & Biltz, C. I. Effect of trimethylamine and its homologues on renal conservation of trimethylamine oxide by the spiny dogfish, Squalus acanthias. Am. J. Physiol. 196, 93–99 (1959).

    CAS  PubMed  Google Scholar 

  189. Acara, M., Camiolo, S. & Rennick, B. Renal N-oxidation of trimethylamine in the chicken during tubular excretion. Drug Metab. Dispos. 5, 82–90 (1977).

    CAS  PubMed  Google Scholar 

  190. Bell, J. D. et al. Nuclear magnetic resonance studies of blood plasma and urine from subjects with chronic renal failure: identification of trimethylamine-N-oxide. Biochim. Biophys. Acta 1096, 101–107 (1991).

    CAS  PubMed  Google Scholar 

  191. Rhee, E. P. et al. A combined epidemiologic and metabolomic approach improves CKD prediction. J. Am. Soc. Nephrol. 24, 1330–1338 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Tang, W. H. 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. 116, 448–455 (2015).

    CAS  PubMed  Google Scholar 

  193. Stubbs, J. R. et al. Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden. J. Am. Soc. Nephrol. 27, 305–313 (2016).

    CAS  PubMed  Google Scholar 

  194. Kim, R. B. et al. Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events. Kidney Int. 89, 1144–1152 (2016).

    CAS  PubMed  Google Scholar 

  195. Shafi, T. et al. Trimethylamine N-oxide and cardiovascular events in hemodialysis patients. J. Am. Soc. Nephrol. 28, 321–331 (2017).

    CAS  PubMed  Google Scholar 

  196. Missailidis, C. et al. Serum trimethylamine-N-oxide is strongly related to renal function and predicts outcome in chronic kidney disease. PLOS ONE 11, e0141738 (2016).

    PubMed  PubMed Central  Google Scholar 

  197. Gruppen, E. G. et al. TMAO is associated with mortality: impact of modestly impaired renal function. Sci. Rep. 7, 13781 (2017).

    PubMed  PubMed Central  Google Scholar 

  198. Hartiala, J. et al. Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine. Arterioscler. Thromb. Vasc. Biol. 34, 1307–1313 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Robinson-Cohen, C. et al. Association of FMO3 variants and trimethylamine N-oxide concentration, disease progression, and mortality in CKD patients. PLOS ONE 11, e0161074 (2016).

    PubMed  PubMed Central  Google Scholar 

  200. Johnson, C., Prokopienko, A. J., West, R. E. 3rd, Nolin, T. D. & Stubbs, J. R. Decreased kidney function is associated with enhanced hepatic flavin monooxygenase activity and increased circulating trimethylamine N-oxide concentrations in mice. Drug Metab. Dispos. 46, 1304–1309 (2018).

    CAS  PubMed  Google Scholar 

  201. Heianza, Y., Ma, W., Manson, J. E., Rexrode, K. M. & Qi, L. Gut microbiota metabolites and risk of major adverse cardiovascular disease events and death: a systematic review and meta-analysis of prospective studies. J. Am. Heart Assoc. 6, e004947 (2017).

    PubMed  PubMed Central  Google Scholar 

  202. Qi, J. et al. Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. J. Cell. Mol. Med. 22, 185–194 (2017).

    PubMed  PubMed Central  Google Scholar 

  203. Schiattarella, G. G. et al. Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis. Eur. Heart J. 38, 2948–2956 (2017).

    CAS  PubMed  Google Scholar 

  204. Gan, X. T. et al. Probiotic administration attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat. Circ. Heart Fail. 7, 491–499 (2014).

    PubMed  Google Scholar 

  205. Costanza, A. C., Moscavitch, S. D., Faria Neto, H. C. & Mesquita, E. T. Probiotic therapy with Saccharomyces boulardii for heart failure patients: a randomized, double-blind, placebo-controlled pilot trial. Int. J. Cardiol. 179, 348–350 (2015).

    PubMed  Google Scholar 

  206. Kochan, P. et al. Lactobacillus rhamnosus administration causes sepsis in a cardiosurgical patient—is the time right to revise probiotic safety guidelines? Clin. Microbiol. Infect. 17, 1589–1592 (2011).

    CAS  PubMed  Google Scholar 

  207. Liong, M. T. Safety of probiotics: translocation and infection. Nutr. Rev. 66, 192–202 (2008).

    PubMed  Google Scholar 

  208. Salehi-Abargouei, A., Maghsoudi, Z., Shirani, F. & Azadbakht, L. Effects of dietary approaches to stop hypertension (DASH)-style diet on fatal or nonfatal cardiovascular diseases—incidence: a systematic review and meta-analysis on observational prospective studies. Nutrition 29, 611–618 (2013).

    PubMed  Google Scholar 

  209. Levitan, E. B., Wolk, A. & Mittleman, M. A. Consistency with the DASH diet and incidence of heart failure. Arch. Intern. Med. 169, 851–857 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Levitan, E. B., Wolk, A. & Mittleman, M. A. Relation of consistency with the dietary approaches to stop hypertension diet and incidence of heart failure in men aged 45 to 79 years. Am. J. Cardiol. 104, 1416–1420 (2009).

    PubMed  PubMed Central  Google Scholar 

  211. Nguyen, H. T. et al. DASH eating pattern is associated with favorable left ventricular function in the multi-ethnic study of atherosclerosis. J. Am. Coll. Nutr. 31, 401–407 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Rifai, L., Pisano, C., Hayden, J., Sulo, S. & Silver, M. A. Impact of the DASH diet on endothelial function, exercise capacity, and quality of life in patients with heart failure. Proc. (Bayl Univ. Med. Cent.) 28, 151–156 (2015).

    Google Scholar 

  213. Mathew, A. V., Seymour, E. M., Byun, J., Pennathur, S. & Hummel, S. L. Altered metabolic profile with sodium-restricted dietary approaches to stop hypertension diet in hypertensive heart failure with preserved ejection fraction. J. Card. Fail. 21, 963–967 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Hummel, S. L. et al. Low-sodium DASH diet improves diastolic function and ventricular-arterial coupling in hypertensive heart failure with preserved ejection fraction. Circ. Heart Fail. 6, 1165–1171 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Hummel, S. L. et al. Low-sodium dietary approaches to stop hypertension diet reduces blood pressure, arterial stiffness, and oxidative stress in hypertensive heart failure with preserved ejection fraction. Hypertension 60, 1200–1206 (2012).

    CAS  PubMed  Google Scholar 

  216. Estruch, R. et al. Primary prevention of cardiovascular disease with a mediterranean diet supplemented with extra-virgin olive oil or nuts. N. Engl. J. Med. 378, e34 (2018).

    CAS  PubMed  Google Scholar 

  217. Papadaki, A. et al. Mediterranean diet and risk of heart failure: results from the PREDIMED randomized controlled trial. Eur. J. Heart Fail. 19, 1179–1185 (2017).

    CAS  PubMed  Google Scholar 

  218. Miro, O. et al. Adherence to mediterranean diet and all-cause mortality after an episode of acute heart failure: results of the MEDIT-AHF study. JACC Heart Fail. 6, 52–62 (2018).

    PubMed  Google Scholar 

  219. Falony, G., Vieira-Silva, S. & Raes, J. Microbiology meets big data: the case of gut microbiota-derived trimethylamine. Annu. Rev. Microbiol. 69, 305–321 (2015).

    CAS  PubMed  Google Scholar 

  220. Craciun, S. & Balskus, E. P. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc. Natl Acad. Sci. USA 109, 21307–21312 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Koeth, R. A. et al. γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab. 20, 799–812 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Meyer, M., Granderath, K. & Andreesen, J. R. Purification and characterization of protein PB of betaine reductase and its relationship to the corresponding proteins glycine reductase and sarcosine reductase from Eubacterium acidaminophilum. Eur. J. Biochem. 234, 184–191 (1995).

    CAS  PubMed  Google Scholar 

  223. Wagner, M. et al. Substrate-specific selenoprotein B of glycine reductase from Eubacterium acidaminophilum. Biochemical and molecular analysis. Eur. J. Biochem. 260, 38–49 (1999).

    CAS  PubMed  Google Scholar 

  224. Zhu, Y. et al. Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota. Proc. Natl Acad. Sci. USA 111, 4268–4273 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Kuka, J. et al. Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation. Life Sci. 117, 84–92 (2014).

    CAS  PubMed  Google Scholar 

  226. Chen, M. L. et al. Resveratrol attenuates trimethylamine-N-oxide (TMAO)-induced atherosclerosis by regulating TMAO synthesis and bile acid metabolism via remodeling of the gut microbiota. MBio 7, e02210 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Johnson, E. L., Heaver, S. L., Walters, W. A. & Ley, R. E. Microbiome and metabolic disease: revisiting the bacterial phylum Bacteroidetes. J. Mol. Med. 95, 1–8 (2017).

    CAS  Google Scholar 

  228. Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Jeffery, I. B., Claesson, M. J., O’Toole, P. W. & Shanahan, F. Categorization of the gut microbiota: enterotypes or gradients? Nat. Rev. Microbiol. 10, 591–592 (2012).

    CAS  PubMed  Google Scholar 

  230. Knights, D. et al. Rethinking “enterotypes”. Cell Host Microbe 16, 433–437 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Li, J. et al. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 32, 834–841 (2014).

    CAS  PubMed  Google Scholar 

  232. Martinez-del Campo, A. et al. Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria. MBio 6, e00042 (2015).

    PubMed  PubMed Central  Google Scholar 

  233. Hur, K. Y. & Lee, M. S. Gut microbiota and metabolic disorders. Diabetes Metab. J. 39, 198–203 (2015).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors’ research work is supported by grants from the National Institutes of Health (NIH) and the Office of Dietary Supplements, including R01HL103866 (S.L.H.), and P20HL113452, R01DK106000, and R01HL126827 (W.H.W.T. and S.L.H.).

Author information

Authors and Affiliations

  1. Center for Microbiome & Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    W. H. Wilson Tang & Stanley L. Hazen

  2. Department for Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    W. H. Wilson Tang & Stanley L. Hazen

  3. Center for Clinical Genomics, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA

    W. H. Wilson Tang

  4. Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA

    W. H. Wilson Tang & Stanley L. Hazen

  5. Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA

    W. H. Wilson Tang, Daniel Y. Li & Stanley L. Hazen

Authors
  1. W. H. Wilson Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Y. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stanley L. Hazen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.H.W.T. and D.Y.L. researched data for the article, and all authors discussed its content. W.H.W.T. and D.Y.L. wrote the manuscript, and W.H.W.T. and S.L.H. reviewed and edited it before submission.

Corresponding author

Correspondence to W. H. Wilson Tang.

Ethics declarations

Competing interests

S.L.H. is named as a co-inventor on pending and issued patents held by the Cleveland Clinic, USA, relating to cardiovascular diagnostics and therapeutics; he is a paid consultant for Proctor & Gamble and has received research funds from Proctor & Gamble and Roche Diagnostics; and he is eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab/Quest Diagnostics or Proctor & Gamble. The other 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.

Related links

NIH Human Microbiome Project: https://hmpdacc.org/

Metagenomics of the Human Intestinal Tract (MetaHIT): http://www.metahit.eu/

Glossary

Meta-organismal

Relating to a polygenomic organism consisting of a community of living beings of different species (such as microbiota and host) associated by interspecies symbiosis.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tang, W.H.W., Li, D.Y. & Hazen, S.L. Dietary metabolism, the gut microbiome, and heart failure. Nat Rev Cardiol 16, 137–154 (2019). https://doi.org/10.1038/s41569-018-0108-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-018-0108-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing