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European Journal of Medical Research
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Nitrate | Review

From nitrate to NO: potential effects of nitrate-reducing bacteria on systemic health and disease

Authors: Hongyu Liu, Yisheng Huang, Mingshu Huang, Min Wang, Yue Ming, Weixing Chen, Yuanxin Chen, Zhengming Tang, Bo Jia

Published in: European Journal of Medical Research | Issue 1/2023

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Abstract

Current research has described improving multisystem disease and organ function through dietary nitrate (DN) supplementation. They have provided some evidence that these floras with nitrate (NO3−) reductase are mediators of the underlying mechanism. Symbiotic bacteria with nitrate reductase activity (NRA) are found in the human digestive tract, including the mouth, esophagus and gastrointestinal tract (GT). Nitrate in food can be converted to nitrite under the tongue or in the stomach by these symbiotic bacteria. Then, nitrite is transformed to nitric oxide (NO) by non-enzymatic synthesis. NO is currently recognized as a potent bioactive agent with biological activities, such as vasodilation, regulation of cardiomyocyte function, neurotransmission, suppression of platelet agglutination, and prevention of vascular smooth muscle cell proliferation. NO also can be produced through the conventional l-arginine–NO synthase (l-NOS) pathway, whereas endogenous NO production by l-arginine is inhibited under hypoxia–ischemia or disease conditions. In contrast, exogenous NO3−/NO2−/NO activity is enhanced and becomes a practical supplemental pathway for NO in the body, playing an essential role in various physiological activities. Moreover, many diseases (such as metabolic or geriatric diseases) are primarily associated with disorders of endogenous NO synthesis, and NO generation from the exogenous NO3−/NO2−/NO route can partially alleviate the disease progression. The imbalance of NO in the body may be one of the potential mechanisms of disease development. Therefore, the impact of these floras with nitrate reductase on host systemic health through exogenous NO3−/NO2−/NO pathway production of NO or direct regulation of floras ecological balance is essential (e.g., regulation of body homeostasis, amelioration of diseases, etc.). This review summarizes the bacteria with nitrate reductase in humans, emphasizing the relationship between the metabolic processes of this microflora and host systemic health and disease. The potential effects of nitrate reduction bacteria on human health and disease were also highlighted in disease models from different human systems, including digestive, cardiovascular, endocrine, nervous, respiratory, and urinary systems, providing innovative ideas for future disease diagnosis and treatment based on nitrate reduction bacteria.
Literature
1.
Armet AM, Deehan EC, O’Sullivan AF, Mota JF, Field CJ, Prado CM, et al. Rethinking healthy eating in light of the gut microbiome. Cell Host Microbe. 2022;30(6):764–85.PubMed
2.
Attaye I, Warmbrunn MV, Boot ANAF, van der Wolk SC, Hutten BA, Daams JG, et al. A systematic review and meta-analysis of dietary interventions modulating gut microbiota and cardiometabolic diseases-striving for new standards in microbiome studies. Gastroenterology. 2022;162(7):1911–32.PubMed
3.
Jukic Peladic N, Dell’Aquila G, Carrieri B, Maggio M, Cherubini A, Orlandoni P. Potential role of probiotics for inflammaging: a narrative review. Nutrients. 2021;13(9):2919.PubMedPubMedCentral
4.
Michels N, Zouiouich S, Vanderbauwhede B, Vanacker J, Indave Ruiz BI, Huybrechts I. Human microbiome and metabolic health: an overview of systematic reviews. Obes Rev. 2022;23(4): e13409.PubMed
5.
Peng X, Cheng L, You Y, Tang C, Ren B, Li Y, et al. Oral microbiota in human systematic diseases. Int J Oral Sci. 2022;14(1):14.PubMedPubMedCentral
6.
Vazquez-Torres A, Baumler AJ. Nitrate, nitrite and nitric oxide reductases: from the last universal common ancestor to modern bacterial pathogens. Curr Opin Microbiol. 2016;29:1–8.PubMed
7.
Lundberg JO, Weitzberg E. Nitric oxide signaling in health and disease. Cell. 2022;185(16):2853–78.PubMed
8.
Wang S, El-Fahmawi A, Christian DA, Fang Q, Radaelli E, Chen L, et al. Infection-induced intestinal dysbiosis is mediated by macrophage activation and nitrate production. MBio. 2019;10(3):e00935-e1019.PubMedPubMedCentral
9.
Lim Y, Tang KD, Karpe AV, Beale DJ, Totsika M, Kenny L, et al. Chemoradiation therapy changes oral microbiome and metabolomic profiles in patients with oral cavity cancer and oropharyngeal cancer. Head Neck. 2021;43(5):1521–34.PubMed
10.
Nasseri-Moghaddam S, Nokhbeh-Zaeem H, Saniee P, Pedramnia S, Sotoudeh M, Malekzadeh R. Oral nitrate reductase activity and erosive gastro-esophageal reflux disease: a nitrate hypothesis for GERD pathogenesis. Dig Dis Sci. 2012;57(2):413–8.PubMed
11.
Li Z, Dou L, Zhang Y, He S, Zhao D, Hao C, et al. Characterization of the oral and esophageal microbiota in esophageal precancerous lesions and squamous cell carcinoma. Front Cell Infect Microbiol. 2021;11: 714162.PubMedPubMedCentral
12.
Blekkenhorst LC, Bondonno NP, Liu AH, Ward NC, Prince RL, Lewis JR, et al. Nitrate, the oral microbiome, and cardiovascular health: a systematic literature review of human and animal studies. Am J Clin Nutr. 2018;107(4):504–22.PubMed
13.
Vanhatalo A, L’Heureux JE, Kelly J, Blackwell JR, Wylie LJ, Fulford J, et al. Network analysis of nitrate-sensitive oral microbiome reveals interactions with cognitive function and cardiovascular health across dietary interventions. Redox Biol. 2021;41: 101933.PubMedPubMedCentral
14.
Vanhatalo A, Blackwell JR, L’Heureux JE, Williams DW, Smith A, van der Giezen M, et al. Nitrate-responsive oral microbiome modulates nitric oxide homeostasis and blood pressure in humans. Free Radical Biol Med. 2018;124:21–30.
15.
Cordero-Herrera I, Kozyra M, Zhuge Z, McCann Haworth S, Moretti C, Peleli M, et al. AMP-activated protein kinase activation and NADPH oxidase inhibition by inorganic nitrate and nitrite prevent liver steatosis. Proc Natl Acad Sci USA. 2019;116(1):217–26.PubMed
16.
Sonoda K, Kono Y, Kitamori K, Ohtake K, Shiba S, Kasono K, et al. Beneficial effects of dietary nitrite on a model of nonalcoholic steatohepatitis induced by high-fat/high-cholesterol diets in SHRSP5/Dmcr rats: a preliminary study. Int J Mol Sci. 2022;23(6):2931.PubMedPubMedCentral
17.
Ikonomidis I, Pavlidis G, Tsoumani M, Kousathana F, Katogiannis K, Tsilivarakis D, et al. Endothelial dysfunction is associated with decreased nitric oxide bioavailability in dysglycaemic subjects and first-degree relatives of type 2 diabetic patients. J Clin Med. 2022;11(12):3299.PubMedPubMedCentral
18.
Guimarães DD, Cruz JC, Carvalho-Galvão A, Zhuge Z, Marques SM, Naves LM, et al. Dietary nitrate reduces blood pressure in rats with angiotensin II-induced hypertension via mechanisms that involve reduction of sympathetic hyperactivity. Hypertension (Dallas, Tex: 1979). 2019;73(4):839–48.PubMed
19.
Sharma NM, Haibara AS, Katsurada K, Liu X, Patel KP. Central angiotensin II-protein inhibitor of neuronal nitric oxide synthase (PIN) axis contribute to neurogenic hypertension. Nitric Oxide Biol Chem. 2020;94:54–62.
20.
Kakavandi NR, Hasanvand A, Ghazi-Khansari M, Sezavar AH, Nabizadeh H, Parohan M. Maternal dietary nitrate intake and risk of neural tube defects: a systematic review and dose-response meta-analysis. Food Chem Toxicol. 2018;118:287–93.PubMed
21.
Morou-Bermúdez E, Torres-Colón JE, Bermúdez NS, Patel RP, Joshipura KJ. Pathways linking oral bacteria, nitric oxide metabolism, and health. J Dent Res. 2022;101(6):623–31.PubMedPubMedCentral
22.
Sun T, Yu H, Fu J. Respiratory tract microecology and bronchopulmonary dysplasia in preterm infants. Front Pediatr. 2021;9: 762545.PubMedPubMedCentral
23.
Soodaeva S, Klimanov I, Kubysheva N, Popova N, Batyrshin I. The state of the nitric oxide cycle in respiratory tract diseases. Oxid Med Cell Longev. 2020;2020:4859260.PubMedPubMedCentral
24.
Briskey D, Tucker PS, Johnson DW, Coombes JS. Microbiota and the nitrogen cycle: implications in the development and progression of CVD and CKD. Nitric Oxide. 2016;57:64–70.PubMed
25.
Carlstrom M, Montenegro MF. Oxidative stress and compromised nitric oxide signaling in cardiorenal disease therapeutic value of stimulating the nitrate-nitrite-nitric oxide pathway. J Intern Med. 2019;285(1):2–18.PubMed
26.
Cosola C, Sabatino A, di Bari I, Fiaccadori E, Gesualdo L. Nutrients, nutraceuticals, and xenobiotics affecting renal health. Nutrients. 2018;10(7):808.PubMedPubMedCentral
27.
Kobayashi J. Effect of diet and gut environment on the gastrointestinal formation of N-nitroso compounds: a review. Nitric Oxide. 2018;73:66–73.PubMed
28.
Ma L, Hu L, Jin L, Wang J, Li X, Wang W, et al. Rebalancing glucolipid metabolism and gut microbiome dysbiosis by nitrate-dependent alleviation of high-fat diet-induced obesity. BMJ Open Diabetes Res Care. 2020;8(1): e001255.PubMedPubMedCentral
29.
Rocha BS, Laranjinha J. Nitrate from diet might fuel gut microbiota metabolism: minding the gap between redox signaling and inter-kingdom communication. Free Radic Biol Med. 2020;149:37–43.PubMed
30.
Tiso M, Schechter AN. Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions. PLoS ONE. 2015;10(3): e0119712.PubMedPubMedCentral
31.
Qu XM, Wu ZF, Pang BX, Jin LY, Qin LZ, Wang SL. From nitrate to nitric oxide: the role of salivary glands and oral bacteria. J Dent Res. 2016;95(13):1452–6.PubMed
32.
Shannon OM, Gregory S, Siervo M. Dietary nitrate, aging and brain health: the latest evidence. Curr Opin Clin Nutr Metab Care. 2022;25:393–400.PubMed
33.
Babateen AM, Shannon OM, O’Brien GM, Okello E, Smith E, Olgacer D, et al. Incremental doses of nitrate-rich beetroot juice do not modify cognitive function and cerebral blood flow in overweight and obese older adults: a 13-week pilot randomised clinical trial. Nutrients. 2022;14(5):1052.PubMedPubMedCentral
34.
Piknova B, Schechter AN, Park JW, Vanhatalo A, Jones AM. Skeletal muscle nitrate as a regulator of systemic nitric oxide homeostasis. Exerc Sport Sci Rev. 2022;50(1):2.PubMed
35.
Brunetta HS, Petrick HL, Momken I, Handy RM, Pignanelli C, Nunes EA, et al. Nitrate consumption preserves HFD-induced skeletal muscle mitochondrial ADP sensitivity and lysine acetylation: a potential role for SIRT1. Redox Biol. 2022;52: 102307.PubMedPubMedCentral
36.
Ashworth A, Cutler C, Farnham G, Liddle L, Burleigh M, Rodiles A, et al. Dietary intake of inorganic nitrate in vegetarians and omnivores and its impact on blood pressure, resting metabolic rate and the oral microbiome. Free Radic Biol Med. 2019;138:63–72.PubMed
37.
Alzahrani HS, Jackson KG, Hobbs DA, Lovegrove JA. The role of dietary nitrate and the oral microbiome on blood pressure and vascular tone. Nutr Res Rev. 2021;34(2):222–39.PubMed
38.
Rosier BT, Takahashi N, Zaura E, Krom BP, MartÍnez-Espinosa RM, van Breda SGJ, et al. The importance of nitrate reduction for oral health. J Dent Res. 2022;101(8):887–97.PubMed
39.
Lundberg JO, Carlström M, Weitzberg E. Metabolic effects of dietary nitrate in health and disease. Cell Metab. 2018;28(1):9–22.PubMed
40.
González-Soltero R, Bailén M, de Lucas B, Ramírez-Goercke MI, Pareja-Galeano H, Larrosa M. Role of oral and gut microbiota in dietary nitrate metabolism and its impact on sports performance. Nutrients. 2020;12(12):3611.PubMedPubMedCentral
41.
Pignatelli P, Fabietti G, Ricci A, Piattelli A, Curia MC. How periodontal disease and presence of nitric oxide reducing oral bacteria can affect blood pressure. Int J Mol Sci. 2020;21(20):7538.PubMedPubMedCentral
42.
Said Abasse K, Essien EE, Abbas M, Yu X, Xie W, Sun J, et al. Association between dietary nitrate, nitrite intake, and site-specific cancer risk: a systematic review and meta-analysis. Nutrients. 2022;14(3):666.PubMedPubMedCentral
43.
Moazeni M, Heidari Z, Golipour S, Ghaisari L, Sillanpää M, Ebrahimi A. Dietary intake and health risk assessment of nitrate, nitrite, and nitrosamines: a Bayesian analysis and Monte Carlo simulation. Environ Sci Pollut Res Int. 2020;27(36):45568–80.PubMed
44.
Tannenbaum SR, Correa P. Nitrate and gastric cancer risks. Nature. 1985;317(6039):675–6.PubMed
45.
Tricker AR, Preussmann R. Carcinogenic N-nitrosamines in the diet: occurrence, formation, mechanisms and carcinogenic potential. Mutat Res. 1991;259(3–4):277–89.PubMed
46.
Tricker AR, Pfundstein B, Theobald E, Preussmann R, Spiegelhalder B. Mean daily intake of volatile N-nitrosamines from foods and beverages in West Germany in 1989–1990. Food Chem Toxicol. 1991;29(11):729–32.PubMed
47.
Alexander J, Benford DJ, Cockburn A, Cravedi J-P, Dogliotti E, Domenico Ad, et al., editors. Nitrate in vegetables scientific opinion of the panel on contaminants in the food chain 12008.
48.
Ohara M, Suyama T. Nitrate reductase activity during the embryonal development of the frog. Nature. 1952;169(4294):285–6.PubMed
49.
Akiyama K, Kimura A, Suzuki H, Takeyama Y, Gluckman TL, Terhakopian A, et al. Production of oxidative products of nitric oxide in infarcted human heart. J Am Coll Cardiol. 1998;32(2):373–9.PubMed
50.
Burleigh MC, Liddle L, Monaghan C, Muggeridge DJ, Sculthorpe N, Butcher JP, et al. Salivary nitrite production is elevated in individuals with a higher abundance of oral nitrate-reducing bacteria. Free Radic Biol Med. 2018;120:80–8.PubMed
51.
Daims H, Lucker S, Wagner M. A new perspective on microbes formerly known as nitrite-oxidizing bacteria. Trends Microbiol. 2016;24(9):699–712.PubMedPubMedCentral
52.
Duncan C, Dougall H, Johnston P, Green S, Brogan R, Leifert C, et al. Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat Med. 1995;1(6):546–51.PubMed
53.
Blot S. Antiseptic mouthwash, the nitrate-nitrite-nitric oxide pathway, and hospital mortality: a hypothesis generating review. Intensive Care Med. 2021;47(1):28–38.PubMed
54.
Flores M, Toldra F. Chemistry, safety, and regulatory considerations in the use of nitrite and nitrate from natural origin in meat products—invited review. Meat Sci. 2021;171: 108272.PubMed
55.
Shannon OM, Allen JD, Bescos R, Burke L, Clifford T, Easton C, et al. Dietary inorganic nitrate as an ergogenic aid: an expert consensus derived via the modified Delphi technique. Sports Med (Auckland, NZ). 2022;52:2537–58.
56.
Kondo H, Akoumianakis I, Badi I, Akawi N, Kotanidis CP, Polkinghorne M, et al. Effects of canagliflozin on human myocardial redox signalling: clinical implications. Eur Heart J. 2021;42(48):4947–60.PubMedPubMedCentral
57.
Qin C, Bian X-L, Wu H-Y, Xian J-Y, Lin Y-H, Cai C-Y, et al. Prevention of the return of extinguished fear by disrupting the interaction of neuronal nitric oxide synthase with its carboxy-terminal PDZ ligand. Mol Psychiatry. 2021;26(11):6506–19.PubMed
58.
Wong NF, Xu-Friedman MA. Induction of activity-dependent plasticity at auditory nerve synapses. J Neurosci. 2022;42(32):6211–20.PubMedPubMedCentral
59.
60.
61.
Tran DL, Le Thi P, Lee SM, Hoang Thi TT, Park KD. Multifunctional surfaces through synergistic effects of heparin and nitric oxide release for a highly efficient treatment of blood-contacting devices. J Control Release. 2021;329:401–12.PubMed
62.
Liu T, Schroeder H, Power GG, Blood AB. A physiologically relevant role for NO stored in vascular smooth muscle cells: a novel theory of vascular NO signaling. Redox Biol. 2022;53: 102327.PubMedPubMedCentral
63.
Durgin BG, Wood KC, Hahn SA, McMahon B, Baust JJ, Straub AC. Smooth muscle cell CYB5R3 preserves cardiac and vascular function under chronic hypoxic stress. J Mol Cell Cardiol. 2022;162:72–80.PubMed
64.
Jones T, Dunn EL, Macdonald JH, Kubis H-P, McMahon N, Sandoo A. The effects of beetroot juice on blood pressure, microvascular function and large-vessel endothelial function: a randomized, double-blind, placebo-controlled pilot study in healthy older adults. Nutrients. 2019;11(8):1792.PubMedPubMedCentral
65.
Benjamim CJR, Porto AA, Valenti VE, Sobrinho ACDS, Garner DM, Gualano B, et al. Nitrate derived from beetroot juice lowers blood pressure in patients with arterial hypertension: a systematic review and meta-analysis. Front Nutr. 2022;9: 823039.PubMedPubMedCentral
66.
Zamani H, de Joode MEJR, Hossein IJ, Henckens NFT, Guggeis MA, Berends JE, et al. The benefits and risks of beetroot juice consumption: a systematic review. Crit Rev Food Sci Nutr. 2021;61(5):788–804.PubMed
67.
Craig JC, Broxterman RM, Smith JR, Allen JD, Barstow TJ. Effect of dietary nitrate supplementation on conduit artery blood flow, muscle oxygenation, and metabolic rate during handgrip exercise. J Appl Physiol (1985). 2018;125(2):254–62.PubMed
68.
Brookes ZLS, Belfield LA, Ashworth A, Casas-Agustench P, Raja M, Pollard AJ, et al. Effects of chlorhexidine mouthwash on the oral microbiome. J Dent. 2021;113: 103768.PubMed
69.
Rosier BT, Moya-Gonzalvez EM, Corell-Escuin P, Mira A. Isolation and characterization of nitrate-reducing bacteria as potential probiotics for oral and systemic health. Front Microbiol. 2020;11: 555465.PubMedPubMedCentral
70.
Walker MY, Pratap S, Southerland JH, Farmer-Dixon CM, Lakshmyya K, Gangula PR. Role of oral and gut microbiome in nitric oxide-mediated colon motility. Nitric Oxide Biol Chem. 2018;73:81–8.
71.
Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. Defining the normal bacterial flora of the oral cavity. J Clin Microbiol. 2005;43(11):5721–32.PubMedPubMedCentral
72.
Kilian M, Chapple ILC, Hannig M, Marsh PD, Meuric V, Pedersen AML, et al. The oral microbiome—an update for oral healthcare professionals. Br Dent J. 2016;221(10):657–66.PubMed
73.
Krishnan K, Chen T, Paster BJ. A practical guide to the oral microbiome and its relation to health and disease. Oral Dis. 2017;23(3):276–86.PubMed
74.
Li H, Duncan C, Townend J, Killham K, Smith LM, Johnston P, et al. Nitrate-reducing bacteria on rat tongues. Appl Environ Microbiol. 1997;63(3):924–30.PubMedPubMedCentral
75.
Liddle L, Burleigh MC, Monaghan C, Muggeridge DJ, Sculthorpe N, Pedlar CR, et al. Variability in nitrate-reducing oral bacteria and nitric oxide metabolites in biological fluids following dietary nitrate administration: an assessment of the critical difference. Nitric Oxide Biol Chem. 2019;83:1–10.
76.
Hyde ER, Luk B, Cron S, Kusic L, McCue T, Bauch T, et al. Characterization of the rat oral microbiome and the effects of dietary nitrate. Free Radical Biol Med. 2014;77:249–57.
77.
Hyde ER, Andrade F, Vaksman Z, Parthasarathy K, Jiang H, Parthasarathy DK, et al. Metagenomic analysis of nitrate-reducing bacteria in the oral cavity: implications for nitric oxide homeostasis. PLoS ONE. 2014;9(3): e88645.PubMedPubMedCentral
78.
Goh CE, Trinh P, Colombo PC, Genkinger JM, Mathema B, Uhlemann A-C, et al. Association between nitrate-reducing oral bacteria and cardiometabolic outcomes: results from ORIGINS. J Am Heart Assoc. 2019;8(23): e013324.PubMedPubMedCentral
79.
Jones AM, Vanhatalo A, Seals DR, Rossman MJ, Piknova B, Jonvik KL. Dietary nitrate and nitric oxide metabolism: mouth, circulation, skeletal muscle, and exercise performance. Med Sci Sports Exerc. 2021;53(2):280–94.PubMed
80.
Hansen TH, Kern T, Bak EG, Kashani A, Allin KH, Nielsen T, et al. Impact of a vegan diet on the human salivary microbiota. Sci Rep. 2018;8(1):5847.PubMedPubMedCentral
81.
Ahmed KA, Kim K, Ricart K, Van Der Pol W, Qi X, Bamman MM, et al. Potential role for age as a modulator of oral nitrate reductase activity. Nitric Oxide Biol Chem. 2021;108:1–7.
82.
Tribble GD, Angelov N, Weltman R, Wang B-Y, Eswaran SV, Gay IC, et al. Frequency of tongue cleaning impacts the human tongue microbiome composition and enterosalivary circulation of nitrate. Front Cell Infect Microbiol. 2019;9:39.PubMedPubMedCentral
83.
Senkus KE, Crowe-White KM. Influence of mouth rinse use on the enterosalivary pathway and blood pressure regulation: a systematic review. Crit Rev Food Sci Nutr. 2020;60(17):2874–86.PubMed
84.
Macfarlane S, Furrie E, Macfarlane GT, Dillon JF. Microbial colonization of the upper gastrointestinal tract in patients with Barrett’s esophagus. Clin Infect Dis. 2007;45(1):29–38.PubMed
85.
Pajecki D, Zilberstein B, Cecconello I, Dos Santos MAA, Yagi OK, Gama-Rodrigues JJ. Larger amounts of nitrite and nitrate-reducing bacteria in megaesophagus of Chagas’ disease than in controls. J Gastrointest Surg. 2007;11(2):199–203.PubMed
86.
Park CH, Lee JG, Lee AR, Eun CS, Han DS. Network construction of gastric microbiome and organization of microbial modules associated with gastric carcinogenesis. Sci Rep. 2019;9(1):12444.PubMedPubMedCentral
87.
Sanduleanu S, Jonkers D, De Bruïne A, Hameeteman W, Stockbrügger RW. Double gastric infection with Helicobacter pylori and non-Helicobacter pylori bacteria during acid-suppressive therapy: increase of pro-inflammatory cytokines and development of atrophic gastritis. Aliment Pharmacol Ther. 2001;15(8):1163–75.PubMed
88.
Mowat C, Williams C, Gillen D, Hossack M, Gilmour D, Carswell A, et al. Omeprazole, Helicobacter pylori status, and alterations in the intragastric milieu facilitating bacterial N-nitrosation. Gastroenterology. 2000;119(2):339–47.PubMed
89.
Jo HJ, Kim J, Kim N, Park JH, Nam RH, Seok Y-J, et al. Analysis of gastric microbiota by pyrosequencing: minor role of bacteria other than Helicobacter pylori in the gastric carcinogenesis. Helicobacter. 2016;21(5):364–74.PubMed
90.
Conley MN, Roberts C, Sharpton TJ, Iwaniec UT, Hord NG. Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats. Mol Nutr Food Res. 2017;61(5):1600372.PubMedPubMedCentral
91.
Rocha BS, Correia MG, Pereira A, Henriques I, Da Silva GJ, Laranjinha J. Inorganic nitrate prevents the loss of tight junction proteins and modulates inflammatory events induced by broad-spectrum antibiotics: a role for intestinal microbiota? Nitric Oxide Biol Chem. 2019;88:27–34.
92.
Petersson J, Jädert C, Phillipson M, Borniquel S, Lundberg JO, Holm L. Physiological recycling of endogenous nitrate by oral bacteria regulates gastric mucus thickness. Free Radical Biol Med. 2015;89:241–7.
93.
Petersson J, Phillipson M, Jansson EA, Patzak A, Lundberg JO, Holm L. Dietary nitrate increases gastric mucosal blood flow and mucosal defense. Am J Physiol Gastrointest Liver Physiol. 2007;292(3):G718–24.PubMed
94.
Mohamed NI, Suddek GM, El-Kashef DH. Molsidomine alleviates acetic acid-induced colitis in rats by reducing oxidative stress, inflammation and apoptosis. Int Immunopharmacol. 2021;99: 108005.PubMed
95.
Florin TH, Neale G, Cummings JH. The effect of dietary nitrate on nitrate and nitrite excretion in man. Br J Nutr. 1990;64(2):387–97.PubMed
96.
Dellavalle CT, Xiao Q, Yang G, Shu X-O, Aschebrook-Kilfoy B, Zheng W, et al. Dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women’s Health Study. Int J Cancer. 2014;134(12):2917–26.PubMed
97.
Bradbury KE, Appleby PN, Key TJ. Fruit, vegetable, and fiber intake in relation to cancer risk: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC). Am J Clin Nutr. 2014;100(Suppl 1):394S-S398.PubMed
98.
Machha A, Schechter AN. Inorganic nitrate: a major player in the cardiovascular health benefits of vegetables? Nutr Rev. 2012;70(6):367–72.PubMed
99.
Gangolli SD, van den Brandt PA, Feron VJ, Janzowsky C, Koeman JH, Speijers GJ, et al. Nitrate, nitrite and N-nitroso compounds. Eur J Pharmacol. 1994;292(1):1–38.PubMed
100.
Hord NG, Tang Y, Bryan NS. Food sources of nitrates and nitrites: the physiologic context for potential health benefits. Am J Clin Nutr. 2009;90(1):1–10.PubMed
101.
van Velzen AG, Sips AJAM, Schothorst RC, Lambers AC, Meulenbelt J. The oral bioavailability of nitrate from nitrate-rich vegetables in humans. Toxicol Lett. 2008;181(3):177–81.PubMed
102.
Vasco E, Dias MG, Oliveira L. The first harmonised total diet study in Portugal: nitrate occurrence and exposure assessment. Food Chem. 2022;392: 133152.PubMed
103.
104.
Karwowska M, Kononiuk A. Nitrates/nitrites in food-risk for nitrosative stress and benefits. Antioxidants (Basel). 2020;9(3):241.PubMed
105.
DeMartino AW, Kim-Shapiro DB, Patel RP, Gladwin MT. Nitrite and nitrate chemical biology and signalling. Br J Pharmacol. 2019;176(2):228–45.PubMed
106.
Kevil CG, Kolluru GK, Pattillo CB, Giordano T. Inorganic nitrite therapy: historical perspective and future directions. Free Radic Biol Med. 2011;51(3):576–93.PubMedPubMedCentral
107.
Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J. 2001;357(Pt 3):593–615.PubMedPubMedCentral
108.
Oliveira-Paula GH, Pinheiro LC, Tanus-Santos JE. Mechanisms impairing blood pressure responses to nitrite and nitrate. Nitric Oxide. 2019;85:35–43.PubMed
109.
Rajapakse NW, Giam B, Kuruppu S, Head GA, Kaye DM. Impaired l-arginine-nitric oxide pathway contributes to the pathogenesis of resistant hypertension. Clin Sci (Lond). 2019;133(20):2061–7.PubMed
110.
Belzer V, Hanani M. Nitric oxide as a messenger between neurons and satellite glial cells in dorsal root ganglia. Glia. 2019;67(7):1296–307.PubMed
111.
Boccellino M, Galasso G, Ambrosio P, Stiuso P, Lama S, Di Zazzo E, et al. H9c2 cardiomyocytes under hypoxic stress: biological effects mediated by sentinel downstream targets. Oxid Med Cell Longev. 2021;2021:6874146.PubMedPubMedCentral
112.
Schiffer TA, Lundberg JO, Weitzberg E, Carlström M. Modulation of mitochondria and NADPH oxidase function by the nitrate-nitrite-NO pathway in metabolic disease with focus on type 2 diabetes. Biochim Biophys Acta. 2020;1866(8): 165811.
113.
Carlstrom M, Montenegro MF. Therapeutic value of stimulating the nitrate-nitrite-nitric oxide pathway to attenuate oxidative stress and restore nitric oxide bioavailability in cardiorenal disease. J Intern Med. 2019;285(1):2–18.PubMed
114.
Lundberg JO, Gladwin MT, Weitzberg E. Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discovery. 2015;14(9):623–41.PubMed
115.
Lee DY, Lee SY, Jo C, Yoon Y, Jeong JY, Hur SJ. Effect on health from consumption of meat and meat products. J Anim Sci Technol. 2021;63(5):955–76.PubMedPubMedCentral
116.
Hezel MP, Liu M, Schiffer TA, Larsen FJ, Checa A, Wheelock CE, et al. Effects of long-term dietary nitrate supplementation in mice. Redox Biol. 2015;5:234–42.PubMedPubMedCentral
117.
Bryan NS, Alexander DD, Coughlin JR, Milkowski AL, Boffetta P. Ingested nitrate and nitrite and stomach cancer risk: an updated review. Food Chem Toxicol. 2012;50(10):3646–65.PubMed
118.
McNally B, Griffin JL, Roberts LD. Dietary inorganic nitrate: from villain to hero in metabolic disease? Mol Nutr Food Res. 2016;60(1):67–78.PubMed
119.
Godfrey S, Labhasetwar P, Wate S, Pimpalkar S. How safe are the global water coverage figures? Case study from Madhya Pradesh. India Environ Monit Assess. 2011;176(1–4):561–74.PubMed
120.
Verheijen FW, Verbeek E, Aula N, Beerens CE, Havelaar AC, Joosse M, et al. A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. Nat Genet. 1999;23(4):462–5.PubMed
121.
Qin L, Liu X, Sun Q, Fan Z, Xia D, Ding G, et al. Sialin (SLC17A5) functions as a nitrate transporter in the plasma membrane. Proc Natl Acad Sci USA. 2012;109(33):13434–9.PubMedPubMedCentral
122.
Reimer RJ. SLC17: a functionally diverse family of organic anion transporters. Mol Aspects Med. 2013;34(2–3):350–9.PubMedPubMedCentral
123.
Lundberg JO. Nitrate transport in salivary glands with implications for NO homeostasis. Proc Natl Acad Sci USA. 2012;109(33):13144–5.PubMedPubMedCentral
124.
Hezel MP, Weitzberg E. The oral microbiome and nitric oxide homoeostasis. Oral Dis. 2015;21(1):7–16.PubMed
125.
Feng X, Wu Z, Xu J, Xu Y, Zhao B, Pang B, et al. Dietary nitrate supplementation prevents radiotherapy-induced xerostomia. Elife. 2021;10: e70710.PubMedPubMedCentral
126.
Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008;7(2):156–67.PubMed
127.
Sabbah DA, Hajjo R, Sweidan K. Review on epidermal growth factor receptor (EGFR) structure, signaling pathways, interactions, and recent updates of EGFR inhibitors. Curr Top Med Chem. 2020;20(10):815–34.PubMed
128.
Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochem Biophys Acta. 2011;1813(11):1978–86.PubMed
129.
Shen W, Tang D, Wan P, Peng Z, Sun M, Guo X, et al. Identification of tissue-specific microbial profile of esophageal squamous cell carcinoma by full-length 16S rDNA sequencing. Appl Microbiol Biotechnol. 2022;106(8):3215–29.PubMed
130.
Kovaleva O, Podlesnaya P, Rashidova M, Samoilova D, Petrenko A, Mochalnikova V, et al. Prognostic significance of the microbiome and stromal cells phenotype in esophagus squamous cell carcinoma. Biomedicines. 2021;9(7):743.PubMedPubMedCentral
131.
Wallace JL, Miller MJ. Nitric oxide in mucosal defense: a little goes a long way. Gastroenterology. 2000;119(2):512–20.PubMed
132.
Lanas A, Bajador E, Serrano P, Fuentes J, Carreño S, Guardia J, et al. Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding. N Engl J Med. 2000;343(12):834–9.PubMed
133.
Jansson EA, Petersson J, Reinders C, Sobko T, Björne H, Phillipson M, et al. Protection from nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers by dietary nitrate. Free Radical Biol Med. 2007;42(4):510–8.
134.
Jin L, Qin L, Xia D, Liu X, Fan Z, Zhang C, et al. Active secretion and protective effect of salivary nitrate against stress in human volunteers and rats. Free Radical Biol Med. 2013;57:61–7.
135.
Eriksson KE, Yang T, Carlström M, Weitzberg E. Organ uptake and release of inorganic nitrate and nitrite in the pig. Nitric Oxide Biol Chem. 2018;75:16–26.
136.
Lundberg JO, Govoni M. Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radical Biol Med. 2004;37(3):395–400.
137.
Hu L, Jin L, Xia D, Zhang Q, Ma L, Zheng H, et al. Nitrate ameliorates dextran sodium sulfate-induced colitis by regulating the homeostasis of the intestinal microbiota. Free Radical Biol Med. 2020;152:609–21.
138.
Dicksved J, Halfvarson J, Rosenquist M, Järnerot G, Tysk C, Apajalahti J, et al. Molecular analysis of the gut microbiota of identical twins with Crohn’s disease. ISME J. 2008;2(7):716–27.PubMed
139.
Nishikawa J, Kudo T, Sakata S, Benno Y, Sugiyama T. Diversity of mucosa-associated microbiota in active and inactive ulcerative colitis. Scand J Gastroenterol. 2009;44(2):180–6.PubMed
140.
Walker AW, Sanderson JD, Churcher C, Parkes GC, Hudspith BN, Rayment N, et al. High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol. 2011;11:7.PubMedPubMedCentral
141.
Björne H, Weitzberg E, Lundberg JO. Intragastric generation of antimicrobial nitrogen oxides from saliva–physiological and therapeutic considerations. Free Radical Biol Med. 2006;41(9):1404–12.
142.
Jädert C, Phillipson M, Holm L, Lundberg JO, Borniquel S. Preventive and therapeutic effects of nitrite supplementation in experimental inflammatory bowel disease. Redox Biol. 2014;2:73–81.PubMed
143.
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3(11): e442.PubMedPubMedCentral
144.
Larsen FJ, Ekblom B, Sahlin K, Lundberg JO, Weitzberg E. Effects of dietary nitrate on blood pressure in healthy volunteers. N Engl J Med. 2006;355(26):2792–3.PubMed
145.
Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Rehman F, et al. Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension (Dallas, Tex: 1979). 2010;56(2):274–81.PubMed
146.
Vanhatalo A, Bailey SJ, Blackwell JR, DiMenna FJ, Pavey TG, Wilkerson DP, et al. Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise. Am J Physiol Regul Integr Comp Physiol. 2010;299(4):R1121–31.PubMed
147.
Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, et al. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension (Dallas, Tex: 1979). 2008;51(3):784–90.PubMed
148.
Koch CD, Gladwin MT, Freeman BA, Lundberg JO, Weitzberg E, Morris A. Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health. Free Radical Biol Med. 2017;105:48–67.
149.
Bryan NS. Functional nitric oxide nutrition to combat cardiovascular disease. Curr Atheroscler Rep. 2018;20(5):21.PubMed
150.
Carlstrom M, Lundberg JO, Weitzberg E. Mechanisms underlying blood pressure reduction by dietary inorganic nitrate. Acta Physiol (Oxf). 2018;224(1): e13080.PubMed
151.
Velmurugan S, Gan JM, Rathod KS, Khambata RS, Ghosh SM, Hartley A, et al. Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study. Am J Clin Nutr. 2016;103(1):25–38.PubMed
152.
Batista RIM, Nogueira RC, Ferreira GC, Oliveira-Paula GH, Damacena-Angelis C, Pinheiro LC, et al. Antiseptic mouthwash inhibits antihypertensive and vascular protective effects of L-arginine. Eur J Pharmacol. 2021;907: 174314.PubMed
153.
Petersson J, Carlström M, Schreiber O, Phillipson M, Christoffersson G, Jägare A, et al. Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash. Free Radical Biol Med. 2009;46(8):1068–75.
154.
Babateen AM, Shannon OM, Mathers JC, Siervo M. Validity and reliability of test strips for the measurement of salivary nitrite concentration with and without the use of mouthwash in healthy adults. Nitric Oxide Biol Chem. 2019;91:15–22.
155.
Bescos R, Ashworth A, Cutler C, Brookes ZL, Belfield L, Rodiles A, et al. Effects of chlorhexidine mouthwash on the oral microbiome. Sci Rep. 2020;10(1):5254.PubMedPubMedCentral
156.
Sundqvist ML, Lundberg JO, Weitzberg E. Effects of antiseptic mouthwash on resting metabolic rate: a randomized, double-blind, crossover study. Nitric Oxide Biol Chem. 2016;61:38–44.
157.
Dewhurst-Trigg R, Yeates T, Blackwell JR, Thompson C, Linoby A, Morgan PT, et al. Lowering of blood pressure after nitrate-rich vegetable consumption is abolished with the co-ingestion of thiocyanate-rich vegetables in healthy normotensive males. Nitric Oxide Biol Chem. 2018;74:39–46.
158.
Huppertz B. Placental origins of preeclampsia: challenging the current hypothesis. Hypertension (Dallas, Tex: 1979). 2008;51(4):970–5.PubMed
159.
Bramham K, Parnell B, Nelson-Piercy C, Seed PT, Poston L, Chappell LC. Chronic hypertension and pregnancy outcomes: systematic review and meta-analysis. BMJ. 2014;348: g2301.PubMedPubMedCentral
160.
Chappell LC, Enye S, Seed P, Briley AL, Poston L, Shennan AH. Adverse perinatal outcomes and risk factors for preeclampsia in women with chronic hypertension: a prospective study. Hypertension (Dallas, Tex: 1979). 2008;51(4):1002–9.PubMed
161.
Ormesher L, Myers JE, Chmiel C, Wareing M, Greenwood SL, Tropea T, et al. Effects of dietary nitrate supplementation, from beetroot juice, on blood pressure in hypertensive pregnant women: a randomised, double-blind, placebo-controlled feasibility trial. Nitric Oxide Biol Chem. 2018;80:37–44.
162.
Guignabert C, Tu L, Girerd B, Ricard N, Huertas A, Montani D, et al. New molecular targets of pulmonary vascular remodeling in pulmonary arterial hypertension: importance of endothelial communication. Chest. 2015;147(2):529–37.PubMed
163.
Kinsella JP, Neish SR, Ivy DD, Shaffer E, Abman SH. Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. J Pediatr. 1993;123(1):103–8.PubMed
164.
Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalation nitric oxide in persistent pulmonary hypertension of the newborn. Lancet. 1992;340(8823):819–20.PubMed
165.
Roberts JD, Fineman JR, Morin FC, Shaul PW, Rimar S, Schreiber MD, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The inhaled nitric oxide study group. N Engl J Med. 1997;336(9):605–10.PubMed
166.
Hendgen-Cotta UB, Luedike P, Totzeck M, Kropp M, Schicho A, Stock P, et al. Dietary nitrate supplementation improves revascularization in chronic ischemia. Circulation. 2012;126(16):1983–92.PubMed
167.
Thum T, Fraccarollo D, Thum S, Schultheiss M, Daiber A, Wenzel P, et al. Differential effects of organic nitrates on endothelial progenitor cells are determined by oxidative stress. Arterioscler Thromb Vasc Biol. 2007;27(4):748–54.PubMed
168.
Hung H-C, Joshipura KJ, Jiang R, Hu FB, Hunter D, Smith-Warner SA, et al. Fruit and vegetable intake and risk of major chronic disease. J Natl Cancer Inst. 2004;96(21):1577–84.PubMed
169.
Joshipura KJ, Ascherio A, Manson JE, Stampfer MJ, Rimm EB, Speizer FE, et al. Fruit and vegetable intake in relation to risk of ischemic stroke. JAMA. 1999;282(13):1233–9.PubMed
170.
Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, et al. Heart disease and stroke statistics-2022 update: a report from the American Heart Association. Circulation. 2022;145(8):e153–639.PubMed
171.
Notay K, Incognito AV, Millar PJ. Acute beetroot juice supplementation on sympathetic nerve activity: a randomized, double-blind, placebo-controlled proof-of-concept study. Am J Physiol Heart Circ Physiol. 2017;313(1):H59–65.PubMed
172.
Bock JM, Ueda K, Schneider AC, Hughes WE, Limberg JK, Bryan NS, et al. Inorganic nitrate supplementation attenuates peripheral chemoreflex sensitivity but does not improve cardiovagal baroreflex sensitivity in older adults. Am J Physiol Heart Circ Physiol. 2018;314(1):H45–51.PubMed
173.
Pellegrino D, Shiva S, Angelone T, Gladwin MT, Tota B. Nitrite exerts potent negative inotropy in the isolated heart via eNOS-independent nitric oxide generation and cGMP-PKG pathway activation. Biochem Biophys Acta. 2009;1787(7):818–27.PubMed
174.
Cannon RO, Epstein SE. “Microvascular angina” as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol. 1988;61(15):1338–43.PubMed
175.
Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA. Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. J Am Coll Cardiol. 1995;25(4):807–14.PubMed
176.
Kanno S, Lee PC, Zhang Y, Ho C, Griffith BP, Shears LL, et al. Attenuation of myocardial ischemia/reperfusion injury by superinduction of inducible nitric oxide synthase. Circulation. 2000;101(23):2742–8.PubMed
177.
Emdin M, Aimo A, Castiglione V, Vergaro G, Georgiopoulos G, Saccaro LF, et al. Targeting cyclic guanosine monophosphate to treat heart failure: JACC review topic of the week. J Am Coll Cardiol. 2020;76(15):1795–807.PubMed
178.
Raubenheimer K, Hickey D, Leveritt M, Fassett R, Ortiz de Zevallos Munoz J, Allen JD, et al. Acute effects of nitrate-rich beetroot juice on blood pressure, hemostasis and vascular inflammation markers in healthy older adults: a randomized, placebo-controlled crossover study. Nutrients. 2017;9(11):1270.PubMedPubMedCentral
179.
Mónica FZ, Bian K, Murad F. The endothelium-dependent nitric oxide-cGMP pathway. Adv Pharmacol. 2016;77:1–27.PubMed
180.
Padala SK, Lavelle MP, Sidhu MS, Cabral KP, Morrone D, Boden WE, et al. Antianginal therapy for stable ischemic heart disease: a contemporary review. J Cardiovasc Pharmacol Ther. 2017;22(6):499–510.PubMed
181.
Reddy YNV, Lewis GD, Shah SJ, LeWinter M, Semigran M, Davila-Roman VG, et al. INDIE-HFpEF (inorganic nitrite delivery to improve exercise capacity in heart failure with preserved ejection fraction): rationale and design. Circ Heart Fail. 2017;10(5): e003862.PubMedPubMedCentral
182.
Münzel T, Daiber A. Inorganic nitrite and nitrate in cardiovascular therapy: a better alternative to organic nitrates as nitric oxide donors? Vascul Pharmacol. 2018;102:1–10.PubMed
183.
Thadani U. Secondary preventive potential of nitrates in ischaemic heart disease. Eur Heart J. 1996;17(Suppl F):30–6.PubMed
184.
Steitieh D, Amin N. Angina pectoris worsened by mouthwash. Proc (Bayl Univ Med Cent). 2019;32(4):570–1.PubMed
185.
van Heerebeek L, Hamdani N, Falcão-Pires I, Leite-Moreira AF, Begieneman MPV, Bronzwaer JGF, et al. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation. 2012;126(7):830–9.PubMed
186.
Franssen C, Chen S, Unger A, Korkmaz HI, De Keulenaer GW, Tschöpe C, et al. Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction. JACC Heart Fail. 2016;4(4):312–24.PubMed
187.
Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. 2015;131(6):550–9.PubMed
188.
van Empel VPM, Mariani J, Borlaug BA, Kaye DM. Impaired myocardial oxygen availability contributes to abnormal exercise hemodynamics in heart failure with preserved ejection fraction. J Am Heart Assoc. 2014;3(6): e001293.PubMedPubMedCentral
189.
Srivaratharajah K, Coutinho T, deKemp R, Liu P, Haddad H, Stadnick E, et al. Reduced myocardial flow in heart failure patients with preserved ejection fraction. Circ Heart Fail. 2016;9(7): e002562.PubMed
190.
Lai Y-C, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, et al. SIRT3-AMP-activated protein kinase activation by nitrite and metformin improves hyperglycemia and normalizes pulmonary hypertension associated with heart failure with preserved ejection fraction. Circulation. 2016;133(8):717–31.PubMedPubMedCentral
191.
Larsen FJ, Schiffer TA, Borniquel S, Sahlin K, Ekblom B, Lundberg JO, et al. Dietary inorganic nitrate improves mitochondrial efficiency in humans. Cell Metab. 2011;13(2):149–59.PubMed
192.
Coggan AR, Leibowitz JL, Spearie CA, Kadkhodayan A, Thomas DP, Ramamurthy S, et al. Acute dietary nitrate intake improves muscle contractile function in patients with heart failure: a double-blind, placebo-controlled, randomized trial. Circ Heart Failure. 2015;8(5):914–20.PubMed
193.
Davidson KW, Barry MJ, Mangione CM, Cabana M, Caughey AB, Davis EM, et al. Screening for prediabetes and type 2 diabetes: US preventive services task force recommendation statement. JAMA. 2021;326(8):736–43.PubMed
194.
Bozkurt B, Aguilar D, Deswal A, Dunbar SB, Francis GS, Horwich T, et al. Contributory risk and management of comorbidities of hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome in chronic heart failure: a scientific statement from the american heart association. Circulation. 2016;134(23):e535–78.PubMed
195.
He S, Wang J, Zhang X, Qian X, Yan S, Wang W, et al. Long-term influence of type 2 diabetes and metabolic syndrome on all-cause and cardiovascular death, and microvascular and macrovascular complications in Chinese adults—a 30-year follow-up of the Da Qing Diabetes Study. Diabetes Res Clin Pract. 2022;191: 110048.PubMed
196.
Carter P, Gray LJ, Troughton J, Khunti K, Davies MJ. Fruit and vegetable intake and incidence of type 2 diabetes mellitus: systematic review and meta-analysis. BMJ. 2010;341: c4229.PubMedPubMedCentral
197.
Liese AD, Nichols M, Sun X, D’Agostino RB, Haffner SM. Adherence to the DASH Diet is inversely associated with incidence of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes Care. 2009;32(8):1434–6.PubMedPubMedCentral
198.
Long J, Cai Q, Steinwandel M, Hargreaves MK, Bordenstein SR, Blot WJ, et al. Association of oral microbiome with type 2 diabetes risk. J Periodontal Res. 2017;52(3):636–43.PubMedPubMedCentral
199.
Wang R-R, Xu Y-S, Ji M-M, Zhang L, Li D, Lang Q, et al. Association of the oral microbiome with the progression of impaired fasting glucose in a Chinese elderly population. J Oral Microbiol. 2019;11(1):1605789.PubMedPubMedCentral
200.
Graves DT, Corrêa JD, Silva TA. The oral microbiota is modified by systemic diseases. J Dent Res. 2019;98(2):148–56.PubMed
201.
Lundberg JO, Weitzberg E, Cole JA, Benjamin N. Nitrate, bacteria and human health. Nat Rev Microbiol. 2004;2(7):593–602.PubMed
202.
Bahadoran Z, Mirmiran P, Ghasemi A. Role of nitric oxide in insulin secretion and glucose metabolism. Trends Endocrinol Metab. 2020;31(2):118–30.PubMed
203.
Chu S, Bohlen HG. High concentration of glucose inhibits glomerular endothelial eNOS through a PKC mechanism. Am J Physiol Renal Physiol. 2004;287(3):F384–92.PubMed
204.
Cosentino F, Eto M, De Paolis P, van der Loo B, Bachschmid M, Ullrich V, et al. High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation. 2003;107(7):1017–23.PubMed
205.
Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res. 2010;106(8):1319–31.PubMedPubMedCentral
206.
Zatterale F, Longo M, Naderi J, Raciti GA, Desiderio A, Miele C, et al. Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Front Physiol. 2019;10:1607.PubMed
207.
208.
Carlström M, Larsen FJ, Nyström T, Hezel M, Borniquel S, Weitzberg E, et al. Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice. Proc Natl Acad Sci USA. 2010;107(41):17716–20.PubMedPubMedCentral
209.
Ohtake K, Ehara N, Chiba H, Nakano G, Sonoda K, Ito J, et al. Dietary nitrite reverses features of postmenopausal metabolic syndrome induced by high-fat diet and ovariectomy in mice. Am J Physiol Endocrinol Metab. 2017;312(4):E300–8.PubMed
210.
Nyström T, Ortsäter H, Huang Z, Zhang F, Larsen FJ, Weitzberg E, et al. Inorganic nitrite stimulates pancreatic islet blood flow and insulin secretion. Free Radical Biol Med. 2012;53(5):1017–23.
211.
Khalifi S, Rahimipour A, Jeddi S, Ghanbari M, Kazerouni F, Ghasemi A. Dietary nitrate improves glucose tolerance and lipid profile in an animal model of hyperglycemia. Nitric Oxide Biol Chem. 2015;44:24–30.
212.
Gheibi S, Jeddi S, Carlström M, Gholami H, Ghasemi A. Effects of long-term nitrate supplementation on carbohydrate metabolism, lipid profiles, oxidative stress, and inflammation in male obese type 2 diabetic rats. Nitric Oxide Biol Chem. 2018;75:27–41.
213.
Li T, Lu X, Sun Y, Yang X. Effects of spinach nitrate on insulin resistance, endothelial dysfunction markers and inflammation in mice with high-fat and high-fructose consumption. Food Nutr Res. 2016;60:32010.PubMed
214.
Ghasemi A, Jeddi S. Anti-obesity and anti-diabetic effects of nitrate and nitrite. Nitric Oxide Biol Chem. 2017;70:9–24.
215.
Bahadoran Z, Ghasemi A, Mirmiran P, Azizi F, Hadaegh F. Beneficial effects of inorganic nitrate/nitrite in type 2 diabetes and its complications. Nutr Metab (Lond). 2015;12:16.PubMed
216.
Gheibi S, Bakhtiarzadeh F, Jeddi S, Farrokhfall K, Zardooz H, Ghasemi A. Nitrite increases glucose-stimulated insulin secretion and islet insulin content in obese type 2 diabetic male rats. Nitric Oxide Biol Chem. 2017;64:39–51.
217.
Jiang H, Torregrossa AC, Potts A, Pierini D, Aranke M, Garg HK, et al. Dietary nitrite improves insulin signaling through GLUT4 translocation. Free Radical Biol Med. 2014;67:51–7.
218.
Roberts LD, Ashmore T, Kotwica AO, Murfitt SA, Fernandez BO, Feelisch M, et al. Inorganic nitrate promotes the browning of white adipose tissue through the nitrate-nitrite-nitric oxide pathway. Diabetes. 2015;64(2):471–84.PubMed
219.
Joshipura KJ, Muñoz-Torres FJ, Morou-Bermudez E, Patel RP. Over-the-counter mouthwash use and risk of pre-diabetes/diabetes. Nitric Oxide Biol Chem. 2017;71:14–20.
220.
Mills CE, Govoni V, Faconti L, Casagrande M-L, Morant SV, Crickmore H, et al. A randomised, factorial trial to reduce arterial stiffness independently of blood pressure: Proof of concept? The VaSera trial testing dietary nitrate and spironolactone. Br J Clin Pharmacol. 2020;86(5):891–902.PubMedPubMedCentral
221.
Shepherd AI, Gilchrist M, Winyard PG, Jones AM, Hallmann E, Kazimierczak R, et al. Effects of dietary nitrate supplementation on the oxygen cost of exercise and walking performance in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled crossover trial. Free Radical Biol Med. 2015;86:200–8.
222.
Greenway FL, Predmore BL, Flanagan DR, Giordano T, Qiu Y, Brandon A, et al. Single-dose pharmacokinetics of different oral sodium nitrite formulations in diabetes patients. Diabetes Technol Ther. 2012;14(7):552–60.PubMedPubMedCentral
223.
Gilchrist M, Winyard PG, Aizawa K, Anning C, Shore A, Benjamin N. Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes. Free Radical Biol Med. 2013;60:89–97.
224.
Pernicova I, Korbonits M. Metformin–mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10(3):143–56.PubMed
225.
Bauer PV, Duca FA, Waise TMZ, Rasmussen BA, Abraham MA, Dranse HJ, et al. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab. 2018;27(1):101–17.PubMed
226.
de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, Velásquez-Mejía EP, Carmona JA, Abad JM, et al. Metformin is associated with higher relative abundance of mucin-degrading akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care. 2017;40(1):54–62.PubMed
227.
Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528(7581):262–6.PubMedPubMedCentral
228.
Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997;336(16):1117–24.PubMed
229.
Ahluwalia A, Gladwin M, Coleman GD, Hord N, Howard G, Kim-Shapiro DB, et al. Dietary nitrate and the epidemiology of cardiovascular disease: report from a national heart, lung, and blood institute workshop. J Am Heart Assoc. 2016;5(7): e003402.PubMedPubMedCentral
230.
Bahadoran Z, Mirmiran P, Carlstrom M, Ghasemi A. Inorganic nitrate: a potential prebiotic for oral microbiota dysbiosis associated with type 2 diabetes. Nitric Oxide. 2021;116:38–46.PubMed
231.
Bilson J, Sethi JK, Byrne CD. Non-alcoholic fatty liver disease: a multi-system disease influenced by ageing and sex, and affected by adipose tissue and intestinal function. Proc Nutr Soc. 2022;81(2):146–61.PubMed
232.
Long MT, Noureddin M, Lim JK. AGA clinical practice update: diagnosis and management of nonalcoholic fatty liver disease in lean individuals: expert review. Gastroenterology. 2022;163(3):764-774.e1.PubMed
233.
Watanabe S, Hashimoto E, Ikejima K, Uto H, Ono M, Sumida Y, et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. J Gastroenterol. 2015;50(4):364–77.PubMed
234.
Cusi K, Isaacs S, Barb D, Basu R, Caprio S, Garvey WT, et al. American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the american association for the study of liver diseases (AASLD). Endocr Pract. 2022;28(5):528–62.PubMed
235.
Wang H, Hu L, Li L, Wu X, Fan Z, Zhang C, et al. Inorganic nitrate alleviates the senescence-related decline in liver function. Sci China Life Sci. 2018;61(1):24–34.PubMed
236.
Aluko EO, Omobowale TO, Oyagbemi AA, Adejumobi OA, Ajibade TO, Fasanmade AA. Reduction in nitric oxide bioavailability shifts serum lipid content towards atherogenic lipoprotein in rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2018;101:792–7.
237.
Sato I, Yamamoto S, Kakimoto M, Fujii M, Honma K, Kumazaki S, et al. Suppression of nitric oxide synthase aggravates non-alcoholic steatohepatitis and atherosclerosis in SHRSP5/Dmcr rat via acceleration of abnormal lipid metabolism. Pharmacol Rep. 2022;74(4):669–83.PubMed
238.
Eccleston HB, Andringa KK, Betancourt AM, King AL, Mantena SK, Swain TM, et al. Chronic exposure to a high-fat diet induces hepatic steatosis, impairs nitric oxide bioavailability, and modifies the mitochondrial proteome in mice. Antioxid Redox Signal. 2011;15(2):447–59.PubMedPubMedCentral
239.
Lázár Z, Mészáros M, Bikov A. The nitric oxide pathway in pulmonary arterial hypertension: pathomechanism, biomarkers and drug targets. Curr Med Chem. 2020;27(42):7168–88.PubMed
240.
Litvinova L, Atochin DN, Fattakhov N, Vasilenko M, Zatolokin P, Kirienkova E. Nitric oxide and mitochondria in metabolic syndrome. Front Physiol. 2015;6:20.PubMedPubMedCentral
241.
Abdulla MH, Johns EJ. The role of brain angiotensin II (type 2) receptors and nitric oxide in the renal sympathoinhibitory response to acute volume expansion in conscious rats. J Hypertens. 2017;35(2):338–47.PubMed
242.
Kiss JP. Role of nitric oxide in the regulation of monoaminergic neurotransmission. Brain Res Bull. 2000;52(6):459–66.PubMed
243.
Oghbaei H, Alipour MR, Hamidian G, Ahmadi M, Ghorbanzadeh V, Keyhanmanesh R. Two months sodium nitrate supplementation alleviates testicular injury in streptozotocin-induced diabetic male rats. Exp Physiol. 2018;103(12):1603–17.PubMed
244.
Keyhanmanesh R, Hamidian G, Alipour MR, Oghbaei H. Beneficial treatment effects of dietary nitrate supplementation on testicular injury in streptozotocin-induced diabetic male rats. Reprod Biomed Online. 2019;39(3):357–71.PubMed
245.
García-Jaramillo M, Beaver LM, Truong L, Axton ER, Keller RM, Prater MC, et al. Nitrate and nitrite exposure leads to mild anxiogenic-like behavior and alters brain metabolomic profile in zebrafish. PLoS ONE. 2020;15(12): e0240070.PubMedPubMedCentral
246.
Wightman EL, Haskell-Ramsay CF, Thompson KG, Blackwell JR, Winyard PG, Forster J, et al. Dietary nitrate modulates cerebral blood flow parameters and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. Physiol Behav. 2015;149:149–58.PubMed
247.
Gilchrist M, Winyard PG, Fulford J, Anning C, Shore AC, Benjamin N. Dietary nitrate supplementation improves reaction time in type 2 diabetes: development and application of a novel nitrate-depleted beetroot juice placebo. Nitric Oxide Biol Chem. 2014;40:67–74.
248.
249.
Ruiz L, Bacigalupe R, García-Carral C, Boix-Amoros A, Argüello H, Silva CB, et al. Microbiota of human precolostrum and its potential role as a source of bacteria to the infant mouth. Sci Rep. 2019;9(1):8435.PubMedPubMedCentral
250.
Gomez-Arango LF, Barrett HL, McIntyre HD, Callaway LK, Morrison M, Dekker NM. Antibiotic treatment at delivery shapes the initial oral microbiome in neonates. Sci Rep. 2017;7:43481.PubMedPubMedCentral
251.
Gentle SJ, Ahmed KA, Yi N, Morrow CD, Ambalavanan N, Lal CV, et al. Bronchopulmonary dysplasia is associated with reduced oral nitrate reductase activity in extremely preterm infants. Redox Biol. 2021;38: 101782.PubMed
252.
Ambalavanan N, Cotten CM, Page GP, Carlo WA, Murray JC, Bhattacharya S, et al. Integrated genomic analyses in bronchopulmonary dysplasia. J Pediatr. 2015;166(3):531–7.PubMed
253.
Klinger G, Sokolover N, Boyko V, Sirota L, Lerner-Geva L, Reichman B. Perinatal risk factors for bronchopulmonary dysplasia in a national cohort of very-low-birthweight infants. Am J Obstet Gynecol. 2013;208(2):115.e1-115.e9.PubMed
254.
Wagner BD, Sontag MK, Harris JK, Miller JI, Morrow L, Robertson CE, et al. Airway microbial community turnover differs by BPD severity in ventilated preterm infants. PLoS ONE. 2017;12(1): e0170120.PubMedPubMedCentral
255.
Chen S-M, Lin C-P, Jan M-S. Early gut microbiota changes in preterm infants with bronchopulmonary dysplasia: a pilot case-control study. Am J Perinatol. 2021;38(11):1142–9.PubMed
256.
Marsland BJ, Trompette A, Gollwitzer ES. The gut-lung axis in respiratory disease. Ann Am Thorac Soc. 2015;12(Suppl 2):S150–6.PubMed
257.
Kolpen M, Kragh KN, Bjarnsholt T, Line L, Hansen CR, Dalbøge CS, et al. Denitrification by cystic fibrosis pathogens—Stenotrophomonas maltophilia is dormant in sputum. Int J Med Microbiol. 2015;305(1):1–10.PubMed
258.
Kolpen M, Kühl M, Bjarnsholt T, Moser C, Hansen CR, Liengaard L, et al. Nitrous oxide production in sputum from cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection. PLoS ONE. 2014;9(1): e84353.PubMedPubMedCentral
259.
Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382(9888):260–72.PubMed
260.
Baylis C. Nitric oxide deficiency in chronic kidney disease. Am J Physiol Renal Physiol. 2008;294(1):F1–9.PubMed
261.
Tumur Z, Niwa T. Oral sorbent AST-120 increases renal NO synthesis in uremic rats. J Ren Nutr. 2008;18(1):60–4.PubMed
262.
Kuczmarski JM, Martens CR, Kim J, Lennon-Edwards SL, Edwards DG. Cardiac function is preserved following 4 weeks of voluntary wheel running in a rodent model of chronic kidney disease. J Appl Physiol (1985). 2014;117(5):482–91.PubMed
263.
Al Suleimani YM, Al Za’abi M, Ramkumar A, Al Mahruqi AS, Tageldin MH, Nemmar A, et al. Influence of treatment with gum acacia on renal vascular responses in a rat model of chronic kidney disease. Eur Rev Med Pharmacol Sci. 2015;19(3):498–506.PubMed
264.
Sindler AL, Fleenor BS, Calvert JW, Marshall KD, Zigler ML, Lefer DJ, et al. Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging. Aging Cell. 2011;10(3):429–37.PubMed
265.
Okamoto M, Tsuchiya K, Kanematsu Y, Izawa Y, Yoshizumi M, Kagawa S, et al. Nitrite-derived nitric oxide formation following ischemia-reperfusion injury in kidney. Am J Physiol Renal Physiol. 2005;288(1):F182–7.PubMed
266.
Tripatara P, Patel NSA, Webb A, Rathod K, Lecomte FMJ, Mazzon E, et al. Nitrite-derived nitric oxide protects the rat kidney against ischemia/reperfusion injury in vivo: role for xanthine oxidoreductase. J Am Soc Nephrol. 2007;18(2):570–80.PubMed
267.
Tsuchiya K, Tomita S, Ishizawa K, Abe S, Ikeda Y, Kihira Y, et al. Dietary nitrite ameliorates renal injury in L-NAME-induced hypertensive rats. Nitric Oxide Biol Chem. 2010;22(2):98–103.
268.
Tatematsu S, Wakino S, Kanda T, Homma K, Yoshioka K, Hasegawa K, et al. Role of nitric oxide-producing and -degrading pathways in coronary endothelial dysfunction in chronic kidney disease. J Am Soc Nephrol. 2007;18(3):741–9.PubMed
269.
Yang T, Zhang X-M, Tarnawski L, Peleli M, Zhuge Z, Terrando N, et al. Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress. Redox Biol. 2017;13:320–30.PubMedPubMedCentral
270.
Silva KVC, Costa BD, Gomes AC, Saunders B, Mota JF. Factors that moderate the effect of nitrate ingestion on exercise performance in adults: a systematic review with meta-analyses and meta-regressions. Adv Nutr. 2022;13:1866–81.PubMedPubMedCentral
271.
Goh CE, Bohn B, Marotz C, Molinsky R, Roy S, Paster BJ, et al. Nitrite generating and depleting capacity of the oral microbiome and cardiometabolic risk: results from ORIGINS. J Am Heart Assoc. 2022;11(10): e023038.PubMedPubMedCentral
272.
Cerdá B, Pérez M, Pérez-Santiago JD, Tornero-Aguilera JF, González-Soltero R, Larrosa M. Gut microbiota modification: another piece in the puzzle of the benefits of physical exercise in health? Front Physiol. 2016;7:51.PubMedPubMedCentral
273.
Sorrenti V, Fortinguerra S, Caudullo G, Buriani A. Deciphering the Role of polyphenols in sports performance: from nutritional genomics to the gut microbiota toward phytonutritional epigenomics. Nutrients. 2020;12(5):1265.PubMedPubMedCentral
Metadata
Title
From nitrate to NO: potential effects of nitrate-reducing bacteria on systemic health and disease
Authors
Hongyu Liu
Yisheng Huang
Mingshu Huang
Min Wang
Yue Ming
Weixing Chen
Yuanxin Chen
Zhengming Tang
Bo Jia
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01413-y

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