Skip to main content

Advertisement

SpringerLink
Log in

Microbial modulation of cardiovascular disease

  • Review Article
  • Published:

From Nature Reviews Microbiology

View current issue Sign up to alerts

Key Points

  • Microbial communities are associated with the human host, primarily in the intestinal tract, where they affect host metabolism and contribute to the pathogenesis of cardiovascular disease.

  • The susceptibility to atherosclerosis and thrombosis can be transmitted via gut microbial transplantation in mouse models.

  • Microbial-associated molecular patterns are sensed by host pattern recognition receptors and affect cardiovascular disease pathogenesis.

  • Microbial metabolism of common dietary nutrients produces both anti-atherogenic and pro-atherogenic metabolites that engage distinct host receptor systems and affect cardiovascular disease pathogenesis.

  • Plasma levels of the gut microbial metabolite trimethylamine-N-oxide are associated with incident development of cardiovascular disease and its adverse outcomes in humans.

  • Bacterially derived short-chain fatty acids (acetate, propionate and butyrate) can engage host receptor systems and potentially affect cardiovascular pathogenesis.

  • Bacterially derived secondary bile acids can modulate dietary fat absorption and signal through cell-surface and nuclear hormone receptors, potentially affecting cardiovascular disease pathogenesis.

  • Gut microorganism-targeted therapeutic strategies hold promise for the prevention and/or treatment of cardiovascular disease.

Abstract

Although diet has long been known to contribute to the pathogenesis of cardiovascular disease (CVD), research over the past decade has revealed an unexpected interplay between nutrient intake, gut microbial metabolism and the host to modify the risk of developing CVD. Microbial-associated molecular patterns are sensed by host pattern recognition receptors and have been suggested to drive CVD pathogenesis. In addition, the host microbiota produces various metabolites, such as trimethylamine-N-oxide, short-chain fatty acids and secondary bile acids, that affect CVD pathogenesis. These recent advances support the notion that targeting the interactions between the host and microorganisms may hold promise for the prevention or treatment of CVD. In this Review, we summarize our current knowledge of the gut microbial mechanisms that drive CVD, with special emphasis on therapeutic interventions, and we highlight the need to establish causal links between microbial pathways and CVD pathogenesis.

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

Figure 1: Direct engagement of pattern recognition receptors by microorganism-associated molecular patterns driving cardiovascular disease.
Figure 2: The metaorganismal trimethylamine-N-oxide pathway as a driver of cardiovascular disease.
Figure 3: Microbial production of secondary bile acids in cardiovascular disease.

Similar content being viewed by others

References

  1. Mozaffarian, D. et al. Executive summary: heart disease and stroke statistics — 2016 update: a report from the American Heart Assocation. Circulation 133, 447–454 (2016).

    Article  PubMed  Google Scholar 

  2. Ardissino, D. et al. Influence of 9p21.3 genetic variants on clinical and angiographic outcomes in early-onset myocardial infarction. J. Am. Coll. Cardiol. 58, 426–434 (2011).

    Article  PubMed  Google Scholar 

  3. Ripatti, S. et al. A multilocus genetic risk score for coronary heart diease: case-control and prospective cohort analyses. Lancet 376, 1393–1400 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yu, E. et al. Diet, lifestyle, biomarkers, genetic factors, and risk of cardiovascular disease in the Nurses' Health Study. Am. J. Publ. Health 106, 1616–1623 (2016).

    Article  Google Scholar 

  5. Brown, J. M. & Hazen, S. L. The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu. Rev. Med. 66, 343–359 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tang, W. H. & Hazen, S. L. The contributory role of gut microbiota in cardiovascular disease. J. Clin. Invest. 124, 4204–4211 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gregory, J. C. et al. Transmission of atherosclerosis susceptibility with gut microbial transplantation. J. Biol. Chem. 290, 5647–5660 (2015). This study demonstrates for the first time that atherosclerosis susceptibility can be transmitted by gut microbial transplantation, fulfilling a key Koch postulate for microbial contribution to disease causation.

    Article  CAS  PubMed  Google Scholar 

  8. Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016). This study shows the first cell autonomous effects of the gut microorganism-derived metabolite TMAO on platelet activation and thrombosis potential in vivo , that microbial transplantation transmits TMAO levels and thrombosis potential in vivo and that thrombotic event risk in subjects tracks with TMAO levels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kholy, K. E., Genco, R. J. & Van Dyke, T. E. Oral infections and cardiovascular disease. Trends Endocrinol. Metab. 26, 315–321 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Filardo, S. et al. Chlamydia pneumoniae-mediated inflammation in atherosclerosis: A meta-analysis. Mediators Inflamm. 2015, 378658 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Koren, O. et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4592–4598 (2011). This study provides evidence that human atherosclerotic plaques contain bacteria.

    Article  PubMed  Google Scholar 

  12. Mitra, S. et al. In silico analyses of metagenomes from human atherosclerotic plaque samples. Microbiome 3, 38 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Caladrini, C. A. et al. Microbial composition of atherosclerotic plaques. Oral Dis. 20, e128–e134 (2014).

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Saikku, P. et al. Chronic chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study. Ann. Intern. Med. 15, 273–278 (1992).

    Article  Google Scholar 

  16. Kol, A. et al. Chlamydia and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. J. Clin. Invest. 103, 571–577 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen, S. et al. Chlamydia pneumoniae-induced foam cell formation requires MyD88-dependent and -independent signaling and is reciprocally modulated by liver X receptor activation. J. Immunol. 181, 7186–7193 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Grayston, J. T. et al. Azithromycin for the secondary prevention of coronary events. N. Engl. J. Med. 352, 1637–1645 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Cannon, C. P. et al. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N. Engl. J. Med. 352, 1646–1654 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. O'Connor, C. M. et al. Azithromycin for the secondary prevention of coronary heart disease events — The WIZARD Study: a randomized controlled trial. JAMA 290, 1459–1466 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Leung, C., Rivera, L., Furness, J. B. & Angus, P. W. The role of gut microbiota in NAFLD. Nat. Rev. Gastroenterol. Hepatol. 13, 412–425 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Munford, R. S. Endotoxemia — menace, marker, or mistake? J. Leukoc. Biol. 100, 687–698 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Caligiuri, G. et al. Chlamydia pneumoniae infection does not induce or modify atherosclerosis in mice. Circulation 103, 2834–2838 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Hussain, M., Stover, C. M. & Dupont, A. P. gingivalis in periodontal disease and atherosclerosis — scenes of action for antimicrobial peptides and complement. Front. Immunol. 6, 45 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Giacona, M. B. et al. Porphyromonas gingivalis induces its uptake by human macrophages and promotes foam cell formation in vitro. FEMS Microbiol. Lett. 241, 95–101 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Naito, M. et al. Porphyromonas gingivalis-induced platelet aggregation in plasma depends on Hgp44 adhesion but not Rgp proteinase. Mol. Microbiol. 59, 152–167 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Li, L. et al. Porphyromonas gingivalis infection accelerates the progression of atherosclerosis in a heterozygous apolipoprotein E-deficient murine model. Circulation 105, 861–867 (2002).

    Article  PubMed  Google Scholar 

  28. Brodala, N. et al. Porphyromonas gingivalis bacteremia induces coronary and aortic atherosclerosis in normocholesterolemic and hypercholesterolemic pigs. Arterioscler. Thromb. Vasc. Biol. 25, 1446–1451 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Lalla, E. et al. Oral infection with a periodontal pathogen accelerates early atherosclerosis in apolipoprotein E-null mice. Arterioscler. Thromb. Vasc. Biol. 23, 1405–1411 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Mach, F. et al. Influence of Helicobacter pylori infection during atherogenesis in vivo in mice. Circ. Res. 90, E1–E4 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Chen, X. H. et al. Helicobacter pylori infection enhances atherosclerosis in high-cholesterol diet fed C57BL/6 mice [Chinese]. Zhonghua Xin Xue Guan Bing Za Zhi 38, 259–263 (2010).

    CAS  PubMed  Google Scholar 

  32. Liuba, P. et al. Co-infection with Clamydia pneumoniae and Helicobacter pylori results in vascular endothelial dysfunction and enhanced VCAM-1 expression in apoE-knockout mice. J. Vasc. Res. 40, 115–122 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. El Moktari, N. E., Ott, S. J., Nebel, A., Simon, R. & Schreiber, S. A. functional variant in the CARD4 gene and risk of premature coronary heart disease. Int. J. Immunogenet. 33, 307–311 (2006).

    Article  CAS  Google Scholar 

  34. Kanno, S. et al. Activation of an innate immune receptor, Nod1, accelerates atherogenesis in Apoe-/- mice. J. Immunol. 194, 773–780 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Schenk, M., Belisle, J. T. & Modlin, R. L. TLR2 looks at lipoproteins. Immunity 31, 847–849 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Mullick, A. E., Tobias, P. S. & Curtiss, L. K. Modulation of atherosclerosis in mice by Toll-like receptor 2. J. Clin. Invest. 115, 3149–3156 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sale, M. L. et al. Toll-like receptor 6 Ser249Pro polymorphism is associated with lower left ventricular wall thickness and inflammatory response in hypertensive women. Am. J. Hypertens. 23, 649–654 (2010).

    Article  CAS  Google Scholar 

  38. Hamann, L. et al. Association of a common TLR-6 polymorphism with coronary artery disease — implications for healthy ageing? Immun. Ageing 10, 43 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lundberg, A. M. et al. Toll-like receptor 3 and 4 signaling through TRIF and TRAM adaptors in haematopoetic cells promotes atherosclerosis. Cardiovasc. Res. 99, 364–373 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Ballistreri, C. R. et al. TLR4 polymorphisms and ageing: implications for the pathophysiology of age-related diseases. J. Clin. Immunol. 29, 406–415 (2009).

    Article  CAS  Google Scholar 

  41. Michelsen, K. S. et al. Lack of toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc. Natl Acad. Sci. USA 101, 10679–10684 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Stewart, C. R. et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat. Immunol. 11, 155–161 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Ding, Y. et al. Toll-like receptor 4 deficiency decreases atherosclerosis but does not protect against inflammation in obese low-density lipoprotein receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 32, 1596–1604 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kanellakis, P. et al. High-mobility group box protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein e-deficient mice. Arterioscler. Thromb. Vasc. Biol. 31, 313–319 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Salagianni, M. et al. Toll-like receptor 7 protects from atherosclerosis by constraining “inflammatory” macrophage activation. Circulation 126, 952–962 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Tang, W. H. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1578 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Koulis, C. et al. Protective role for Toll-like receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 34, 516–525 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Lee, W. J. & Hase, K. Gut microbiota-generated metabolites in animal health and disease. Nat. Chem. Biol. 10, 416–424 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Rooks, M. G. & Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341–352 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Spanogiannopoulos, P. et al. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat. Rev. Microbiol. 14, 273–287 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011). This paper is the first to directly demonstrate a pathogenic role for a gut microorganism-dependent metabolite, TMAO, in CVD pathogenesis with the use of both mouse models of disease and large-scale clinical studies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013). This study demonstrates a nutrient (carnitine)–gut microbial host metaorganismal pathway (the TMAO pathway), providing a mechanistic link between red meat consumption and CVD pathogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang, Z. et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur. Heart J. 35, 904–910 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Senthong, V. et al. Plasma trimethylamine N-oxide, a gut microbe-generated phosphatidylcholine metabolite, is associated with atherosclerotic burden. J. Am. Coll. Cardiol. 67, 2620–2628 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Senthong, V. et al. Intestinal microbiota-generated metabolite trimethylamine N-oxide and 5-year mortality risk in stable coronary artery disease: the contributory role of intestinal microbiota in a COURAGE-like patient cohort. J. Am. Heart Assoc. 5, e002816 (2016).

    PubMed  PubMed Central  Google Scholar 

  58. Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015). This paper is the first to show that a nonlethal small-molecule inhibitor of a gut microbial enzyme (TMA lyase) can protect mice against diet-enhanced atherosclerosis development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zheng, Y. et al. Dietary phosphatidylcholine and risk of all-cause and cardiovascular-specific mortality among US women and men. Am. J. Clin. Nutr. 104, 173–180 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Randrianarisoa, E. et al. Relationship of serum trimethylamine N-oxide (TMAO) levels with early atherosclerosis in humans. Sci. Rep. 6, 26745 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    Article  CAS  PubMed  Google Scholar 

  62. Skagen, K. et al. The carnitine-butyrobetaine-trimethylamine-oxide pathway and its association with cardiovascular mortality in patients with carotid atherosclerosis. Atherosclerosis 247, 64–69 (2016).

    Article  CAS  PubMed  Google Scholar 

  63. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mafune, A. et al. Associations among serum trimethylamine-N-oxide (TMAO) levels, kidney function and infarcted coronary artery number in patients undergoing cardiovascular surgery: a cross-sectional study. Clin. Exp. Nephrol. 20, 731–739 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  66. 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).

    Article  CAS  PubMed  Google Scholar 

  67. Organ, C. L. et al. Choline diet and its gut microbe-derive metabolite, Trimethylamine N-oxide, exacerbate pressure overload-induced heart failure. Circ. Heart Fail. 9, e002314 (2016). This paper demonstrates a role for the gut microbial metabolite TMAO in pressure-overload-induced heart failure.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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).

    Article  CAS  PubMed  Google Scholar 

  70. 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). This paper demonstrates that the gut microbial metabolite TMAO can induce renal fibrosis and functional impairment and contribute to adverse CVD outcomes in subjects with chronic kidney disease.

    Article  CAS  PubMed  Google Scholar 

  71. Dambrova, M. et al. Diabetes is associated with higher trimethylamine N-oxide plasma levels. Exp. Clin. Endocrinol. Diabetes 124, 251–256 (2016).

    Article  CAS  PubMed  Google Scholar 

  72. Lever, M. et al. Betaine and trimethylamine-N-oxide as predictors of cardiovascular outcomes show different patterns in diabetes mellitus: an observational study. PLOS One 9, e114969 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tang, W. H. et al. Increased trimethylamine N-oxide portends high mortality risk independent of glycemic control in patients with type 2 diabetes mellitus. Clin. Chem. 63, 297–306 (2017).

    Article  CAS  PubMed  Google Scholar 

  74. Miao, J. et al. Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis. Nat. Commun. 6, 6498 (2015). Through unbiased metabolomics screening, this paper demonstrates for the first time a role for the TMAO-producing enzyme flavin-containing monooxygenase 3 in insulin action.

    Article  CAS  PubMed  Google Scholar 

  75. Schugar, R. C. et al. The TMAO-producing enzyme flavin-containing monooxygenase 3 regulates obesity and the beiging of white adipose tissue. Cell Rep. 19, 2451–2461 (2017). This paper is the first to show that pharmacologic inhibition or genetic deletion of FMO3 protects mice from high-fat-diet-induced obesity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yancey, P. H. et al. Living with water stress: evolution of osmolyte systems. Science 217, 1214–1222 (1982).

    Article  CAS  PubMed  Google Scholar 

  79. Lin, T. Y. & Timasheff, S. N. Why do some organisms use a urea-methylamine mixture as osmolyte? Thermodynamic compensation of urea and trimethylamine-N-oxide interactions with protein. Biochemistry 33, 12695–12701 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  81. Li, Q. et al. Synchronous evolution of an odor biosynthesis pathway and behavioral response. Curr. Biol. 23, 11–20 (2013). This paper demonstrates that the gut microbial metabolite TMA can activate a G-protein-coupled receptor to regulate behavioural responses.

    Article  CAS  PubMed  Google Scholar 

  82. Wallrabenstein, I. et al. Human trace amine-associated receptor TAAR5 can be activated by trimethylamine. PLOS One 8, e54950 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Falony, G., Vleira-Silva, S. & Raes, J. Microbiology meets big data: The case of gut microbe-derived trimethylamine. Annu. Rev. Microbiol. 69, 305–321 (2015). This innovative paper describes the power of mining reference genomes for prediction of bacterial enzymatic activity.

    Article  CAS  PubMed  Google Scholar 

  84. Romano, K. A., Vivas, E. I., Amador-Noguez, D. & Rey, F. E. Instestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. mBio 6, e02481 (2015). This paper identifies human commensal bacteria that possess TMA lyase activity and demonstrates that transplantation of these strains can alter host choline homeostasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 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–e00015 (2015).

    Google Scholar 

  86. Levin, B. J. et al. A prominent glycyl radical enzyme in human gut microbiomes metabolizes trans-4-hydroxy-l-proline. Science 355, eaai8386 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Rath, S. et al. Uncovering the trimethylamine-producing bacteria of the human gut microbiota. Microbiome 5, 54 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Mejean, V. et al. TMAO anaerobic respiration in Escherichia coli: involvement of the tor operon. Mol. Microbiol. 11, 1169–1179 (1994).

    Article  CAS  PubMed  Google Scholar 

  89. Lidbury, I., Murrell, J. C. & Chen, Y. Trimethylamine N-oxide metabolism by abundant marine heterotrophic bacteria. Proc. Natl Acad. Sci. USA 111, 2710–2715 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lidbury, I. D., Murrell, J. C. & Chen, Y. Trimethylamine and trimethylamine N-oxide are supplementary energy sources for marine carbon and nitrogen cycling. ISME J. 9, 760–769 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Li, C. Y. et al. Mechanistic insight into trimethylamine N-oxide recognition by the marine bacterium Ruegeria pomeroyi DSS-3. J. Bacteriol. 197, 3378–3387 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Brugere, J. F. et al. Archaebiotics: proposed therapeutic use of archaea to prevent trimethylaminuria and cardiovascular disease. Gut Microbes 5, 5–10 (2014).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  94. Nagata, C. et al. Choline and betaine intakes are not associated with cardiovascular disease mortality risk in Japanese men and women. J. Nutr. 145, 1787–1792 (2015).

    Article  CAS  PubMed  Google Scholar 

  95. Bidulescu, A. et al. Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. BMC Cardiovasc. Disord. 7, 20 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Dalmeijer, G. W. et al. Prospective study on dietary intakes of folate, betaine, and choline and cardiovascular disease risk in women. Eur. J. Clin. Nutr. 62, 386–394 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Heianza, Y. et al. Gut microbiota metabolites and risk of major adverse cardiovascular events and death: a systematic review and meta-analysis of prospective studies. J. Am. Heart Assoc. 6, e004947.

  98. Mueller, D. M. et al. Plasma levels of trimethylamine-N-oxide are confounded by impaired kidney function and poor metabolic control. Atherosclerosis 243, 638–644 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Yin, J. et al. Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J. Am. Heart Assoc. 4, e002699.

  100. Koh, A., De Vadder, F., Kovatcheva-Datchary, P. & Backhed, F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165, 1332–1345 (2016).

    Article  CAS  PubMed  Google Scholar 

  101. Canfora, E. E., Jocken, J. W. & Blaak, E. E. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat. Rev. Endocrinol. 11, 577–591 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Ramezani, A. et al. Role of the gut microbiome in uremia: a potential therapeutic target. Am. J. Kidney Dis. 67, 483–498 (2016).

    Article  CAS  PubMed  Google Scholar 

  103. Miyamoto, J. et al. The role of short-chain fatty acid on blood pressure regulation. Curr. Opin. Nephrol. Hypertens. 25, 379–383 (2016).

    Article  CAS  PubMed  Google Scholar 

  104. Rey, F. E. et al. Dissecting the in vivo metabolic potential of two human gut acetogens. J. Biol. Chem. 285, 22082–22090 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Scott, K. P., Martin, J. C., Campbell, G., Mayer, C.-D. & Flint, H. J. Whole-genome transcription profiling reveals genes up-regulated by growth on fucose in the human gut bacterium “Roseburia inulinivorans”. J. Bacteriol. 188, 4340–4349 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Duncan, S. H., Barcenilla, A., Stewart, C. S., Pryde, S. E. & Flint, H. J. Acetate utilization and butyryl coenzyme A (CoA):acetate-CoA transferase in butyrate-producing bacteria from the human large intestine. Appl. Environ. Microbiol. 68, 5186–5190 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Louis, P. & Flint, H. J. Formation of propionate and butyrate by the human colonic microbiota. Environ. Microbiol. 19, 29–41 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. Brown, A. J. et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278, 11312–11319 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Thangaraju, M. et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 69, 2826–2832 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Wolever, T., Spadafora, P. & Eshuis, H. Interaction between colonic acetate and propionate in humans. Am. J. Clin. Nutr. 53, 681–687 (1991).

    Article  CAS  PubMed  Google Scholar 

  112. Laurent, C. et al. Effect of acetate and propionate on fasting hepatic glucose production in humans. Eur. J. Clin. Nutr. 49, 484–491 (1995).

    CAS  PubMed  Google Scholar 

  113. Fernandes, J., Vogt, J. & Wolever, T. M. Intravenous acetate elicits a greater free fatty acid rebound in normal than hyperinsulinemic humans. Eur. J. Clin. Nutr. 66, 1029–1034 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Venter, C. S., Vorster, H. H. & Cummings, J. H. Effects of dietary propionate on carbohydrate and lipid metabolism in healthy volunteers. Am. J. Gastroenterol. 85, 549–553 (1990).

    CAS  PubMed  Google Scholar 

  115. Robertson, M. D., Bickerton, A. S., Dennis, A. L., Vidal, H. & Frayn, K. N. Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism. Am. J. Clin. Nutr. 82, 559–567 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Cani, P. D. et al. Gut microbiota fermentation of prebiotics increases satieogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am. J. Clin. Nutr. 90, 1236–1243 (2009).

    Article  CAS  PubMed  Google Scholar 

  117. Parnell, J. A. & Reimer, R. A. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am. J. Clin. Nutr. 89, 1751–1759 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Dewulf, E. et al. Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut 62, 1112–1121 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Daud, N. M. et al. The impact of oligofructose on stimulation of gut hormones, appetite regulation and adiposity. Obesity 22, 1430–1438 (2014).

    Article  CAS  PubMed  Google Scholar 

  120. Vulvic, J., Juric, A., Tzortzis, G. & Gibson, G. R. A mixture of trans-galactooligosaccharides reduces markers of metabolic syndrome and modulates the fecal microbiota and immune function of overweight adults. J. Nutr. 143, 324–331 (2013).

    Article  CAS  Google Scholar 

  121. Pedersen, C. et al. Gut hormone release and appetite regulation in healthy non-obese participants following oligofructose intake. A dose escalation study. Appetite 66, 44–53 (2013).

    Article  PubMed  Google Scholar 

  122. Rejinders, D. et al. Effects of gut microbiota manipulation by antibiotics on host metabolism in obese humans: a randomized double-blind placebo-controlled trial. Cell Metab. 24, 341 (2016). This study associates large alterations in short-chain fatty acid levels with insulin sensitivity and energy metabolism in humans.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  124. Cai, T. Q. et al. Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biophys. Res. Commun. 377, 987–991 (2008).

    Article  CAS  Google Scholar 

  125. Shen, Z. et al. Inhibition of G protein-coupled receptor 81 (GPR81) protects against ischemic brain injury. CNS Neurosci. Ther. 21, 271–279 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. He, W. et al. Citric acid cycle intermediates as ligands for ophan G-protein-coupled receptors. Nature 429, 188–193 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Rubic, T. et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat. Immunol. 9, 1261–1269 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. De Vadder, F. et al. Microbiota-produced succinate improves glucose homeostasis via intestinal gluconeogenesis. Cell Metab. 24, 151–157 (2016).

    Article  CAS  PubMed  Google Scholar 

  129. Lukasova, M. et al. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed in immune cells. J. Clin. Invest. 121, 1163–1173 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Russell, D. W. Fifty years of advances in bile acid synthesis and metabolism. J. Lipid Res. 50, S120–S125 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hylemon, P. B. et al. Bile acids as regulatory molecules. J. Lipid Res. 50, 1509–1520 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kuipers, F., Bloks, V. W. & Groen, A. K. Beyond intestinal soap-bile acids in metabolic control. Nat. Rev. Endocrinol. 10, 488–498 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. Dawson, P. A. & Karpen, S. J. Intestinal transport & metabolism of bile acids. J. Lipid Res. 56, 1085–1099 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ridlon, J. M., Kang, D. J., Hylemon, P. B. & Bajaj, J. S. Bile acids and the gut microbiome. Curr. Opin. Gastroenterol. 30, 332–338 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Wahlstrom, A., Sayin, S. I., Marschall, H. U. & Backhed, F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24, 41–50 (2016).

    Article  CAS  PubMed  Google Scholar 

  136. Klaassen, C. D. & Cui, J. Y. Review: mechanisms of how the intestinal microbiota alters the effects of drugs and bile acids. Drug Metab. Dispos. 43, 1505–1521 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ridlon, J. M., Harris, S. C., Bhowmik, S., Kang, D. J. & Hylemon, P. E. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes 7, 22–39 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Hofmann, A. F., Hagey, L. R. & Krasowski, M. D. Bile salts of vertebrates: structural variation and possible evolutionary significance. J. Lipid Res. 51, 226–246 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Joyce, S. A. & Gahan, C. G. Disease-associated changes in bile acid profiles and links to altered gut microbiota. Dig. Dis. 35, 169–177 (2017).

    Article  PubMed  Google Scholar 

  140. Lin, J., Sahin, O., Michael, L. O. & Zhang, Q. Critical role of multidrug efflux pump CmeABC in bile resistance and in vivo colonization of Camphylobacter jejuni. Infect. Immunol. 71, 4250–4259 (2003).

    Article  CAS  Google Scholar 

  141. Yokota, A., Veenstra, M., Kurdi, P., van Veen, H. W. & Konings, W. N. Cholate resistance in Lactococcus lactis is mediated by an ATP-dependent multispecific organic anion transporter. J. Bacteriol. 182, 5196–5201 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Fernandez Murga, M. L., Bernick, D., de Valdez, G. F. & Disalvo, A. E. Permeability and stability properties of membranes formed by lipids extracted from Lactobacillus acidophilus grown at different temperatures. Arch. Biochem. Biophys. 364, 115–121 (1999).

    Article  CAS  PubMed  Google Scholar 

  143. Kimoto, H. Ohmono, S. & Okamoto, T. Enhancement of bile tolerance in Lactococci by Tween 80. J. Appl. Micro. 92, 41–46 (2002).

    Article  CAS  Google Scholar 

  144. Liu, Y. et al. Functional role of tlyC1 encoding a hemolysin-like protein from Bifidobacterium longum BBMN68 in bile tolerance. FEMS Microbiol. Lett 360, 167–173 (2014).

    Article  CAS  PubMed  Google Scholar 

  145. Ruiz, L. et al. The cell-envelope proteome of Bifidobacterium longum in an in vivo bile environment. Microbiology 155, 957–967 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Schubert, R., Jaroni, H., Schoelmerich, J. & Schmidt, K. H. Studies on the mechanism of bile salt-induced liposomal membrane damage. Digestion 28, 181–190 (1983).

    Article  CAS  PubMed  Google Scholar 

  147. Prouty, A. M., Schwesinger, W. H. & Gunn, J. S. Biofilm formation and interaction with surfaces of gallstones by Salmonella spp. Infect. Immunol. 70, 2640–2649 (2002).

    Article  CAS  Google Scholar 

  148. Lepercq, P. et al. Epimerization of chenodeoxycholic acid to ursodeoxycholic acid by Clostridium baratii isolated from human feces. FEMS Microbiol. Lett 235, 65–72 (2004).

    Article  CAS  PubMed  Google Scholar 

  149. Lepercq, P. et al. Isolates from normal human intestinal flora but not lactic acid bacteria exhibit 7α- and 7β-hydroxysteroid dehydrogenase activities. Microb. Ecol. Health Dis. 16, 195–201 (2004).

    Article  CAS  Google Scholar 

  150. Kelsey, M. I., Molina, J. E., Huang, S. K., Hwang, K. K. The identification of microbial metabolites of sulfolithocholic acid. J. Lipid Res 21, 751–756 (1980).

    CAS  PubMed  Google Scholar 

  151. Benson, G. M. et al. Polydeoxycholate in human and hamster feces: a major product of cholate metabolism. J. Lipid Res. 34, 2121–2134 (1993).

    CAS  PubMed  Google Scholar 

  152. Tazuke, Y., Matsuda, K., Adachi, K. & Tsukada, Y. Purification and properties of a novel sulfatase from Pseudomonas testosteroni that hydrolyzed 3 β-hydroxy-5-cholenoic acid 3-sulfate. Biosci. Biotechnol. Biochem. 62, 1739–1744 (1998).

    Article  CAS  PubMed  Google Scholar 

  153. Makishima, M. et al. Identification of a nuclear receptor for bile acids. Science 284, 1362–1365 (1999). This is a landmark paper identifying the first-ever nuclear receptor for bile acids.

    Article  CAS  PubMed  Google Scholar 

  154. Heni, M. et al. Genetic variation in NR1H4 encoding the bile acid receptor FXR determines fasting glucose and free fatty acid levels in humans. J. Clin. Endocrinol. Metab. 98, E1224–E1229 (2013).

    Article  CAS  PubMed  Google Scholar 

  155. Zhang, Y. et al. FXR deficiency causes reduced atherosclerosis in Ldlr-/- mice. Arterioscler. Thromb. Vasc. Biol. 26, 2316–2321 (2006).

    Article  CAS  PubMed  Google Scholar 

  156. Wahlström, A., Kovatcheva-Datchary, P., Stahlman, M., Bäckhed, F. & Marschall, H. U. Crosstalk between bile acids and gut microbiota and its impact on farnesoid X receptor signaling. Dig. Dis. 35, 246–250 (2017).

    Article  PubMed  Google Scholar 

  157. Wahlström, A. et al. Induction of farnesoid X receptor signaling in germ-free mice colonized with a human microbiota. J. Lipid Res. 58, 412–419 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Watanabe, M. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484–489 (2006). This paper is the first to describe the role of the cell-surface bile acid receptor TGR5 in linking postprandial bile acid production to control of energy metabolism.

    Article  CAS  PubMed  Google Scholar 

  159. Pols, T. W. et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab. 14, 747–757 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Staudinger, J. L. et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc. Natl Acad. Sci. USA 98, 3369–3374 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Sui, Y., Xu, J., Rios-Pilier, J. & Zhou, C. Deficiency of PXR decreases atherosclerosis in apoE-deficient mice. J. Lipid Res. 52, 1652–1659 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Makishima, M. et al. Vitamin D receptor as an intestinal bile acid sensor. Science 296, 1313–1316 (2002).

    Article  CAS  PubMed  Google Scholar 

  163. Lu, S. et al. The associations between the polymorphisms of vitamin D receptor and coronary artery disease: a systematic review and meta-analysis. Medicine (Baltimore) 95, e3467 (2016).

    Article  CAS  Google Scholar 

  164. Szeto, F. L. et al. Vitamin D receptor signaling inhibits atherosclerosis in mice. Mol. Endocrinol. 26, 1091–1101 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Raufman, J. P., Cheng, K. & Zimniak, P. Activation of muscarinic receptor signaling by bile acids: physiological and medical implications. Dig. Dis. Sci. 48, 1431–1444 (2003).

    Article  CAS  PubMed  Google Scholar 

  166. Hautala, A. J. et al. Acetylcholine receptor M2 gene variants, heart rate recovery, and risk of cardiac death after an acute myocardial infarction. Ann. Med. 41, 197–207 (2009).

    Article  CAS  PubMed  Google Scholar 

  167. Studer, E. et al. Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes. Hepatology 55, 267–276 (2012).

    Article  CAS  PubMed  Google Scholar 

  168. Skoura, A. et al. Sphingosine-1-phosphate receptor-2 function in myeloid cells regulates vascular inflammation and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 31, 81–85 (2011).

    Article  CAS  PubMed  Google Scholar 

  169. De Magalhaes Filho, C. D., Downes, M. & Evans, R. Bile acid analog intercepts liver fibrosis. Cell 166, 789 (2016).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are supported by grants from the US National Heart Lung and Blood Institute, the US Office of Dietary Supplements and the US National Institute on Alcohol Abuse and Alcoholism (grants R01HL122283 (J.M.B.), P50AA024333 (J.M.B.), R01HL103866 (S.L.H.), P01HL076491 (S.L.H.), R01HL126827 (S.L.H.) and R01DK106000 (S.L.H.)) as well as the Cleveland Clinic Liver Tumor Center of Excellence.

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, NC-10, Cleveland, 44195, Ohio, USA

    J. Mark Brown & Stanley L. Hazen

Authors
  1. J. Mark Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stanley L. Hazen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.M.B. and S.L.H. substantially contributed to the discussion of content and the review and editing of the manuscript before submission.

Corresponding authors

Correspondence to J. Mark Brown or Stanley L. Hazen.

Ethics declarations

Competing interests

S.L.H. is named as inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. He is also a paid consultant for P&G and has received research funds from Astra Zeneca, P&G, Pfizer Inc., Roche Diagnostics and Takeda. S.L.H. has also received royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, Esperion and Siemens. J.M.B. declares no competing interests.

PowerPoint slides

Glossary

Pattern recognition receptors

(PRRs). Host sensors that detect molecules typical for pathogens.

Atherosclerosis

A disease process in which the wall of an artery becomes thickened and inflamed owing to the accumulation of inflammation cells and lipids.

Thrombosis

The formation of a clot inside a vessel.

Ischaemic stroke

A stroke that occurs when a blood vessel to the brain is blocked by a blood clot.

Metabolome

The complete set of small-molecule chemicals found within a biological sample.

Transient ischaemic attack

A brief episode of neurological dysfunction caused by lack of blood flow to the brain; also called a 'mini-stroke'.

Glycaemia

The level of glucose in an individual's blood

Detergents

A surfactant or mix of surfactants that has cleaning or membrane-disturbing properties.

Taurine

A major sulfur-containing amino acid.

Postprandial state

The state immediately following a meal.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brown, J., Hazen, S. Microbial modulation of cardiovascular disease. Nat Rev Microbiol 16, 171–181 (2018). https://doi.org/10.1038/nrmicro.2017.149

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro.2017.149

  • Springer Nature Limited

This article is cited by

Search

Navigation