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Cited by 186Nitric Oxide and Endothelin EffectsOral microbiology and periodontitis researchGut microbiota and health

Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health

Open access
Koch, Carl D., Gladwin, Mark T., Freeman, Bruce A., Lundberg, Jon O., Weitzberg, Eddie, Morris, Alison·2017·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2016.12.015PMC PMC5401802
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Abstract

Abstract Recent insights into the bioactivation and signaling actions of inorganic, dietary nitrate and nitrite now suggest a critical role for the microbiome in the development of cardiac and pulmonary vascular diseases. Once thought to be the inert, end‐products of endothelial‐derived nitric oxide (NO) heme‐oxidation, nitrate and nitrite are now considered major sources of exogenous NO that exhibit enhanced vasoactive signaling activity under conditions of hypoxia and stress. The bioavailability of nitrate and nitrite depend on the enzymatic reduction of nitrate to nitrite by a unique set of bacterial nitrate reductase enzymes possessed by specific bacterial populations in the mammalian mouth and gut. The pathogenesis of pulmonary hypertension (PH), obesity, hypertension and CVD are linked to defects in NO signaling, suggesting a role for commensal oral bacteria to shape the development of PH through the formation of nitrite, NO and other bioactive nitrogen oxides. Oral supplementation with inorganic nitrate or nitrate‐containing foods exert pleiotropic, beneficial vascular effects in the setting of inflammation, endothelial dysfunction, ischemia‐reperfusion injury and in pre‐clinical models of PH, while traditional high‐nitrate dietary patterns are associated with beneficial outcomes in hypertension, obesity and CVD. These observations highlight the potential of the microbiome in the development of novel nitrate‐ and nitrite‐based therapeutics for PH, CVD and their risk factors. Graphical abstract Figure. No caption available. HighlightsThe microbiome may influence pulmonary hypertension via nitrogen oxide signaling.Oral microbiota are necessary for nitrate reduction to vasoactive nitrogen oxides.Dietary nitrate and nitrite are major sources of exogenous nitrogen oxides.Dietary nitrate in vegetables exerts pleiotropic, beneficial nitrogen oxide effects.Diet and probiotic therapy can alter beneficial nitrate and fatty acid metabolism.

Verified 2026-10-09 · 1 reference not checked yet

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Written from the paper’s full text.

TL;DR

This review argues that dietary nitrate and nitrite are bioactivated by oral and gut microbial nitrate reductases to nitrite, nitric oxide, and other bioactive nitrogen oxides that support cardiac and pulmonary vascular health. It synthesizes preclinical and clinical evidence linking this enterosalivary pathway to blood pressure, endothelial function, exercise capacity, and pulmonary hypertension, while noting that no studies directly link the microbiome, nitrate bioavailability, and PH.

Key findings

  • In the enterosalivary nitrate circulation, approximately 25% of circulating nitrate is sequestered into salivary glands and concentrated in saliva up to 20 times plasma levels; oral bacteria reduce nitrate to nitrite. Chlorhexidine mouthwash decreased oral nitrite by 90% (p<0.001), plasma nitrite by 25% (p=0.001), and increased blood pressure by 2–3.5 mmHg in proportion to decreased plasma nitrite (R2=0.56, p=0.002) in humans.
  • At least 19 studies in hypertensive, overweight, and other patient populations showed blood pressure reduction with nitrate supplementation; nitrate/nitrite prevented or reversed endothelial dysfunction in mice and in healthy, hypertensive, obese, hypercholesterolemic, and peripheral arterial disease individuals. In HFpEF, a single dose of beetroot juice (12.9 mmol nitrate) increased cardiopulmonary exercise testing performance by 14% in 17 patients, and 1 week of daily beetroot juice (6.1 mmol nitrate) improved submaximal aerobic endurance by 24%.
  • No human clinical studies have tested oral nitrate or nitrite in PH, but animal data show nitrite is a selective pulmonary vasodilator, inhibits hypoxia- and monocrotaline-induced PH in rats, and dietary nitrate prevented pulmonary vascular remodeling and right ventricular hypertrophy in wild-type and endothelial NOS-deficient mice.
  • The oral cavity contains an estimated 50–100 billion bacteria and nearly 700 identified species; high nitrate reducers include Firmicutes (Staphylococcus, Streptococcus, Veillonella) and Actinobacteria (Actinomyces). Periodontal disease, xerostomia, and gut Firmicutes:Bacteroidetes shifts are associated with inflammation and altered NO signaling, but no studies directly link oral/gut microbial community features, nitrate bioavailability, and PH development.

Methods

  • Narrative review, not a systematic review, synthesizing preclinical and clinical literature on the nitrate-nitrite-NO pathway, oral and gut microbiome, pulmonary hypertension, cardiovascular disease, diet, probiotics, and antimicrobials.
  • Discusses bacterial nitrate reductase pathways (respiratory denitrification via nar/nap, dissimilatory nitrate reduction to ammonia, assimilatory nitrate reduction), nitrate transport (NarK/NarU), and regulation by oxygen, nitrate, pH, and oral/gut oxygen gradients.
  • Reviews dietary nitrate sources and intakes: DASH-related nitrate blood pressure effects began at about 160 mg/day vegetable nitrate; DASH-compliant diets estimated 174–1222 mg/day; average U.S. intake 40–100 mg/day, Europe 30–180 mg/day, and traditional Japanese diet >1100 mg/day for a 60 kg person.

Limitations

  • Stated: there have been no human clinical studies testing oral nitrate or nitrite in PH; no studies directly link oral/gut microbial community features, nitrate bioavailability, and PH development; mechanisms of microbial nitrate reduction and contributions to enterosalivary nitrite/NO remain uncertain; identification of major nitrate-reducing bacteria varies with methodological factors.
  • Stated: safety of brief and chronic supplemental nitrate/nitrite in PH and dysfunctional NO signaling must be ascertained; carcinogenic potential of nitrite is contextual, depending on interactions with amines/amides versus plant polyphenols and ascorbate.
  • Evident from the text: the review is narrative and largely synthesizes animal/preclinical and associative human data; proposed prebiotic, probiotic, and targeted antimicrobial strategies for PH are speculative and not directly tested in PH.

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Registry

Crossref · 10.1016/j.freeradbiomed.2016.12.015

Cites

456 of 457 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    Few connections between the microbiome and vascular and cardiovascular diseases have been identified with mechanistic certainty.

    “Despite an explosion of associative studies involving the microbiome and vascular and cardiovascular diseases, few connections have been identified with mechanistic certainty[2,3].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Tang, 2013, Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk, N. Engl. J. Med. source

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    • cites [3] Koeth, 2013, Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis, Nat. Med. source

      Not checked in the free run.

  • Premisecitation

    Many patients with PH share a common link to the metabolic syndrome.

    “Despite the diversity of patients who develop PH, many share a common link to the metabolic syndrome[4,12–14].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [4] Lai, 2014, Pulmonary arterial hypertension: the clinical syndrome, Circ. Res. source

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    • cites [12] Robbins, 2009, Association of the metabolic syndrome with pulmonary venous hypertension, Chest source

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    • cites [13] Thenappan, 2011, Clinical characteristics of pulmonary hypertension in patients with heart failure and preserved ejection fraction, Circ. Heart Fail. source

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    • cites [14] Pugh, 2011, Unrecognized glucose intolerance is common in pulmonary arterial hypertension, J. Heart Lung Transplant.

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  • Premisenone given

    Oral supplementation with inorganic nitrate or nitrate-containing foods exerts pleiotropic, beneficial vascular effects in inflammation, endothelial dysfunction, ischemia-reperfusion injury and in pre-clinical models of PH.

    “Oral supplementation with inorganic nitrate or nitrate-containing foods exert pleiotropic, beneficial vascular effects in the setting of inflammation, endothelial dysfunction, ischemia-reperfusion injury and in pre-clinical models of PH”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Commensal oral bacteria may shape the development of PH through the formation of nitrite, NO and other bioactive nitrogen oxides.

    “suggesting a role for commensal oral bacteria to shape the development of PH through the formation of nitrite, NO and other bioactive nitrogen oxides.”
    Quote in the paperSubstantial claim
  • Premisenone given

    The contribution of the microbiome in the development of pulmonary hypertension (PH) is emerging as a critical mitigating factor.

    “For example, the contribution of the microbiome in the development of pulmonary hypertension (PH) is emerging as a critical mitigating factor.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 42
  • May combine two claims. 71

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Deficits in mammalian nitric oxide (NO) signaling have been linked to PH pathogenesis, as well as associated risk factors such as hypertension, obesity, reduced insulin sensitivity and CVD.

    “Deficits in mammalian nitric oxide (NO) signaling have been linked to PH pathogenesis, as well as a host of associated risk factors such as hypertension, obesity, reduced insulin sensitivity and CVD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Characterization of body site-specific microbial ecosystems has revealed a highly diverse and regional set of microbial community networks that can exert systemic effects on the host through the production of metabolites, shaping the immune response, and influencing host gene expression.

    “Characterization of body site-specific microbial ecosystems has revealed a highly diverse and regional set of microbial community networks that can exert systemic effects on the host through the production of metabolites, shaping the immune response, and influencing host gene expression[1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Takahashi, 2015, Commensal microbiota-derived signals regulate host immune system through epigenetic modifications, Inflamm. Regen. source

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  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based).

    Interpretationreasoning

    Maintenance of pulmonary and systemic vascular health in mammals in part depends on the enzymatic reduction of dietary nitrates by commensal oral bacteria to vasoactive and anti-inflammatory mediators that provide systemic NO-effects critical under conditions of hypoxemia and stress.

    “Our discussion centers on the hypothesis that maintenance of pulmonary and systemic vascular health in mammals in part depends on the enzymatic reduction of dietary nitrates by commensal oral bacteria to vasoactive and anti-inflammatory mediators that provide systemic NO-effects critical under conditions of hypoxemia and stress.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Obesity, hyperlipidemia, and systemic hypertension are common risk factors for Group I PAH as well as Group II PH and are also a feature of HIV infection.

    “For example, obesity, hyperlipidemia, and systemic hypertension are common risk factors for Group I PAH as well as Group II (secondary to left-sided heart failure or PH-heart failure with preserved ejection fraction, HFpEF)[12,15,16], and are also a feature of HIV infection[17,18].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [12] Robbins, 2009, Association of the metabolic syndrome with pulmonary venous hypertension, Chest source

      Not checked in the free run.

    • cites [15] Lai, 2016, 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 source

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    • cites [16] Burger, 2011, Comparison of body habitus in patients with pulmonary arterial hypertension enrolled in the registry to evaluate early and long-term PAH disease management with normative values from the national health and nutrition examination survey, Mayo Clin. Proc. source

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    • cites [17] Nix, 2014, Metabolic syndrome, diabetes, and cardiovascular risk in HIV, Curr. HIV/AIDS Rep. source

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    • cites [18] Jantarapakde, 2014, Prevalence of metabolic syndrome among antiretroviral-naive and antiretroviral-experienced HIV-1 infected Thai adults, AIDS Patient Care Stds. source

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    Premisenone given

    Changes in microbial populations have been linked to many non-infectious diseases, such as obesity, diabetes, and cardiovascular disease.

    “Changes in these microbial populations have been linked to many ‘non-infectious’ diseases, such as obesity, diabetes, and cardiovascular disease (CVD).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NO acts directly on smooth muscle cells via activation of soluble guanylyl cyclase leading to formation of cGMP, which promotes smooth muscle relaxation and inhibits platelet function and vascular smooth muscle cell proliferation and migration.

    “Chiefly, NO acts directly on smooth muscle cells via activation of soluble guanylyl cyclase leading to formation of the second-messenger, cyclic guanosine monophosphate (cGMP), that in turn promotes smooth muscle relaxation and inhibits both platelet function and vascular smooth muscle cell proliferation and migration[19–21].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Lundberg, 2015, Strategies to increase nitric oxide signalling in cardiovascular disease, Nat. Rev. Drug Discov. source

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    • cites [20] Moncada, 1993, The L-arginine-nitric oxide pathway, N. Engl. J. Med. source

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    • cites [21] Chatterjee, 2008, Endothelial nitric oxide (NO) and its pathophysiologic regulation, Vasc. Pharmacol. source

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    Premisecitation

    The hallmark feature of PAH and other forms of PH is reduced bioavailability of NO signaling and poor endothelial responsiveness to triggers of vasodilatation.

    “The hallmark feature of PAH and other forms of PH is reduced bioavailability of NO signaling and poor endothelial responsiveness to triggers of vasodilatation[28–34].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [28] Gaston, 1994, The biology of nitrogen oxides in the airways, Am. J. Respir. Crit. Care Med. source

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    • cites [29] Kaneko, 1998, Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension, Am. J. Respir. Crit. Care Med. source

      Not checked in the free run.

    • cites [30] Ozkan, 2001, High levels of nitric oxide in individuals with pulmonary hypertension receiving epoprostenol therapy, Lung source

      Not checked in the free run.

    • cites [31] Champion, 2002, Adenoviral gene transfer of endothelial nitric-oxide synthase (eNOS) partially restores normal pulmonary arterial pressure in eNOS-deficient mice, Proc. Natl. Acad. Sci. source

      Not checked in the free run.

    • cites [32] Hsu, 2007, Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability, Blood source

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    • cites [33] Goret, 2008, Acute administration of l-arginine restores nitric oxide-mediated relaxation in isolated pulmonary arteries from pulmonary hypertensive exercise trained rats, Eur. J. Pharmacol. source

      Not checked in the free run.

    • cites [34] Tonelli, 2013, Nitric oxide deficiency in pulmonary hypertension: pathobiology and implications for therapy, Pulm. Circ. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The majority of NO is derived from the oxidation of L-arginine by three isoforms of nitric oxide synthase (NOS) in a reaction requiring oxygen, NADPH, tetrahydrobiopterin (BH4) and other cofactors.

    “Classically, the majority of NO is derived from the oxidation of the essential amino acid, L-arginine by a set of 3 isoforms of the enzyme nitric oxide synthase (NOS) in a reaction requiring oxygen, reduced nicotinamide-adenine dinucleotide phosphate (NADPH), tetrahydrobiopterin (BH4) and other cofactors[20,22].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Moncada, 1993, The L-arginine-nitric oxide pathway, N. Engl. J. Med. source

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    • cites [22] Coggins, 2007, Nitric oxide in the pulmonary vasculature, Arterioscler., Thromb., Vasc. Biol. source

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    Premisecitation

    Inorganic nitrite demonstrates robust NO-signaling effects and contributes to basal vascular tone, blood pressure, protection from endothelial dysfunction and vascular inflammation under conditions of metabolic and inflammatory stress.

    “As with NOS-derived NO, inorganic nitrite demonstrates robust NO-signaling effects[52,53,57,59] and contributes to basal vascular tone[51,55,60,61], blood pressure[62–66], protection from endothelial dysfunction[67–71] and vascular inflammation[72] under conditions of metabolic and inflammatory stress.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [52] Gladwin, 2005, The emerging biology of the nitrite anion, Nat. Chem. Biol. source

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    • cites [53] Huang, 2005, Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control, J. Clin. Investig. source

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    • cites [57] Bueno, 2013, Nitrite signaling in pulmonary hypertension: mechanisms of bioactivation, signaling, and therapeutics, Antioxid. Redox Signal. source

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    • cites [59] Gladwin, 2006, Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation, Am. J. Physiol. Heart Circ. Physiol. source

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    • cites [51] Cosby, 2003, Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation, Nat. Med. source

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    • cites [55] Dejam, 2007, Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation, Circulation source

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    • cites [60] Gladwin, 2000, Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans, Proc. Natl. Acad. Sci. source

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    • cites [61] Lidder, 2013, Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway, Br. J. Clin. Pharmacol. source

      Not checked in the free run.

    • cites [62] Classen, 1990, Hypothesis: the effect of oral nitrite on blood pressure in the spontaneously hypertensive rat. Does dietary nitrate mitigate hypertension after conversion to nitrite?, J. Am. Coll. Nutr. source

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    • cites [63] Beier, 1995, Antihypertensive effect of oral nitrite uptake in the spontaneously hypertensive rat, Arzneimittelforschung

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    Premisecitation

    Nitrite is swallowed and can undergo downstream reactions, including formation of NO and NO-donating species following protonation to HNO2 and secondary nitrosating and nitrating species in the low pH of the stomach, or further reduction by enteric bacterial nitrite reductases.

    “Nitrite is then swallowed where it can undergo a diversity of downstream reactions, including formation of NO and NO-donating species following a) protonation to HNO2 and an array of secondary nitrosating and nitrating species in reactions facilitated by the low pH of the stomach[80,83,89–91], or b) further reduction by enteric bacterial nitrite reductases (NiRs)[74].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [80] Licht, 1986, Mechanisms for nitrite loss from the stomach, Carcinogenesis source

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    • cites [83] McKnight, 1997, Chemical synthesis of nitric oxide in the stomach from dietary nitrate in humans, Gut source

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    • cites [89] Benjamin, 1994, Stomach NO synthesis, Nature source

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    • cites [90] Lundberg, 1994, Intragastric nitric oxide production in humans: measurements in expelled air, Gut source

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    • cites [91] Fukuto, 2012, Small molecule signaling agents: the integrated chemistry and biochemistry of nitrogen oxides, oxides of carbon, dioxygen, hydrogen sulfide, and their derived species, Chem. Res. Toxicol. source

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    • cites [74] Sobko, 2005, Gastrointestinal bacteria generate nitric oxide from nitrate and nitrite, Nitric Oxide source

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    Premisecitation

    These reactions can beneficially regulate cardio-metabolic function and will be attenuated or abolished by chemical or physical destruction of the oral microbiota.

    “These reactions can beneficially regulate cardio-metabolic function and will be attenuated or abolished by chemical or physical destruction of the oral microbiota[60,75,76,97–99].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [60] Gladwin, 2000, Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans, Proc. Natl. Acad. Sci. source

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    • cites [75] Lundberg, 2004, Inorganic nitrate is a possible source for systemic generation of nitric oxide, Free Radic. Biol. Med. source

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    • cites [76] Govoni, 2008, The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash, Nitric Oxide source

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    • cites [97] Webb, 2008, Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite, Hypertension source

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    • cites [98] Hendgen-Cotta, 2012, Dietary nitrate supplementation improves revascularization in chronic ischemia, Circulation source

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    • cites [99] Woessner, 2016, A stepwise reduction in plasma and salivary nitrite with increasing strengths of mouthwash following a dietary nitrate load, Nitric Oxide source

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    Premisenone given

    These reactions and their products can instigate salutary NO signaling responses, post-translational protein modifications and altered patterns of gene expression.

    “In turn, these reactions and their products can not only instigate salutary NO signaling responses, but also post-translational protein modifications and altered patterns of gene expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Oral supplementation with either nitrite or nitrate increases circulating nitrite levels and prevents and reverses endothelial dysfunction in a dose-dependent manner in mice and in healthy, hypertensive, and obese individuals, or in those with hypercholesterolemia and peripheral arterial disease.

    “Oral supplementation with either nitrite or nitrate increases circulating nitrite levels and prevents and reverses endothelial dysfunction in a dose-dependent manner both in mice[68,69] and in healthy[70,71,97,111,112], hypertensive[113], and obese individuals[114], or in those with hypercholesterolemia[115] and peripheral arterial disease[116].”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [68] Stokes, 2009, Dietary nitrite prevents hypercholesterolemic microvascular inflammation and reverses endothelial dysfunction, Am. J. Physiol. Heart Circ. Physiol. source

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    • cites [69] Sindler, 2011, Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging, Aging Cell. source

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    • cites [70] Rodriguez-Mateos, 2015, Interactions between cocoa flavanols and inorganic nitrate: additive effects on endothelial function at achievable dietary amounts, Free Radic. Biol. Med. source

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    • cites [71] Lara, 2016, Effects of inorganic nitrate and beetroot supplementation on endothelial function: a systematic review and meta-analysis, Eur. J. Nutr. source

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    • cites [97] Webb, 2008, Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite, Hypertension source

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    • cites [111] Liu, 2013, Effects of a nitrate-rich meal on arterial stiffness and blood pressure in healthy volunteers, Nitric Oxide source

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    • cites [112] Lee, 2015, Effects of chronic dietary nitrate supplementation on the hemodynamic response to dynamic exercise, Am. J. Physiol. Regul. Integr. Comp. Physiol. source

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    • cites [113] Kapil, 2015, Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study, Hypertension source

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    Premisecitation

    In heart failure and cardiomyopathy, dietary nitrate improves left ventricular function in mice and overall cardiac contractility and exercise performance in humans.

    “Additionally, in the setting of heart failure and cardiomyopathy, dietary nitrate improves left ventricular function in mice[133] and overall cardiac contractility and exercise performance in humans[134–137]”
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    • cites [133] Rammos, 2016, Impact of dietary nitrate on age-related diastolic dysfunction, Eur. J. Heart Fail. source

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    • cites [134] Coggan, 2015, Acute dietary nitrate intake improves muscle contractile function in patients with heart failure: a, Circ. Heart Fail. source

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    • cites [135] Coggan, 2016, Dietary Nitrate and Skeletal Muscle Contractile Function in Heart Failure, Curr. Heart Fail Rep. source

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    • cites [136] Kerley, 2016, Dietary nitrate increases exercise tolerance in patients with non-ischemic, dilated cardiomyopathy-a double-blind, randomized, placebo-controlled, crossover trial, J. Heart Lung Transplant. source

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    • cites [137] Zamani, 2015, Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction, Circulation source

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  • May combine two claims.

    Premisenone given

    There have been no human clinical studies testing the effects of oral nitrate or nitrite in PH, though animal model data support a therapeutic role.

    “In terms of PH, there have been no human clinical studies testing the effects of oral nitrate or nitrite, though animal model data support a therapeutic role.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Inhaled NO induces vasodilation in PAH and is capable of reversing hypoxic pulmonary vasoconstriction.

    “Inhaled NO induces vasodilation in PAH and is capable of reversing hypoxic pulmonary vasoconstriction[139–141].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [139] Frostell, 1991, Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction, Circulation source

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    • cites [140] Pepke-Zaba, 1991, Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension, Lancet source

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    • cites [141] Totzeck, 2012, Nitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation, Circulation source

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    Premisecitation

    Nitrite administered via inhalation or infusion is a selective pulmonary vasodilator with increased activity in hypoxia.

    “Similarly, nitrite administered via inhalation or infusion is a selective pulmonary vasodilator with increased activity in hypoxia[142–144]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [142] Blood, 2011, Inhaled nitrite reverses hemolysis-induced pulmonary vasoconstriction in newborn lambs without blood participation, Circulation source

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    • cites [143] Hunter, 2004, Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator, Nat. Med. source

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    • cites [144] Ingram, 2010, Low-dose sodium nitrite vasodilates hypoxic human pulmonary vasculature by a means that is not dependent on a simultaneous elevation in plasma nitrite, Am. J. Physiol. Heart Circ. Physiol. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Relatively little is known about the identity and function of specific bacteria and their effects on nitrate metabolism.

    “Yet, despite the importance of these microbial populations, relatively little is known about the identity and function of specific bacteria and their effects on nitrate metabolism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Delivered via intravenous, inhaled, or oral routes, nitrite reduces pulmonary and right heart pressures and prevents or reverses characteristic vascular remodeling and right ventricular hypertrophy (RVH) in several animal models of PAH.

    “Delivered via intravenous, inhaled, or oral routes, nitrite reduces pulmonary and right heart pressures and prevents or reverses characteristic vascular remodeling and right ventricular hypertrophy (RVH) in several animal models of PAH[15,117,143,146–149].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [15] Lai, 2016, 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 source

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    • cites [117] Alef, 2011, Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats, J. Clin. Investig. source

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    • cites [143] Hunter, 2004, Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator, Nat. Med. source

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    • cites [146] Casey, 2009, Pulmonary vasodilator responses to sodium nitrite are mediated by an allopurinol-sensitive mechanism in the rat, Am. J. Physiol. Heart Circ. Physiol. source

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    • cites [147] Pankey, 2012, Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension, Nitric Oxide source

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    • cites [148] Dias-Junior, 2006, Low-dose intravenous nitrite improves hemodynamics in a canine model of acute pulmonary thromboembolism, Free Radic. Biol. Med. source

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    • cites [149] Horstman, 1998, Prolonged inhaled NO attenuates hypoxic, but not monocrotaline-induced, pulmonary vascular remodeling in rats, Anesth. Analg. source

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    Premisenone given

    For many years, dietary nitrate and nitrite were considered harmful for regular human consumption due to concerns about methemoglobinemia and potential carcinogenic effects.

    “For many years, dietary nitrate and nitrite were considered harmful for regular human consumption due to two prominent health concerns, the development of methemoglobinemia and the potential for carcinogenic effects.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Methemoglobinemia becomes clinically significant when baseline levels of metHgb (1-3%) rise to 5-12%, with cyanosis and fatal toxicity occurring at levels between 30-50%.

    “Methemogobinemia becomes clinically significant when baseline levels of metHgb (1–3%) rise to 5–12%, with cyanosis and fatal toxicity occurring at levels between 30–50%[153].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Cortazzo, 2014, Methemoglobinemia: a review and recommendations for management, J. Cardiothorac. Vasc. Anesth. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The toxic effects of nitrate and nitrite are driven by the more reactive nitrite after either oral reduction by the enterosalivary pathway or direct consumption.

    “Ostensibly, the toxic effects of nitrate and nitrite are driven by the more reactive nitrite after either oral reduction by the enterosalivary pathway or direct consumption.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Up to 80% of oral bacteria are dominated by about 200 species in the Phyla Firmicutes and Proteobacteria, with contributions from Bacteroidetes, Actinobacteria and Fusobacteria totaling upwards of 95% of all identified oral microbiota.

    “Up to 80% of oral bacteria are dominated by about 200 species in the Phyla Firmicutes (esp. Streptococcus, Veillonella, Granulicatella, Gemella spp.) and Proteobacteria (esp. Neisseria, Haemophilus spp.), with contributions from Bacteroidetes, Actinobacteria and Fusobacteria totaling upwards of 95% of all identified oral microbiota (Figure 2)[171–177].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [171] Dewhirst, 2010, The human oral microbiome, J. Bacteriol. source

      Not checked in the free run.

    • cites [172] Zaura, 2009, Defining the healthy “core microbiome” of oral microbial communities, BMC Microbiol. source

      Not checked in the free run.

    • cites [173] Segata, 2012, Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples, Genome Biol. source

      Not checked in the free run.

    • cites [174] Eren, 2014, Oligotyping analysis of the human oral microbiome, PNAS source

      Not checked in the free run.

    • cites [175] Bik, 2010, Bacterial diversity in the oral cavity of 10 healthy individuals, ISME J. source

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    • cites [176] Aas, 2005, Defining the normal bacterial flora of the oral cavity, J. Clin. Microbiol. source

      Not checked in the free run.

    • cites [177] Ahn, 2011, Oral microbiome profiles: 16S rRNA pyrosequencing and microarray assay comparison, PLoS One source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Culture-independent sequencing of the bacterial 16S ribosome has suggested an estimated 50-100 billion bacteria in the mouth, comprised of nearly 700 identified bacterial species.

    “Culture-independent sequencing of the bacterial 16S ribosome has suggested an estimated 50–100 billion bacteria in the mouth, comprised of nearly 700 identified bacterial species[170,171].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [170] Chen, 2010, The human oral microbiome database: a web accessible resource for investigating oral microbe taxonomic and genomic information, Database source

      Not checked in the free run.

    • cites [171] Dewhirst, 2010, The human oral microbiome, J. Bacteriol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Local variation in site-specific core microbial members speaks to heterogeneity of influences bacterial communities experience, including host factors such as age, diet, geography and oral health.

    “Local variation in site-specific “core” microbial members speaks to the heterogeneity of influences bacterial communities experience, including host factors such as age, diet, geography and oral health[180–182].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [180] McLean, 2014, Advancements toward a systems level understanding of the human oral microbiome, Front. Cell. Infect. Microbiol. source

      Not checked in the free run.

    • cites [181] Chen, 2014, Application of high-throughput sequencing in understanding human oral microbiome related with health and disease, Front. Microbiol. source

      Not checked in the free run.

    • cites [182] Kumar, 2016, From focal sepsis to periodontal medicine: a century of exploring the role of the oral microbiome in systemic disease, J. Physiol.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Saccharolytic bacteria such as Streptococcus and Lactobacillus have been associated with dental caries, while proteolytic bacteria such as Prevotella and Porphyromonas have been associated with periodontitis and halitosis.

    “For instance, saccharolytic (sugar metabolizing) bacteria such as Streptococcus and Lactobacillus have been associated with dental caries, while proteolytic (protein metabolizing) bacteria such as Prevotella and Porphyromonas have been associated with periodontitis and halitosis[183].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [183] Takahashi, 2015, Oral microbiome metabolism: from "Who Are They?" to "What Are They Doing?", J. Dental Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Further diversity exists between the varied micro-ecologies of the mouth, such as the tooth surface, gingiva, hard and soft palate, and even regionally on the tongue.

    “Further diversity exists between the varied micro-ecologies of the mouth[174,178], such as the tooth surface, gingiva, hard and soft palate, and even regionally on the tongue (Figure 2)[173,176,179].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [174] Eren, 2014, Oligotyping analysis of the human oral microbiome, PNAS source

      Not checked in the free run.

    • cites [178] Xu, 2015, Oral cavity contains distinct niches with dynamic microbial communities, Environ. Microbiol. source

      Not checked in the free run.

    • cites [173] Segata, 2012, Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples, Genome Biol. source

      Not checked in the free run.

    • cites [176] Aas, 2005, Defining the normal bacterial flora of the oral cavity, J. Clin. Microbiol. source

      Not checked in the free run.

    • cites [179] Krishnan, 2016, A practical guide to the oral microbiome and its relation to health and disease, Oral Dis.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    More recent work has linked Porphyromonas gingivalis to atherosclerosis, smoking, and several cancers.

    “while more recent work has linked Porphyromonas gingivalis to atherosclerosis[185], smoking[186], and several cancers[187].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [185] Ford, 2007, Anti-P. gingivalis response correlates with atherosclerosis, J. Dent. Res. source

      Not checked in the free run.

    • cites [186] Morris, 2013, Comparison of the respiratory microbiome in healthy nonsmokers and smokers, Am. J. Respir. Crit. Care Med. source

      Not checked in the free run.

    • cites [187] Atanasova, 2014, Looking in the Porphyromonas gingivalis cabinet of curiosities: the microbium, the host and cancer association, Mol. Oral Microbiol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An ever-growing number of specific microbial taxa have been associated with both oral and systemic diseases.

    “Amid this complexity, an ever-growing number of specific microbial taxa have been associated with both oral and systemic diseases[181,182].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [181] Chen, 2014, Application of high-throughput sequencing in understanding human oral microbiome related with health and disease, Front. Microbiol. source

      Not checked in the free run.

    • cites [182] Kumar, 2016, From focal sepsis to periodontal medicine: a century of exploring the role of the oral microbiome in systemic disease, J. Physiol.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reduction of nitrate to nitrite by molybdenum-dependent nitrate reductases is the initial and rate-limiting step in anaerobic nitrogen metabolism.

    “Reduction of nitrate to nitrite by molybdenum-dependent nitrate reductases is the initial and rate-limiting step in anaerobic nitrogen metabolism[77].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Sparacino-Watkins, 2014, Nitrate and periplasmic nitrate reductases, Chem. Soc. Rev. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nitrate reduction is classified into three major pathways: respiratory denitrification, dissimilatory nitrate reduction to ammonia (DNRA), and assimilatory nitrate reduction.

    “Broadly, nitrate reduction is classified into three major pathways (Figure 3)[77,195–197]: 1) Respiratory denitrification, catalyzed by membrane-bound nitrate reductase, nar, or periplasmic nap, is the major electrochemical respiratory pathway for bacterial energy generation under hypoxia via generation of a proton motive force, serving as a two-electron sink in the final step of ATP generation”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [77] Sparacino-Watkins, 2014, Nitrate and periplasmic nitrate reductases, Chem. Soc. Rev. source

      Not checked in the free run.

    • cites [195] Kox, 2015, The nitrogen cycle, Princ. Plant-Microbe Interact. source

      Not checked in the free run.

    • cites [196] Brittain, 1992, Bacterial nitrite-reducing enzymes, Eur. J. Biochem. source

      Not checked in the free run.

    • cites [197] Maia, 2014, How biology handles nitrite, Chem. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The nitrate-nitrite-NO pathway is affected by microbial diversity and oral pathology.

    “Indeed, even the nitrate-nitrite-NO pathway is affected by microbial diversity[190] and oral pathology[191–193].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [190] Hyde, 2014, Metagenomic analysis of nitrate-reducing bacteria in the oral cavity: implications for nitric oxide homeostasis, PLoS One source

      Not checked in the free run.

    • cites [191] Doel, 2004, Protective effect of salivary nitrate and microbial nitrate reductase activity against caries, Eur. J. Oral Sci. source

      Not checked in the free run.

    • cites [192] Schreiber, 2010, Denitrification in human dental plaque, BMC Biol. source

      Not checked in the free run.

    • cites [193] Sánchez, 2014, Total salivary nitrates and nitrites in oral health and periodontal disease, Nitric Oxide source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both the oral virome and mycobiome have the potential to alter bacterial nitrate metabolism through alterations in bacterial populations and their metabolism, direct reduction of nitrate and alterations in metabolic substrate, changing local host and environmental conditions such as stimulating inflammation, and propagation of oral and systemic disease.

    “Both the oral virome and mycobiome thus have the potential to alter bacterial nitrate metabolism through alterations in bacterial populations and their metabolism, direct reduction of nitrate and alterations in metabolic substrate, changing local host and environmental conditions such as stimulating inflammation, and propagation of oral and systemic disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Multiple fungal species, including the ubiquitous Candida, contain a fungal nitrate reductase enzyme and are known nitrate-reducers in the environment.

    “Importantly, multiple fungal species, including the ubiquitous Candida, contain a fungal nitrate reductase enzyme and are known nitrate-reducers in the environment[229,230].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [229] Gorfer, 2011, Community profiling and gene expression of fungal assimilatory nitrate reductases in agricultural soil, ISME J. source

      Not checked in the free run.

    • cites [230] Shoun, 2012, Fungal denitrification and nitric oxide reductase cytochrome P450nor, Philos. Trans. R. Soc. Lond. B Biol. Sci. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Alterations in bacterial communities may be more important than changes in single bacterial species, and due consideration must be paid to functional community networks in the design and implementation of targeted therapies.

    “Thus, alterations in bacterial communities may be more important than changes in single bacterial species, and due consideration must be paid to functional community networks in the design and implementation of targeted therapies[218,219].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [218] Bashan, 2016, Universality of human microbial dynamics, Nature source

      Not checked in the free run.

    • cites [219] Lee, 2014, Characterization of microbial associations in human oral microbiome, Biomed. Mater. Eng.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    One of the main functions of low gastric pH is to clear pathogenic bacteria before they enter the distal GI tract.

    “One of the main functions of low gastric pH is to clear pathogenic bacteria before they enter the distal GI tract.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Helicobacter pylori is linked to peptic ulcer disease, gastric cancer, as well as diabetes, autoimmune disease, chronic inflammation, CVD and endothelial dysfunction.

    “Epidemiologically, H. pylori is linked to peptic ulcer disease, gastric cancer, as well as diabetes, autoimmune disease, chronic inflammation, CVD and endothelial dysfunction[240–245].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [240] Wang, 2015, Association of Helicobacter pyloriinfection with chronic obstructive pulmonary disease and chronic bronchitis: a meta-analysis of 16 studies, Infect. Dis. source

      Not checked in the free run.

    • cites [241] Franceschi, 2014, Helicobacter pyloriand extragastric diseases, Helicobacter source

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    • cites [242] Gobert, 2016, The immune Battle against helicobacter pylori infection: NO offense, Trends Microbiol. source

      Not checked in the free run.

    • cites [243] J. Danesh, Coronary Heart Disease, Helicobacter Pylori, Dental Disease, Chlamydia Pneumoniae, and Cytome Galovirus: Meta-Analyses of Prospective Studies, 138, 1999, pp. S434 S437. 〈http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=10539843&retmode=ref&cmd=prlinks〉. source

      Not checked in the free run.

    • cites [244] Tabata, 2016, Helicobacter pylori-seropositivity along with pro-inflammatory interleukin-1 polymorphisms correlated with myocardial infarction, Ctrsc

      Not checked in the free run.

    • cites [245] Grabczewska, 2006, Endothelial function parameters in patients with unstable angina and infection with Helicobacter pylori and Chlamydia pneumoniae, Eur. J. Intern. Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    This may relate to the paradoxical association between nitrate-reducing oral bacteria and protection from dental caries.

    “This may relate to the paradoxical association between nitrate-reducing oral bacteria and protection from dental caries[191,205,232,238,239].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [191] Doel, 2004, Protective effect of salivary nitrate and microbial nitrate reductase activity against caries, Eur. J. Oral Sci. source

      Not checked in the free run.

    • cites [205] Koopman, 2016, Nitrate and the origin of saliva influence composition and short chain fatty acid production of oral microcosms, Micro. Ecol. source

      Not checked in the free run.

    • cites [232] Silva Mendez, 1999, Antimicrobial effect of acidified nitrite on cariogenic bacteria, Oral Microbiol. Immunol. source

      Not checked in the free run.

    • cites [238] Nascimento, 2009, Correlations of oral bacterial arginine and urea catabolism with caries experience, Oral Microbiol. Immunol. source

      Not checked in the free run.

    • cites [239] Li, 2007, Salivary nitrate--an ecological factor in reducing oral acidity, Oral Microbiol. Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite can exert pH-dependent antimicrobial effects via formation of reactive secondary nitrogen oxides that can disrupt aerobic respiration, inhibit bacterial acid production, and disrupt biofilm formation.

    “Nitrite can exert pH-dependent antimicrobial effects[204,232,233] via formation of reactive secondary nitrogen oxides that can disrupt aerobic respiration[234], inhibit bacterial acid production, and disrupt biofilm formation[235–237].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [204] Hyde, 2014, Characterization of the rat oral microbiome and the effects of dietary nitrate, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [232] Silva Mendez, 1999, Antimicrobial effect of acidified nitrite on cariogenic bacteria, Oral Microbiol. Immunol. source

      Not checked in the free run.

    • cites [233] Tiso, 2015, Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions, PLoS One source

      Not checked in the free run.

    • cites [234] Rowe, 1979, Nitrite inhibition of aerobic bacteria, Curr. Microbiol. source

      Not checked in the free run.

    • cites [235] Schlag, 2007, Inhibition of staphylococcal biofilm formation by nitrite, J. Bacteriol. source

      Not checked in the free run.

    • cites [236] Zemke, 2014, Nitrite modulates bacterial antibiotic susceptibility and biofilm formation in association with airway epithelial cells, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [237] Arora, 2015, Nitric oxide regulation of bacterial biofilms, Biochemistry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A growing body of evidence has linked acid-reducing medications such as proton pump inhibitors and histamine H2 antagonists with increased risk of enteric infections such as clostridium difficile and profound alterations.

    “Supporting the importance of such mechanisms, a growing body of evidence has linked acid-reducing medications such as proton pump inhibitors and histamine H2 antagonists, with increased risk of enteric infections such as clostridium difficile[248–250] and profound alterations”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [248] McDonald, 2015, Continuous proton pump inhibitor therapy and the associated risk of recurrent Clostridium difficile infection, JAMA Intern. Med. source

      Not checked in the free run.

    • cites [249] Leonard, 2007, Systematic review of the risk of enteric infection in patients taking acid suppression, Am. J. Gastroenterol. source

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    • cites [250] Janarthanan, 2012, Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis, Am. J. Gastroenterol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    H. pylori can alter stomach pH via expression of urease that allows for the formation of both ammonia and bicarbonate from urea, thus reducing the acidity of the stomach and potentially reducing the nascent pH-dependent formation of NO from salivary nitrite.

    “Second, H. pylori can alter stomach pH via expression of urease that allows for the formation of both ammonia and bicarbonate from urea, thus reducing the acidity of the stomach and potentially reducing the nascent pH-dependent formation of NO from salivary nitrite[242,246,247].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [242] Gobert, 2016, The immune Battle against helicobacter pylori infection: NO offense, Trends Microbiol. source

      Not checked in the free run.

    • cites [246] Briskey, 2016, Microbiota and the nitrogen cycle: Implications in the development and progression of CVD and CKD, Nitric Oxide source

      Not checked in the free run.

    • cites [247] Kuwahara, 2000, Helicobacter pylori urease suppresses bactericidal activity of peroxynitrite via carbon dioxide production, Infect. Immun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Facultative anaerobes preferentially use aerobic respiration but can use anaerobic fermentation for growth in anoxic or low-oxygen environments, a mechanism dominated by the respiratory nitrate reductive pathway.

    “From the standpoint of energetics, facultative anaerobes prefer aerobic respiration, although they maintain the capacity to use anaerobic fermentation for growth in anoxic or low oxygen environments, a mechanism dominated by the respiratory nitrate reductive pathway[77].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Sparacino-Watkins, 2014, Nitrate and periplasmic nitrate reductases, Chem. Soc. Rev. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The respiratory nitrate reductase nar expresses two major operons, NarGHI and NarZYW.

    “For instance, the respiratory nitrate reductase, nar, expresses two major operons, NarGHI and NarZYW[77,256].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [77] Sparacino-Watkins, 2014, Nitrate and periplasmic nitrate reductases, Chem. Soc. Rev. source

      Not checked in the free run.

    • cites [256] Hille, 2014, The mononuclear molybdenum enzymes, Chem. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NarZYW is constitutively expressed at low levels in the aerobic setting and only up-regulated in response to high nitrate concentrations, likely aiding in the transition from aerobic to anaerobic respiration.

    “Conversely, NarZYW is constitutively expressed at low levels in the aerobic setting and only up-regulated in response to high nitrate concentrations, likely aiding in the transition from aerobic to anaerobic respiration [256,259,260].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [256] Hille, 2014, The mononuclear molybdenum enzymes, Chem. Rev. source

      Not checked in the free run.

    • cites [259] Constantinidou, 2006, A reassessment of the FNR regulon and transcriptomic analysis of the effects of nitrate, nitrite, NarXL, and NarQP as Escherichia coli K12 adapts from aerobic to anaerobic growth, J. Biol. Chem. source

      Not checked in the free run.

    • cites [260] Dong, 2012, two-component system regulates nitrate and nitrite respiration in Shewanella oneidensis, PLoS One source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The DNRA nitrate reductase nap shares some regulatory elements with nar such as the oxygen-dependent FNR.

    “Comparatively, while the DNRA nitrate reductase, nap, shares some regulatory elements with nar such as the oxygen-dependent FNR[77,256,261–264]”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [77] Sparacino-Watkins, 2014, Nitrate and periplasmic nitrate reductases, Chem. Soc. Rev. source

      Not checked in the free run.

    • cites [256] Hille, 2014, The mononuclear molybdenum enzymes, Chem. Rev. source

      Not checked in the free run.

    • cites [261] Stewart, 1994, Regulation of nitrate and nitrite reductase synthesis in enterobacteria, Antonie Van. Leeuwenhoek. source

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    • cites [262] Stewart, 1993, Nitrate regulation of anaerobic respiratory gene expression in Escherichia coli, Mol. Microbiol. source

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    • cites [263] Sears, 2000, Control of periplasmic nitrate reductase gene expression (napEDABC) from Paracoccus pantotrophus in response to oxygen and carbon substrates, Microbiology source

      Not checked in the free run.

    • cites [264] Gavira, 2002, Regulation of nap gene expression and periplasmic nitrate reductase activity in the phototrophic bacterium Rhodobacter sphaeroides DSM158, J. Bacteriol. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    nap is maximally expressed under low oxygen and low nitrate conditions, a difference suggested to possibly relate to a selective advantage over nar in the distal GI tract.

    “it is notable that nap is maximally expressed under low oxygen and low nitrate conditions, a difference suggested to possibly relate to a selective advantage over nar in the distal GI tract[77,265].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [77] Sparacino-Watkins, 2014, Nitrate and periplasmic nitrate reductases, Chem. Soc. Rev. source

      Not checked in the free run.

    • cites [265] Potter, 1999, Competition between Escherichia coli strains expressing either a periplasmic or a membrane-bound nitrate reductase: does Nap confer a selective advantage during …, Biochem J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NarGHI is highly oxygen-responsive, under primary transcriptional control via the oxygen sensor FNR, and appears to be the major contributor to respiratory anaerobic activity.

    “The first, NarGHI, is highly oxygen-responsive, under primary transcriptional control via the oxygen sensor fumarate nitrate reductase regulator (FNR), and appears to be the major contributor to respiratory anaerobic activity[256–258].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [256] Hille, 2014, The mononuclear molybdenum enzymes, Chem. Rev. source

      Not checked in the free run.

    • cites [257] Rabin, 1992, In vivo requirement of integration host factor for nar (nitrate reductase) operon expression in Escherichia coli K-12, Proc. Natl. Acad. Sci. source

      Not checked in the free run.

    • cites [258] Noriega, 2010, Asymmetric cross-regulation between the nitrate-responsive NarX-NarL and NarQ-NarP two-component regulatory systems from Escherichia coli K-12, Mol. Microbiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the gut, longitudinally, oxygen concentrations generally fall, with the highest pO2 in the proximal gut including the gastric fundus (77 mmHg; ~10%) and small bowel (30-45 mmHg, ~4-6%), and declining through the colon to concentrations of less than 3 mmHg in the sigmoid colon and rectum.

    “Longitudinally, oxygen concentrations generally fall, with the highest pO2 in the proximal gut including the gastric fundus (77mmHg; ~10%) and small bowel (30–45mmHg, ~4–6%), and declining through the colon to concentrations of less than 3 mmHg (ρ%) in the sigmoid colon and rectum[267].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [267] Espey, 2013, Role of oxygen gradients in shaping redox relationships between the human intestine and its microbiota, Free Radic. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In recent experiments using gut facultative anaerobes Escherichia coli and several Lactobacillus sp., there was an increase in the expression of nitrate reductase enzymes, an increase in nitrite formation, and a clear growth benefit in the setting of adequate nitrate as oxygen concentration decreases below 4%.

    “In a recent set of experiments using gut facultative anaerobes, Escherichia coli and several Lactobacillus sp., there was an increase in the expression of nitrate reductase enzymes, an increase in nitrite formation, and a clear growth benefit in the setting of adequate nitrate as oxygen concentration decreases below 4% [233].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] Tiso, 2015, Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions, PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under conditions of host stress or inflammation, selective pressures on the microbiota change, leading to increased nitrate, nitrite and reactive nitrogen oxides, reduced pH, and a hostile environment.

    “Conversely, under conditions of host stress or inflammation, selective pressures on the microbiota change, leading to increased nitrate, nitrite and reactive nitrogen oxides, reduced pH, and a hostile environment”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [271] Vermeiren, 2009, Nitric oxide production by the human intestinal microbiota by dissimilatory nitrate reduction to ammonium, J. Biomed. Biotechnol.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dysbiosis and systemic inflammation due to periodontal disease and overall oral health may impact or reverse the beneficial effects of physiological enterosalivary nitrate metabolism and promote the development of PH.

    “it is possible that dysbiosis and systemic inflammation due to periodontal disease and overall oral health may impact or reverse the beneficial effects of physiological enterosalivary nitrate metabolism and promote the development of PH.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both salivary nitrate and nitrite concentrations and gingival expression of NO-forming NOS have been found to be increased in periodontal disease, which also tend to increase with disease severity and improve with periodontal treatment.

    “Interestingly, both salivary nitrate and nitrite concentrations and gingival expression of NO-forming NOS have been found to be increased in periodontal disease, which also tend to increase with disease severity and improve with periodontal treatment[99,193,291,292].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [99] Woessner, 2016, A stepwise reduction in plasma and salivary nitrite with increasing strengths of mouthwash following a dietary nitrate load, Nitric Oxide source

      Not checked in the free run.

    • cites [193] Sánchez, 2014, Total salivary nitrates and nitrites in oral health and periodontal disease, Nitric Oxide source

      Not checked in the free run.

    • cites [291] Parwani, 2012, Salivary nitric oxide levels in inflammatory periodontal disease - a case-control and interventional study, Int J. Dent. Hyg. source

      Not checked in the free run.

    • cites [292] Wadhwa, 2013, Determination of levels of nitric oxide in smoker and nonsmoker patients with chronic periodontitis, J. Periodontal Impant Sci. source

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  • May combine two claims.

    Premisecitation

    In the setting of salivary gland dysfunction, there is a decrease in salivary nitrate concentration and corollary increase in urinary excretion, thereby reducing total body nitrate content and its enterosalivary circulation.

    “In the setting of salivary gland dysfunction, there is a decrease in salivary nitrate concentration and corollary increase in urinary excretion, thereby reducing total body nitrate content and its enterosalivary circulation[84,193,231,293].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [84] Xia, 2003, Alterations of nitrate and nitrite content in saliva, serum, and urine in patients with salivary dysfunction, J. Oral Pathol. Med. source

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    • cites [193] Sánchez, 2014, Total salivary nitrates and nitrites in oral health and periodontal disease, Nitric Oxide source

      Not checked in the free run.

    • cites [231] Lundberg, 2012, Nitrate transport in salivary glands with implications for NO homeostasis, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

    • cites [293] Xia, 2003, Destruction of parotid glands affects nitrate and nitrite metabolism, J. Dent. Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The gut harbors over 1 kg of bacterial biomass and upwards of 1000 different species.

    “Relative to the oral cavity, the gut harbors over 1kg of bacterial biomass and upwards of 1000 different species[307].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [307] Nicholson, 2005, Gut microorganisms, mammalian metabolism and personalized health care, Nat. Rev. Microbiol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ecological conditions vary immensely along both the length of the GI tract as well as in cross-section from lumen to the mucosal brush-border.

    “Ecological conditions vary immensely along both the length of the GI tract as well as in cross-section from lumen to the mucosal brush-border[173,267,308,309].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [173] Segata, 2012, Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples, Genome Biol. source

      Not checked in the free run.

    • cites [267] Espey, 2013, Role of oxygen gradients in shaping redox relationships between the human intestine and its microbiota, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [308] Maynard, 2012, Reciprocal interactions of the intestinal microbiota and immune system, Nature source

      Not checked in the free run.

    • cites [309] Yasuda, 2015, Biogeography of the intestinal mucosal and lumenal microbiome in the rhesus macaque, Cell Host Microbe source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Numerous facets of GI microbial community composition and metabolism have been associated with various disease states, including CVD, obesity, diabetes, and features of metabolic syndrome.

    “Numerous facets of GI microbial community composition and metabolism have been associated with various disease states, including CVD, obesity, diabetes, and features of metabolic syndrome[274,310–313].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [274] Turnbaugh, 2009, A core gut microbiome in obese and lean twins, Nature source

      Not checked in the free run.

    • cites [310] Serino, 2009, Intestinal microflora and metabolic diseases, Diabetes Metab. source

      Not checked in the free run.

    • cites [311] Qin, 2012, A metagenome-wide association study of gut microbiota in type 2 diabetes, Nature source

      Not checked in the free run.

    • cites [312] Serino, 2014, Far from the eyes, close to the heart: dysbiosis of gut microbiota and cardiovascular consequences, Curr. Cardiol. Rep. source

      Not checked in the free run.

    • cites [313] Le Chatelier, 2013, Richness of human gut microbiome correlates with metabolic markers, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated rates of generation of these oxidative inflammatory mediators can have direct effects on enterocytes and mucosal integrity, impair NO-dependent vascular function, reduce nitrate and nitrite absorption, and exert selective pressure on bacteria by augmenting innate anti-bacterial effects.

    “Elevated rates of generation of these oxidative inflammatory mediators can have direct effects on enterocytes and mucosal integrity, impair NO-dependent vascular function, reduce nitrate and nitrite absorption, and exert selective pressure on bacteria by augmenting innate anti-bacterial effects[204,233,321–324].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [204] Hyde, 2014, Characterization of the rat oral microbiome and the effects of dietary nitrate, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [233] Tiso, 2015, Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions, PLoS One source

      Not checked in the free run.

    • cites [321] Jädert, 2014, Preventive and therapeutic effects of nitrite supplementation in experimental inflammatory bowel disease, Redox Biol. source

      Not checked in the free run.

    • cites [322] Chokshi, 2008, The role of nitric oxide in intestinal epithelial injury and restitution in neonatal necrotizing enterocolitis, Semin. Perinatol. source

      Not checked in the free run.

    • cites [323] Scales, 2016, A tale of two sites: how inflammation can reshape the microbiomes of the gut and lungs, J. Leukoc. Biol. source

      Not checked in the free run.

    • cites [324] Petersson, 2007, Dietary nitrate increases gastric mucosal blood flow and mucosal defense, Am. J. Physiol. Gastrointest. Liver Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevations in the Firmicutes:Bacteroidetes ratio have been associated with a high-fat diet and obesity, irritable bowel syndrome, hypertension, type 1 diabetes, and HIV.

    “Elevations in the Firmicutes:Bacteroidetes ratio have been associated with a high-fat diet and obesity[274,328,329], irritable bowel syndrome[330], hypertension[331], type 1 diabetes[276], and HIV[332].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [274] Turnbaugh, 2009, A core gut microbiome in obese and lean twins, Nature source

      Not checked in the free run.

    • cites [328] Ley, 2006, Microbial ecology: human gut microbes associated with obesity, Nature source

      Not checked in the free run.

    • cites [329] Turnbaugh, 2006, An obesity-associated gut microbiome with increased capacity for energy harvest, Nature source

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    • cites [330] Kassinen, 2007, The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects, Gastroenterology source

      Not checked in the free run.

    • cites [331] Yang, 2015, Gut dysbiosis is linked to hypertension, Hypertension source

      Not checked in the free run.

    • cites [276] Wen, 2008, Innate immunity and intestinal microbiota in the development of Type 1 diabetes, Nature source

      Not checked in the free run.

    • cites [332] Salas, 2014, Microbiome in human immunodeficiency virus infection, Clin. Lab. Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Consequently, microbial diversity is reduced while local and systemic inflammation and decreased NO bioavailability persist, propagating vascular injury and the risk of developing PH.

    “Consequently, microbial diversity is reduced[325,326] while local and systemic inflammation and decreased NO bioavailability persist, propagating vascular injury and the risk of developing PH.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [325] Moilanen, 1995, Nitric oxide in inflammation and immune response, Ann. Med. source

      Not checked in the free run.

    • cites [326] Stuehr, 1989, Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide, J. Exp. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The typically low-abundance Enterobacteraceae expand in concert with inflammation and degree of dysbiosis of the Firmicutes:Bacteroidetes ratio.

    “The typically low-abundance Enterobacteraceae expand in concert with inflammation[336] and degree of dysbiosis of the Firmicutes:Bacteroidetes ratio[333,337,338].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [336] Biagi, 2010, Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians, PLoS One source

      Not checked in the free run.

    • cites [333] Winter, 2013, Host-derived nitrate boosts growth of E. coli in the inflamed gut, Science source

      Not checked in the free run.

    • cites [337] Vázquez-Torres, 2016, Nitrate, nitrite and nitric oxide reductases: from the last universal common ancestor to modern bacterial pathogens, Curr. Opin. Microbiol. source

      Not checked in the free run.

    • cites [338] Stecher, 2007, Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota, PLoS Biol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This alteration in turn can promote chronic inflammation and contribute to the impaired NO signaling and inflammation-rich intravascular environment that is a hallmark PH.

    “This alteration in turn can promote chronic inflammation and contribute to the impaired NO signaling and inflammation-rich intravascular environment that is a hallmark PH.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Commensal gut bacteria are able to directly produce NO and also modify NO production.

    “commensal gut bacteria are able to directly produce NO and also modify NO production, potentially influencing regional blood flow, mucosal integrity, microbial diversity, and effective nitrate and nitrite uptake.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [217] Sobko, 2006, Generation of NO by probiotic bacteria in the gastrointestinal tract, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [233] Tiso, 2015, Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions, PLoS One source

      Not checked in the free run.

    • cites [271] Vermeiren, 2009, Nitric oxide production by the human intestinal microbiota by dissimilatory nitrate reduction to ammonium, J. Biomed. Biotechnol.

      Not checked in the free run.

    • cites [278] Sobko, 2004, Gastrointestinal nitric oxide generation in germ-free and conventional rats, Am. J. Physiol. Gastrointest. Liver Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In the setting of inflammation, excess nitrite and nitrate are formed along with reactive oxygen radicals and nitrogen oxides through NO oxidation, thereby increasing the amount of substrate available for respiratory denitrification and rapid bacterial growth.

    “Presumably, in the setting of inflammation, excess nitrite and nitrate are formed along with reactive oxygen radicals and nitrogen oxides through NO oxidation, thereby increasing the amount of substrate available for respiratory denitrification and rapid bacterial growth[323,337].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [323] Scales, 2016, A tale of two sites: how inflammation can reshape the microbiomes of the gut and lungs, J. Leukoc. Biol. source

      Not checked in the free run.

    • cites [337] Vázquez-Torres, 2016, Nitrate, nitrite and nitric oxide reductases: from the last universal common ancestor to modern bacterial pathogens, Curr. Opin. Microbiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    H2S is a biologically important thiol that shares significant overlapping signaling activity with NO, reacts with NO-derived reactive species and has been implicated in modulating the pathogenesis of several inflammatory bowel diseases.

    “H2S is a biologically important thiol that shares significant overlapping signaling activity with NO, reacts with NO-derived reactive species and has been implicated in modulating the pathogenesis of several inflammatory bowel diseases[91,343,344].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [91] Fukuto, 2012, Small molecule signaling agents: the integrated chemistry and biochemistry of nitrogen oxides, oxides of carbon, dioxygen, hydrogen sulfide, and their derived species, Chem. Res. Toxicol. source

      Not checked in the free run.

    • cites [343] Cortese-Krott, 2015, On the chemical biology of the nitrite/sulfide interaction, Nitric Oxide source

      Not checked in the free run.

    • cites [344] Singh, 2015, Hydrogen sulfide in physiology and diseases of the digestive tract, Microorganisms source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Respiratory denitrification of nitrite and NOS-derived NO likely serve beneficial roles in modifying the local microenvironment, and maintaining adequate blood flow and mucus generation.

    “From the standpoint of NO signaling and PH, respiratory denitrification of nitrite and NOS-derived NO likely serve beneficial roles in modifying the local microenvironment, and maintaining adequate blood flow and mucus generation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Increased H2S formation by SRB can promote oxidant formation, impair colonic epithelial H2S detoxification and induce cytotoxicity and disruption of intestinal barrier integrity, thereby driving local and systemic inflammation.

    “while on the other, increased H2S formation by SRB can promote oxidant formation, impair colonic epithelial H2S detoxification and induce cytotoxicity and disruption of intestinal barrier integrity, thereby driving local and systemic inflammation[344,347,352,353].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [344] Singh, 2015, Hydrogen sulfide in physiology and diseases of the digestive tract, Microorganisms source

      Not checked in the free run.

    • cites [347] Guo, 2016, Emerging roles of hydrogen sulfide in inflammatory and neoplastic colonic diseases, Front. Physiol. source

      Not checked in the free run.

    • cites [352] Arijs, 2013, Decreased mucosal sulfide detoxification capacity in patients with Crohn's disease, Inflamm. Bowel Dis. source

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    • cites [353] De Preter, 2012, Decreased mucosal sulfide detoxification is related to an impaired butyrate oxidation in ulcerative colitis, Inflamm. Bowel Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    H2S directly interfaces with nitrogen oxide reduction and the generation of intestinal NO by serving as an electron donor during nitrite reduction to NO by nitrite reductase, or by reacting with the nitrogen oxide S-nitrosothiol.

    “H2S directly interfaces with nitrogen oxide reduction and the generation of intestinal NO by serving as an electron donor during nitrite reduction to NO by nitrite reductase, or by reacting with the nitrogen oxide S-nitrosothiol[91,102,346].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [91] Fukuto, 2012, Small molecule signaling agents: the integrated chemistry and biochemistry of nitrogen oxides, oxides of carbon, dioxygen, hydrogen sulfide, and their derived species, Chem. Res. Toxicol. source

      Not checked in the free run.

    • cites [102] Vitturi, 2015, Convergence of biological nitration and nitrosation via symmetrical nitrous anhydride, Nat. Chem. Biol. source

      Not checked in the free run.

    • cites [346] Vermeiren, 2012, Sulfide- and nitrite-dependent nitric oxide production in the intestinal tract, Microb. Biotechnol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    H2S is required for both efficient nitrite reduction to NO in the gut and in NO formation from nitrite in hypoxic systemic tissues.

    “Notably, H2S is required for both efficient nitrite reduction to NO in the gut and in NO formation from nitrite in hypoxic systemic tissues[343,346].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [343] Cortese-Krott, 2015, On the chemical biology of the nitrite/sulfide interaction, Nitric Oxide source

      Not checked in the free run.

    • cites [346] Vermeiren, 2012, Sulfide- and nitrite-dependent nitric oxide production in the intestinal tract, Microb. Biotechnol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There remains conflicting evidence regarding the precise role of H2S in the gut.

    “Indeed, there remains conflicting evidence regarding the precise role of H2S in the gut[344,347].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [344] Singh, 2015, Hydrogen sulfide in physiology and diseases of the digestive tract, Microorganisms source

      Not checked in the free run.

    • cites [347] Guo, 2016, Emerging roles of hydrogen sulfide in inflammatory and neoplastic colonic diseases, Front. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Major epidemiological studies have consistently identified that vegetable- and fruit-rich diets improve every major risk factor for PH and CVD, including blood pressure, ischemic stroke, ischemic heart disease, obesity, insulin resistance and diabetes, and metabolic syndrome.

    “Major epidemiological studies have consistently identified that vegetable- and fruit-rich diets improve every major risk factor for PH and CVD, including blood pressure[361,363,364], ischemic stroke[365], ischemic heart disease[366], obesity, insulin resistance and diabetes[367], and metabolic syndrome[365,366,368,369].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [361] Appel, 1997, A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group, N. Engl. J. Med. source

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    • cites [363] Rouse, 1983, Blood-pressure-lowering effect of a vegetarian diet: controlled trial in normotensive subjects, Lancet source

      Not checked in the free run.

    • cites [364] Lindahl, 1984, A vegan regimen with reduced medication in the treatment of hypertension, Br. J. Nutr. source

      Not checked in the free run.

    • cites [365] Joshipura, 1999, Fruit and vegetable intake in relation to risk of ischemic stroke, JAMA source

      Not checked in the free run.

    • cites [366] Hung, 2004, Fruit and vegetable intake and risk of major chronic disease, J. Natl. Cancer Inst. source

      Not checked in the free run.

    • cites [367] Carter, 2010, Fruit and vegetable intake and incidence of type 2 diabetes mellitus: systematic review and meta-analysis, BMJ source

      Not checked in the free run.

    • cites [368] Wang, 2014, Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies, BMJ source

      Not checked in the free run.

    • cites [369] Joshipura, 2001, The effect of fruit and vegetable intake on risk for coronary heart disease, Ann. Intern. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Current dietary investigations have found unsaturated fatty acids such as oleic and linoleic acid and dietary nitrate to be concentrated in the traditional Mediterranean diet, a diet with beneficial effects on the development of CVD and its risk factors.

    “Current dietary investigations have found these fatty acids and dietary nitrate to be concentrated in the traditional Mediterranean diet, a diet with beneficial effects on the development of CVD and its risk factors[362,375–377].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [362] de Lorgeril, 2013, Mediterranean diet and cardiovascular disease: historical perspective and latest evidence, Curr. Atheroscler. Rep. source

      Not checked in the free run.

    • cites [375] Charles, 2014, Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [376] Martinez-Gonzalez, 2009, Mediterranean food pattern and the primary prevention of chronic disease: recent developments, Nutr. Rev. source

      Not checked in the free run.

    • cites [377] Estruch, 2013, Primary prevention of cardiovascular disease with a Mediterranean diet, N. Engl. J. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study of the high vegetable-containing, traditional Japanese diet, Sobko et al. found the average daily nitrate consumption in Japan to be >1100 mg/day for a 60 kg person, and associated with increased circulating nitrate and nitrite and with reduced blood pressure.

    “Comparing this level of consumption to a study of the high vegetable-containing, traditional Japanese diet, a population with historically low rates of cardiovascular disease, Sobko et al. found the average daily nitrate consumption in Japan to be >1100mg/day for a 60kg person, and associated with increased circulating nitrate and nitrite and with reduced blood pressure[373].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [373] Sobko, 2010, Dietary nitrate in Japanese traditional foods lowers diastolic blood pressure in healthy volunteers, Nitric Oxide source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Estimates of average daily nitrate consumption in the U.S. and Europe reach only 40-100 mg and 30-180 mg, respectively.

    “Unsurprisingly, estimates of average daily nitrate consumption in the U.S. and Europe, regions with high rates of CVD and vascular disease, reach only 40–100mg and 30–180mg, respectively[157,161,372].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [157] Rathod, 2016, A “green” diet-based approach to cardiovascular health? Is inorganic nitrate the answer?, Mol. Nutr. Food Res. source

      Not checked in the free run.

    • cites [161] Hord, 2009, Food sources of nitrates and nitrites: the physiologic context for potential health benefits, Am. J. Clin. Nutr. source

      Not checked in the free run.

    • cites [372] Gangolli, 1994, Nitrate, nitrite and N-nitroso compounds, Eur. J. Pharmacol.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Seven Countries Study found lower rates of CVD and cancer with the traditional Mediterranean diet, despite 37% of total daily energy coming from fat, versus only 11% in the traditional Japanese diet.

    “In contrast to the high-nitrate diet of Japan, the Seven Countries Study[378] found lower rates of CVD and cancer with the traditional Mediterranean diet, despite 37% of total daily energy coming from fat, versus only 11% in the traditional Japanese diet[378,379].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [378] A. Keys, Coronary Heart Disease in Seven Countries. 1970, 1997. source

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    • cites [379] Simopoulos, 2001, The Mediterranean diets: what is so special about the diet of Greece? The scientific evidence, J. Nutr. source

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  • May combine two claims.

    Premisecitation

    U.S. consumption of total polyunsaturated fatty acids and ALA are around 6-7% and 0.6-0.7% of total energy intake, respectively.

    “Comparatively, U.S. consumption of total polyunsaturated fatty acids and ALA are around 6–7% and 0.6–0.7% of total energy intake, respectively[382,383].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [382] Kris-Etherton, 2000, Polyunsaturated fatty acids in the food chain in the United States, Am. J. Clin. Nutr. source

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    • cites [383] Gebauer, 2006, n-3 fatty acid dietary recommendations and food sources to achieve essentiality and cardiovascular benefits, Am. J. Clin. Nutr. source

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  • May combine two claims.

    Premisecitation

    NO2-FAs exert pleiotropic post-translational, anti-oxidant and anti-inflammatory effects that include inhibition of vascular smooth muscle proliferation and neointima formation after injury, cardioprotection, improved endothelial function, and activation of downstream NO signaling pathways.

    “NO2-FAs exert pleiotropic post-translational, anti-oxidant and anti-inflammatory effects[105,321,385] that include inhibition of vascular smooth muscle proliferation and neointima formation after injury, cardioprotection, improved endothelial function[94,386–390], and activation of downstream NO signaling pathways[385,389,391–394].”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [94] Schopfer, 2011, Formation and signaling actions of electrophilic lipids, Chem. Rev. source

      Not checked in the free run.

    • cites [386] Nadtochiy, 2015, Nitroalkenes confer acute Cardioprot. via Aden. Nucleotide translocase

      Not checked in the free run.

    • cites [387] Cole, 2009, Nitro-fatty acid inhibition of neointima formation after endoluminal vessel injury, Circ. Res. source

      Not checked in the free run.

    • cites [388] Rudolph, 2010, Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion, Cardiovasc. Res. source

      Not checked in the free run.

    • cites [389] Kansanen, 2011, Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism, J. Biol. Chem. source

      Not checked in the free run.

    • cites [390] Kelley, 2008, Nitro-oleic acid, a novel and irreversible inhibitor of xanthine oxidoreductase, J. Biol. Chem. source

      Not checked in the free run.

    • cites [391] Kelley, 2014, Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity, Cardiovasc. Res. source

      Not checked in the free run.

    • cites [392] Khoo, 2010, Activation of vascular endothelial nitric oxide synthase and heme oxygenase-1 expression by electrophilic nitro-fatty acids, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [393] Cui, 2006, Nitrated fatty acids: Endogenous anti-inflammatory signaling mediators, J. Biol. Chem. source

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    • cites [394] Narala, 2014, The role of nitrated fatty acids and peroxisome proliferator-activated receptor gamma in modulating inflammation, Int. Immunopharmacol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    These numbers, along with the relative incidence of CVD and vascular risk factors, support the hypothesis of a possible synergistic, diet-mediated NO-effect between inorganic nitrates and unsaturated fatty acids.

    “These numbers, along with the relative incidence of CVD and vascular risk factors support the hypothesis of a possible synergistic, diet-mediated NO-effect between inorganic nitrates and unsaturated fatty acids[19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Lundberg, 2015, Strategies to increase nitric oxide signalling in cardiovascular disease, Nat. Rev. Drug Discov. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In subsequent years, there has been an explosion of work demonstrating clinical benefit of probiotics in modifying cardiovascular risk, inflammatory and infectious bowel disorders, and even ventilator-associated pneumonia.

    “In subsequent years, there has been an explosion of work demonstrating clinical benefit of probiotics in modifying cardiovascular risk, inflammatory and infectious bowel disorders, and even ventilator-associated pneumonia (reviewed in:[399,403]).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [399] Gogineni, 2013, Probiotics: history and evolution, J. Anc.

      Not checked in the free run.

    • cites [403] Ettinger, 2014, The influence of the human microbiome and probiotics on cardiovascular health, Gut Microbes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Probiotic therapy exerts a beneficial effect on dental caries, periodontitis, and pharyngitis in the oral cavity, as well as on obesity, hypertension, insulin resistance, and heart failure via the gut.

    “Given, however, that probiotic therapy exerts a beneficial effect on dental caries, periodontitis, and pharyngitis in the oral cavity[408–411], as well as on obesity, hypertension, insulin resistance, and heart failure via the gut(reviewed:[399,403])”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [408] Toiviainen, 2015, Impact of orally administered lozenges with Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB-12 on the number of salivary mutans streptococci, amount of plaque, gingival inflammation and the oral microbiome in healthy adults, Clin. Oral Investig. source

      Not checked in the free run.

    • cites [409] Romani Vestman, 2015, Oral microbiota shift after 12-week supplementation with Lactobacillus reuteri DSM 17938 and PTA 5289; a randomized control trial, PLoS One source

      Not checked in the free run.

    • cites [410] Terai, 2015, Screening of probiotic candidates in human oral bacteria for the prevention of dental disease, PLoS One source

      Not checked in the free run.

    • cites [411] Anusha, 2015, The magic of magic bugs in oral cavity: probiotics, J. Adv. Pharm. Technol. Res. source

      Not checked in the free run.

    • cites [399] Gogineni, 2013, Probiotics: history and evolution, J. Anc.

      Not checked in the free run.

    • cites [403] Ettinger, 2014, The influence of the human microbiome and probiotics on cardiovascular health, Gut Microbes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L. rhamnosus can generate and isomerize cLA and exert anti-obesity effects in diet-induced obese mice in a cLA-dependent manner.

    “to generate and isomerize cLA and exert anti-obesity effects in diet-induced obese mice in a cLA-dependent manner[279,403,415,416]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [279] Kishino, 2013, Polyunsaturated fatty acid saturation by gut lactic acid bacteria affecting host lipid composition, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

    • cites [403] Ettinger, 2014, The influence of the human microbiome and probiotics on cardiovascular health, Gut Microbes source

      Not checked in the free run.

    • cites [415] Lee, 2007, Antiobesity effect of trans-10,cis-12-conjugated linoleic acid-producing Lactobacillus plantarum PL62 on diet-induced obese mice, J. Appl. Microbiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In polymicrobial environments, Lactobacilli engage in advantageous, mutualistic interactions with other bacteria to survive under hypoxia and alter NO generation.

    “In polymicrobial environments, Lactobacilli engage in advantageous, mutualistic interactions with other bacteria to survive under hypoxia and alter NO generation[217,413]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [217] Sobko, 2006, Generation of NO by probiotic bacteria in the gastrointestinal tract, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [413] Heinken, 2015, Anoxic conditions promote, Appl. Environ. Microbiol. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Members of Bifidobacterium and Lactobacillus are among the only probiotics accepted in Canada and Italy as ones with sufficient evidence to market beneficial health claims and achieve GRAS status in the U.S.

    “Indeed, members of these genera are among the only probiotics accepted in Canada and Italy as ones with sufficient evidence to market beneficial health claims[400] and achieve GRAS status (“generally recognized as safe”) in the U.S.[399]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [400] Hill, 2014, Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic, Nat. Rev. Gastroenterol. Hepatol. source

      Not checked in the free run.

    • cites [399] Gogineni, 2013, Probiotics: history and evolution, J. Anc.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lactobacilli improve inflammation associated with inflammatory bowel conditions and reduce blood pressure in pre-hypertensive and hypertensive patients.

    “as well as improve inflammation associated with inflammatory bowel conditions and reduce blood pressure in pre-hypertensive and hypertensive patients[401,403,414].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [401] McFarland, 2015, From yaks to yogurt: the history, development, and current use of probiotics, Clin. Infect. Dis. source

      Not checked in the free run.

    • cites [403] Ettinger, 2014, The influence of the human microbiome and probiotics on cardiovascular health, Gut Microbes source

      Not checked in the free run.

    • cites [414] Dong, 2013, Effect of probiotic fermented milk on blood pressure: a meta-analysis of randomised controlled trials, Br. J. Nutr. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lactobacilli are common and robust bacteria in the mouth and gut, able to tolerate low pH and to generate NO in culture.

    “At the genus level, Lactobacilli are common and robust bacteria in the mouth and gut, able to tolerate low pH and to generate NO in culture[74,412].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Sobko, 2005, Gastrointestinal bacteria generate nitric oxide from nitrate and nitrite, Nitric Oxide source

      Not checked in the free run.

    • cites [412] Edlund, 2015, Meta-omics uncover temporal regulation of pathways across oral microbiome genera during in vitro sugar metabolism, ISME J. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The U.S. Food and Drug Administration has banned the public sale of certain antibacterial soaps.

    “the U.S. Food and Drug Administration has now banned the public sale of certain antibacterial soaps[423].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [423] O.O.T. Commissioner, Press Announcements - FDA Issues Final Rule on Safety and Effectiveness of Antibacterial Soaps. 〈http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm517478.htm〉, 2016. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L. rhamnosus mediates physiological effects in the mouth and has good adherence to saliva-coated surfaces.

    “Functionally, L. rhamnosus mediates physiological effects in the mouth and has good adherence to saliva-coated surfaces[408,417].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [408] Toiviainen, 2015, Impact of orally administered lozenges with Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB-12 on the number of salivary mutans streptococci, amount of plaque, gingival inflammation and the oral microbiome in healthy adults, Clin. Oral Investig. source

      Not checked in the free run.

    • cites [417] Meurman, 2009, Effect of amine fluoride-stannous fluoride preparations on oral yeasts in the elderly: a randomised placebo-controlled trial, Gerodontology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Overuse and antibiotic resistance have proliferated.

    “Overuse and antibiotic resistance have proliferated[422]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [422] Neu, 1992, The crisis in antibiotic resistance, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L. rhamnosus has been linked to weight reduction, prevention of ischemia-reperfusion injury, and attenuation of cardiac hypertrophy and post-infarction heart failure in rodents.

    “It has also been linked to weight reduction, prevention of ischemia-reperfusion injury, and attenuation of cardiac hypertrophy and post-infarction heart failure in rodents[403,418,419]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [403] Ettinger, 2014, The influence of the human microbiome and probiotics on cardiovascular health, Gut Microbes source

      Not checked in the free run.

    • cites [418] Gan, 2014, Probiotic administration attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat, Circ. Heart Fail. source

      Not checked in the free run.

    • cites [419] Zhao, 2012, Carboxy terminus of heat shock protein (HSP) 70-interacting protein (CHIP) inhibits HSP70 in the heart, J. Physiol. Biochem. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Antibiotics are blunt tools of mass microbial destruction that can permanently alter the microbiome and predispose to diseases such as obesity and diabetes.

    “In current use, antibiotics are blunt tools of mass microbial destruction that can permanently alter the microbiome and predispose to numerous diseases such as obesity and diabetes[421].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [421] Blaser, 2016, Antibiotic use and its consequences for the normal microbiome, Science source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Low levels of common antibiotics contaminate groundwater and soil and can disrupt bacterial denitrification.

    “Recent ecological findings show that even low levels of common antibiotics contaminate groundwater and soil and can disrupt bacterial denitrification[424–426]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [424] DeVries, 2015, The effect of ultralow-dose antibiotics exposure on soil nitrate and N2O flux, Sci. Rep. source

      Not checked in the free run.

    • cites [425] Yan, 2013, The effect of environmental and therapeutic concentrations of antibiotics on nitrate reduction rates in river sediment, Water Res. source

      Not checked in the free run.

    • cites [426] Ahmad, 2014, Inhibitory effect of veterinary antibiotics on denitrification in groundwater: a microcosm approach, Sci. World J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A Streptococcus mutans-specific peptide was developed and tested in a model of human saliva, where selective depletion of S. mutans triggered community-wide shifts in major nitrate-reducing and non-nitrate-reducing populations.

    “Recently, a Streptococcus mutans-specific peptide was developed and tested in a model of human saliva, where selective depletion of S. mutans triggered community-wide shifts in major nitrate-reducing and non-nitrate-reducing populations[439].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [439] Guo, 2015, Precision-guided antimicrobial peptide as a targeted modulator of human microbial ecology, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Seven days of chlorhexidine mouthwash significantly raises resting blood pressures in healthy volunteers.

    “After publication by Ahluwalia et al. that 7 days of chlorhexidine mouthwash significantly raises resting blood pressures in healthy volunteers[106]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] Kapil, 2013, Physiological role for nitrate-reducing oral bacteria in blood pressure control, Free Radic. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two studies have shown increased blood pressures after chlorhexidine-containing mouthwash treatment in hypertensive men on antihypertensive therapy and during exercise in healthy volunteers.

    “Two studies have since shown increased blood pressures after chlorhexidine-containing mouthwash treatment in a population of hypertensive men on antihypertensive therapy[428] and during exercise in healthy volunteers[429]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [428] Bondonno, 2015, Antibacterial mouthwash blunts oral nitrate reduction and increases blood pressure in treated hypertensive men and women, Am. J. Hypertens. source

      Not checked in the free run.

    • cites [429] McDonagh, 2015, 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. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The study of probiotics has identified specific bacterial strains and their combinations that are capable of inducing pre-clinical and clinical effects.

    “The study of probiotics has identified specific bacterial strains and their combinations that are capable of inducing pre-clinical and clinical effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    A rich fund of knowledge already exists in the form of effective PH therapies targeting NO signaling and ongoing clinical testing of inhaled and oral formulations of inorganic nitrate and nitrite, as well as synthetic nitro-fatty acids.

    “Despite these complexities, a rich fund of knowledge already exists in the form of effective PH therapies targeting NO signaling and ongoing clinical testing of inhaled and oral formulations of inorganic nitrate and nitrite, as well as synthetic nitro-fatty acids.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Augmentation of key bacteria or bacterial functions may improve efficacy of therapies with fewer side effects.

    “and augmentation of key bacteria or bacterial functions may improve efficacy of therapies with fewer side effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    The breadth of signaling responses instigated by nitrate, nitrite, NO and downstream products of nitrogen oxide reactions uniquely exists at the nexus of NO biology and the human-microbe interface.

    “The breadth of signaling responses instigated by nitrate, nitrite, NO and downstream products of nitrogen oxide reactions uniquely exists at the nexus of NO biology and the human-microbe interface.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Changes to resident microbiota could influence response to drug therapy.

    “but they could influence response to drug therapy”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Whether changes to resident microbiota are beneficial or harmful in PH is unknown.

    “Whether changes to resident microbiota are beneficial or harmful in PH is unknown”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The microbiome represents a novel testable and modifiable factor in PH disease pathogenesis.

    “but represent a novel testable and modifiable factor in disease pathogenesis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Relationships of the microbiome to PH have never been directly examined.
100 of 100

  • The paper relies on this without support.

    Animal model findings of nitrate/nitrite benefit in pulmonary hypertension are predictive of human pulmonary hypertension.

    “though animal model data support a therapeutic role”

  • The paper relies on this without support.

    The enterosalivary nitrate-nitrite-NO pathway operates similarly in humans and rodents.

    “Studies in Sprague-Dawley rats[78] and normal human volunteers[106] showed that depletion of oral bacterial nitrate reductases by chlorhexidine mouthwash correlated with a 90% decrease in oral nitrite levels (p<0.001) in humans”

  • The paper relies on this without support.

    The oral microbiome's nitrate-reducing capacity is critical for systemic NO bioavailability in humans.

    “These data also support the concept that an intricate and dependent relationship exists between mammals and commensal, oral, nitrate-reducing microbiota in maintaining adequate NO signaling.”

  • The paper relies on this without support.

    The vast majority of oral and GI nitrate reducers are facultative anaerobes.

    “The vast majority of oral and GI nitrate reducers are facultative anaerobes.”

  • The paper relies on this without support.

    Nitrite is the common early intermediate in all bacterial nitrate-reductive pathways.

    “Nitrite is the common early intermediate in all bacterial nitrate-reductive pathways, but it is unlikely that all three mechanisms contribute in equal amounts.”

  • The authors state this as an assumption.

    In a healthy mouth, ATP-generating respiration would predominate.

    “The logical assumption would be that in a healthy mouth, ATP-generating respiration would predominate.”

  • The paper relies on this without support.

    To date, there are no studies that directly link microbial community features of the oral and gut microbiome, nitrate bioavailability, and the development of PH.

    “To date, there are no studies that directly link microbial community features of the oral and gut microbiome, nitrate bioavailability, and the development of PH.”

  • The paper relies on this without support.

    There are no studies that directly investigate an association between the gut microbiome, nitrate, and PH.

    “There are no studies that directly investigate an association between the gut microbiome, nitrate, and PH.”

  • The paper relies on this without support.

    There is no conclusive link between dysregulated salivary flow, altered oral microbial populations, and PH.

    “While there is no conclusive link between these factors, these associations offer a potentially novel line of investigation.”

  • The paper relies on this without support.

    Relationships of the microbiome to PH have never been directly examined.

    “Relationships of the microbiome to PH have never been directly examined, but represent a novel testable and modifiable factor in disease pathogenesis.”
10 of 10

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The enterosalivary cycle represents a critical regulatory step that may become less efficient with age.

    “The enterosalivary cycle, in which approximately 25% of circulating nitrate is concentrated in saliva and converted to nitrite, represents a critical regulatory step that may become less efficient with age [17,231].”

    From Dietary Nitrate-Rich Vegetables as Natural Modulators of Health: Mechanisms and Benefits in Ageing Populations (2026) · cites this paper as [231]

    The section on the nitrate-nitrite-NO pathway states that approximately 25% of circulating nitrate is concentrated in saliva and reduced to nitrite. The section on the physiological importance of microbial nitrate reduction describes the pathway’s contribution to nitric oxide availability. Neither section establishes that the enterosalivary cycle becomes less efficient with age (page numbers unavailable). (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The balance of evidence indicates that NO3- represents a potent dietary means for reducing systemic blood pressure.

    “Although the balance of evidence indicates that NO3- represents an potent dietary means for reducing systemic BP [22], [25], [27], [40], [6]”

    From Nitrate-responsive oral microbiome modulates nitric oxide homeostasis and blood pressure in humans (2018) · cites this paper as [25]

  • Approximately 25% of circulating nitrate is concentrated in saliva and converted to nitrite.

    “approximately 25% of circulating nitrate is concentrated in saliva and converted to nitrite”

    From Dietary Nitrate-Rich Vegetables as Natural Modulators of Health: Mechanisms and Benefits in Ageing Populations (2026) · cites this paper as [231]

  • Dysfunction of nitric oxide signaling is associated with pulmonary hypertension, obesity, and cardiovascular disease.

    “Dysfunction of nitric oxide signaling is associated with pulmonary hypertension, obesity, and cardiovascular disease.171”

    From The oral microbiome: Role of key organisms and complex networks in oral health and disease (2021) · cites this paper as [171]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Hypertensive mouthwash study described as men-only

    Minor

    The text describes the cited study as involving hypertensive men, but the title of reference 428 says it involved both men and women.

1 of 1

Cites

2 retracted

Flagged first, then by citations

3 of the 460 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. Gilbert, 1889, Arterites infectieuses experimentales, C. R. Hebd. Des. Séances Mémoires De. La Soc. Biol., 6, 583
  2. Sun, 2016, The role of intestinal microflora and its possible mechanisms in hypertension, Lipid Cardiovasc. Res.
  3. Nadtochiy, 2015, Nitroalkenes confer acute Cardioprot. via Aden. Nucleotide translocase, 1

Cited by

Sorted by citations

Related

Authors
Koch, C. D., Gladwin, M. T., Freeman, B. A., Lundberg, J. O., Weitzberg, E., & Morris, A.
Affiliations
  • University of Pittsburgh Medical Center (US)
  • University of Pittsburgh (US)
  • Karolinska Institutet (SE)
Corresponding author
Koch, Carl D.
ORCID
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2017-04
Volume
105
Pages
48-67
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2016.12.015
PMC
PMC5401802
OpenAlex
W2563427802
Semantic Scholar
cc25eaf8a902182222770fb2a314cfc869ea60db
Cited by
186
References
460
Citations by year
2026: 18 · 2025: 17 · 2024: 24 · 2023: 23 · 2022: 27 · 2021: 19 · 2020: 20 · 2019: 20 · 2018: 9 · 2017: 9
FWCI
1.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute
  • Swedish Heart and Lung Foundation
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
dietary nitrate, nitrite, oral microbiota, gut microbiota, nitric oxide signaling, pulmonary hypertension, cardiovascular disease, hypertension, obesity, nitrate reductase, endothelial dysfunction, ischemia-reperfusion injury, inorganic nitrate supplementation, hypoxia, cardiovascular therapeutics
MeSH terms
Animals, Cardiovascular Diseases, Fatty Acids, Humans, Mouth, Nitrates, Nitric Oxide, Pulmonary Circulation, Signal Transduction, Microbiota

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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