Oral Microbiome and Nitric Oxide: the Missing Link in the Management of Blood Pressure

  • Nathan S. BryanEmail author
  • Gena Tribble
  • Nikola Angelov
Gut Microbiome, Sympathetic Nervous System, and Hypertension (MK Raizada and EM Richards, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Gut Microbiome, Sympathetic Nervous System, and Hypertension


Having high blood pressure puts you at risk for heart disease and stroke, which are leading causes of death in the USA and worldwide. One out of every three Americans has hypertension, and it is estimated that despite aggressive treatment with medications, only about half of those medicated have managed blood pressure. Recent discoveries of the oral microbiome that reduces inorganic nitrate to nitrite and nitric oxide provide a new therapeutic target for the management of hypertension. The presence or absence of select and specific bacteria may determine steady-state blood pressure levels. Eradication of oral bacteria through antiseptic mouthwash or overuse of antibiotics causes blood pressure to increase. Allowing recolonization of nitrate- and nitrite-reducing bacteria can normalize blood pressure. This review will provide evidence of the link between oral microbiota and the production of nitric oxide and regulation of systemic blood pressure. Management of systemic hypertension through maintenance of the oral microbiome is a completely new paradigm in cardiovascular medicine.


Gut microbiome Blood pressure Hypertension Nitric oxide Diet Nitrate Nitrite 


Compliance with Ethical Standards

Conflict of Interest

Dr. Bryan reports personal fees and other from HumanN, Inc. In addition, he has a patent 8,298,589 with royalties paid to University of Texas, a patent 8,303,995 with royalties paid to University of Texas, a patent 8,435,570 with royalties paid to University of Texas, a patent 8,962,038 with royalties paid to University of Texas, a patent 9,119,823 with royalties paid to University of Texas, and a patent 9,241,999 with royalties paid to University of Texas. XXX declare no conflicts of interest relevant to this manuscript. Drs. Tribble and Angelov declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

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


Papers of Particular Interest, Published Recently, Have Been Highlighted as: • Of importance•• Of major importance

  1. 1.
    Kearney PM, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365(9455):217–23.CrossRefPubMedGoogle Scholar
  2. 2.
    Go AS, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28–e292.CrossRefPubMedGoogle Scholar
  3. 3.
    Bum EN, et al. Anticonvulsant properties of the methanolic extract of Cyperus Articulatus (Cyperaceae). J Ethnopharmacol. 2001;76(2):145–50.CrossRefPubMedGoogle Scholar
  4. 4.
    Franklin SS. Cardiovascular risks related to increased diastolic, systolic and pulse pressure. An epidemiologist’s point of view. Pathol Biol (Paris). 1999;47(6):594–603.Google Scholar
  5. 5.
    Franklin SS, et al. Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension. 2001;37(3):869–74.CrossRefPubMedGoogle Scholar
  6. 6.
    Chobanian AV, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206–52.CrossRefPubMedGoogle Scholar
  7. 7.
    Hsu CY, et al. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med. 2005;165(8):923–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Levy D, et al. The progression from hypertension to congestive heart failure. JAMA. 1996;275(20):1557–62.CrossRefPubMedGoogle Scholar
  9. 9.
    Vasan RS, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345(18):1291–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Organization, WH. World Health Statistics. Luxembourg: World Health Organization; 2015.Google Scholar
  11. 11.
    Wright Jr JT, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103–16.CrossRefPubMedGoogle Scholar
  12. 12.
    Wang YR, Alexander GC, Stafford RS. Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States. Arch Intern Med. 2007;167(2):141–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Cutler JA, et al. Trends in hypertension prevalence, awareness, treatment, and control rates in United States adults between 1988–1994 and 1999–2004. Hypertension. 2008;52(5):818–27.CrossRefPubMedGoogle Scholar
  14. 14.
    •• Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetycholine. Nature. 1980;288(5789):373–6. The original discovery of an endothelium derived relaxing factor that led to Nobel Prize Google Scholar
  15. 15.
    • Ignarro LJ, et al. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987;84:9265–9. The identification of EDRF as nitric oxide which led to Nobel Prize for Dr. Ignarro Google Scholar
  16. 16.
    • Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327(6122):524–6. First demonstration that EDRF is nitric oxide Google Scholar
  17. 17.
    Antonakoudis G, et al. Blood pressure control and cardiovascular risk reduction. Hippokratia. 2007;11(3):114–9.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Lieberman EH, et al. Flow-induced vasodilation of the human brachial artery is impaired in patients <40 years of age with coronary artery disease. Am J Cardiol. 1996;78(11):1210–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Ludmer PL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986;315(17):1046–51.CrossRefPubMedGoogle Scholar
  20. 20.
    Napoli C, Ignarro LJ. Nitric oxide and pathogenic mechanisms involved in the development of vascular diseases. Arch Pharm Res. 2009;32(8):1103–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Creager MA, et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86(1):228–34.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Celermajer DS, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993;88(5 Pt 1):2149–55.CrossRefPubMedGoogle Scholar
  23. 23.
    Forstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch. 2010;459(6):923–39.CrossRefPubMedGoogle Scholar
  24. 24.
    Robles Alonso V, Guarner F. Linking the gut microbiota to human health. Br J Nutr. 2013;109(Suppl 2):S21–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008;7(8):156–67.CrossRefPubMedGoogle Scholar
  26. 26.
    Lundberg JO, et al. Nitrate, bacteria and human health. Nat Rev Microbiol. 2004a;2(7):593–602.CrossRefPubMedGoogle Scholar
  27. 27.
    Nunez De Gonzalez, M.T., et al., Survey of residual nitrite and nitrate in conventional and organic/natural/uncured/indirectly cured meats available at retail in the United States. J Agric Food Chem, 2012. 60(15): p. 3981–3990.Google Scholar
  28. 28.
    Nunez De Gonzalez, M.T., et al., A survey of nitrate and nitrite concentrations in conventional and organic-labeled raw vegetables at retail. J Food Sci, 2015. 80(5): p. C942–C949.Google Scholar
  29. 29.
    Kelm M. Nitric oxide metabolism and breakdown. Biochim Biophys Acta. 1999;1411:273–89.CrossRefPubMedGoogle Scholar
  30. 30.
    • Bryan NS, et al. Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues. Nat Chem Biol. 2005;1(5):290–7. Report showing evidence that nitrite acts as a signaling molecule independent of its reduction to nitric oxide Google Scholar
  31. 31.
    Zweier JL, et al. Enzyme-independent formation of nitric oxide in biological tissues. Nat Med. 1995;1(8):804–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Lundberg JO, et al. Intragastric nitric oxide production in humans: measurements in expelled air. Gut. 1994;35(11):1543–6.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Benjamin N, et al. Stomach NO synthesis. Nature. 1994;368(6471):502.CrossRefPubMedGoogle Scholar
  34. 34.
    • Bryan NS, Ivy JL. Inorganic nitrite and nitrate: evidence to support consideration as dietary nutrients. Nutr Res. 2015;35(8):643–54. Comprehensive human evidence presented for establishment of dietary guidelines for nitrite and nitrate Google Scholar
  35. 35.
    • Bryan NS, Loscalzo J. Nitrite and nitrate in human health and disease. In: Bendich A, editor. Nutrition and health. New York: Humana Press; 2011. First edited book on the therapeutic and safety profile of nitrite and nitrate Google Scholar
  36. 36.
    •• Duncan C, et al. Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat Med. 1995a;1(6):546–51. First demonstration that inorganic nitrate could be metabolized to nitrite and nitric oxide by oral nitrate reducing bacteria Google Scholar
  37. 37.
    Lundberg JO, Govoni M. Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radic Biol Med. 2004;37(3):395–400.CrossRefPubMedGoogle Scholar
  38. 38.
    Spiegelhalder B, Eisenbrand G, Preussmann R. Influence of dietary nitrate on nitrite content of human saliva: possible relevance to in vivo formation of N-nitroso compounds. Food Cosmet Toxicol. 1976;14(6):545–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Hunault CC, et al. Bioavailability of sodium nitrite from an aqueous solution in healthy adults. Toxicol Lett. 2009;190(1):48–53.CrossRefPubMedGoogle Scholar
  40. 40.
    Duncan C, et al. Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat Med. 1995b;1(6):546–51.CrossRefPubMedGoogle Scholar
  41. 41.
    Lundberg J, et al. Nitrate, bacteria, and human health. Nat Rev Microbiol. 2004b;2:593–602.CrossRefPubMedGoogle Scholar
  42. 42.
    Doel J, et al. Evaluation of bacterial nitrate reduction in the human oral cavity. Eur J Oral Sci. 2005;113:14–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Hyde ER, et al. Metagenomic analysis of nitrate-reducing bacteria in the oral cavity: implications for nitric oxide homeostasis. PLoS One. 2014;9(3):e88645.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    • Bryan NS, et al. Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2007;104(48):19144–9. Study showing dietary nitrite and nitrate could protect the heart from injury from heart attack Google Scholar
  45. 45.
    Bryan NS, et al. Dietary nitrite restores NO homeostasis and is cardioprotective in endothelial nitric oxide synthase-deficient mice. Free Radic Biol Med. 2008;45(4):468–74.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Webb AJ, et al. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension. 2008;51(3):784–90.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Carlstrom M, et al. Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice. PNAS. 2010;107(41):17716–20.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Carlstrom M, et al. Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension. Cardiovasc Res. 2011;89(3):574–85.CrossRefPubMedGoogle Scholar
  49. 49.
    Kleinbongard P, et al. Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radic Biol Med. 2003;35(7):790–6.CrossRefPubMedGoogle Scholar
  50. 50.
    Bryan NS. Nitrite in nitric oxide biology: cause or consequence? A systems-based review. Free Radic Biol Med. 2006;41(5):691–701.CrossRefPubMedGoogle Scholar
  51. 51.
    Angelo M, Singel DJ, Stamler JS. An S-nitrosothiol (SNO) synthase function of hemoglobin that utilizes nitrite as a substrate. Proc Natl Acad Sci U S A. 2006;103(22):8366–71.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Furchgott RF, Bhadrakom S. Reactions of strips of rabbit aorta to epinephrine, isopropylarterenol, sodium nitrite and other drugs. J Pharmacol Exp Ther. 1953;108(2):129–43.PubMedGoogle Scholar
  53. 53.
    Cosby K, et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003a;9:1498–505.CrossRefPubMedGoogle Scholar
  54. 54.
    Tannenbaum SR, et al. Nitrite in human saliva. Its possible relationship to nitrosamine formation. J Natl Cancer Inst. 1974;53(1):79–84.CrossRefPubMedGoogle Scholar
  55. 55.
    van Maanen JM, van Geel AA, Kleinjans JC. Modulation of nitrate-nitrite conversion in the oral cavity. Cancer Detect Prev. 1996;20(6):590–6.PubMedGoogle Scholar
  56. 56.
    Walters CL, Casselden RJ, Taylor AM. Nitrite metabolism by skeletal muscle mitochondria in relation to haem pigments. Biochim Biophys Acta. 1967;143(2):310–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Kozlov AV, Staniek K, Nohl H. Nitrite reductase activity is a novel function of mammalian mitochondria. FEBS Lett. 1999;454(1–2):127–30.CrossRefPubMedGoogle Scholar
  58. 58.
    Cosby K, et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003b;9(12):1498–505.CrossRefPubMedGoogle Scholar
  59. 59.
    Li H, et al. Characterization of the effects of oxygen on xanthine oxidase-mediated nitric oxide formation. J Biol Chem. 2004;279(17):16939–46.CrossRefPubMedGoogle Scholar
  60. 60.
    Webb A, et al. Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci U S A. 2004a;101(37):13683–8.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Bryan NS, et al. Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo. Proc Natl Acad Sci U S A. 2004;101(12):4308–13.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Duranski MR, et al. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. J Clin Invest. 2005;115(5):1232–40.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Pluta RM, et al. Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage. JAMA. 2005;293(12):1477–84.CrossRefPubMedGoogle Scholar
  64. 64.
    Hunter CJ, et al. Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nat Med. 2004;10:1122–7.CrossRefPubMedGoogle Scholar
  65. 65.
    Hardwick JB, et al. A novel method for the delivery of nitric oxide therapy to the skin of human subjects using a semi-permeable membrane. Clin Sci (Lond). 2001;100(4):395–400.CrossRefGoogle Scholar
  66. 66.
    Bjorne HH, et al. Nitrite in saliva increases gastric mucosal blood flow and mucus thickness. J Clin Invest. 2004;113(1):106–14.CrossRefPubMedCentralGoogle Scholar
  67. 67.
    Tsuchiya K, et al. Nitrite is an alternative source of NO in vivo. Am J Physiol Heart Circ Physiol. 2005;288(5):H2163–70.CrossRefPubMedGoogle Scholar
  68. 68.
    Kleinbongard P, et al. Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med. 2006;40(2):295–302.CrossRefPubMedGoogle Scholar
  69. 69.
    Petersson J, et al. Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash. Free Radic Biol Med. 2009;46(8):1068–75.CrossRefPubMedGoogle Scholar
  70. 70.
    Webb, A., et al. Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci USA. 2004b. 101(13683–13688).Google Scholar
  71. 71.
    Hendgen-Cotta UB, et al. Dietary nitrate supplementation improves revascularization in chronic ischemia. Circulation. 2012;126(16):1983–92.CrossRefPubMedGoogle Scholar
  72. 72.
    Woessner M, et al. A stepwise reduction in plasma and salivary nitrite with increasing strengths of mouthwash following a dietary nitrate load. Nitric Oxide. 2016;54:1–7.CrossRefPubMedGoogle Scholar
  73. 73.
    Larsen FJ, et al. Effects of dietary nitrate on blood pressure in healthy volunteers. N Engl J Med. 2006;355(26):2792–3.CrossRefPubMedGoogle Scholar
  74. 74.
    •• Kapil V, et al. Physiological role for nitrate-reducing oral bacteria in blood pressure control. Free Radic Biol Med. 2013;55:93–100. Study demonstrating that oral nitrate reducing bacteria can affect systemic blood pressure Google Scholar
  75. 75.
    McDonagh ST, et al. The effects of chronic nitrate supplementation and the use of strong and weak antibacterial agents on plasma nitrite concentration and exercise blood pressure. Int J Sports Med. 2015;36(14):1177–85.CrossRefPubMedGoogle Scholar
  76. 76.
    Pinheiro LC, et al. Oral nitrite circumvents antiseptic mouthwash-induced disruption of enterosalivary circuit of nitrate and promotes nitrosation and blood pressure lowering effect. Free Radic Biol Med. 2016;101:226–35.CrossRefPubMedGoogle Scholar
  77. 77.
    Joshipura K, Ritchie C, Douglass C. Strength of evidence linking oral conditions and systemic disease. Compend Contin Educ Dent Suppl. 2000;30:12–23. quiz 65Google Scholar
  78. 78.
    Torregrossa AC, Aranke M, Bryan NS. Nitric oxide and geriatrics: implications in diagnostics and treatment of the elderly. J Geriatr Cardiol. 2011;8:230–42.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Bryan NS, Bian K, Murad F. Discovery of the nitric oxide signaling pathway and targets for drug development. Front Biosci. 2009;14:1–18.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Nathan S. Bryan
    • 1
    Email author
  • Gena Tribble
    • 2
  • Nikola Angelov
    • 2
  1. 1.Department of Molecular and Human Genetics, Baylor College of MedicineThe University of Texas Health Science Center at HoustonHoustonUSA
  2. 2.Department of PeriodonticsThe University of Texas Health Science Center at HoustonHoustonUSA

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