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

In the paper

“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].”

What the sources say

• Partly supported

  The Study Patients section identifies PAH as Group I and pulmonary venous hypertension (PVH) as Group II. Table 1 in the PVH Patients section reports obesity, hypertension, and hyperlipidemia in both groups, but they were substantially more prevalent in PVH; hyperlipidemia occurred in only 17% of PAH patients. The paper describes these as observed features, not established risk factors for both groups. The separate HIV clause is attached to other citations. (LLM, conf=0.87)

  cites [12] Robbins, 2009, Association of the metabolic syndrome with pulmonary venous hypertension, Chest sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Discussion (pages not provided) identify obesity and hypertension as common comorbidities of Group II PH associated with HFpEF. They do not identify hyperlipidemia as a risk factor or establish that all three are common risk factors for Group I PAH; instead, they report a higher prevalence of obesity and hypertension in PH-HFpEF than in PAH. The HIV clause has separate citations and is not attributed to this source. (LLM, conf=0.86)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The discussion (page not provided) reports more obesity in some Group I PAH subgroups and more statin use and systemic hypertension among obese patients. It treats these comorbidities as possible, not established, PAH risk factors; it does not directly report hyperlipidemia or assess Group II PH. The HIV clause has separate citations in the citing sentence and is not attributed to this source here. (LLM, conf=0.88)

  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. sourceExperimental — accuracy not yet measured
• Supported

  The citation is attached to the claim that these conditions occur in people with HIV, not to the PAH risk-factor claim supported by the earlier citations. The Metabolic Syndrome section (page unavailable) describes abdominal obesity and dyslipidemia in HIV-associated lipodystrophy and reports hypertension alongside adverse lipid levels in HIV cohorts. It does not establish that HIV increases obesity relative to people without HIV, but the citing sentence does not make that comparison. (LLM, conf=0.86)

  cites [17] Nix, 2014, Metabolic syndrome, diabetes, and cardiovascular risk in HIV, Curr. HIV/AIDS Rep. source
• Not checked yetcites [18] Jantarapakde, 2014, Prevalence of metabolic syndrome among antiretroviral-naive and antiretroviral-experienced HIV-1 infected Thai adults, AIDS Patient Care Stds. source

In the paper

“Similarly, nitrite administered via inhalation or infusion is a selective pulmonary vasodilator with increased activity in hypoxia[142–144]”

What the sources say

• Partly supported

  The Results (page unavailable) show that inhaled nitrite reduced pulmonary vascular resistance in newborn lambs, but intravenous nitrite had minimal effect under the study’s hemolysis conditions. The Discussion (page unavailable) reports pulmonary vasodilation from intravenous nitrite during hypoxia in previous studies, while noting that it was transient and used a higher dose. The paper does not establish that either route has increased vasodilator activity in hypoxia compared with nonhypoxic conditions, or that both routes are selectively pulmonary vasodilators. (LLM, conf=0.88)

  cites [142] Blood, 2011, Inhaled nitrite reverses hemolysis-induced pulmonary vasoconstriction in newborn lambs without blood participation, Circulation sourceExperimental — accuracy not yet measured
• Not checked yetcites [143] Hunter, 2004, Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator, Nat. Med. source
• Supported

  The Abstract reports that nebulized nitrite reduced hypoxia-induced pulmonary hypertension in newborn lambs and that intravenous nitrite reduced indexes of pulmonary arterial pressure in hypoxic human volunteers, with no effect observed during normoxia. The Discussion describes nitrite as a pulmonary vasodilator whose action is potentiated by hypoxia and concludes that low-dose sodium nitrite can cause selective vasodilatation in hypoxic vasculature. (LLM, conf=0.88)

  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

In the paper

“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].”

What the sources say

• Partly supported

  The Results (page unavailable) report distinct microbial communities across oral sites, including plaque, keratinized gingiva, hard palate, and tongue dorsum. The paper does not report sampling the soft palate or comparing regions within the tongue, so those examples are not supported by this source. (LLM, conf=0.86)

  cites [174] Eren, 2014, Oligotyping analysis of the human oral microbiome, PNAS sourceExperimental — accuracy not yet measured
• Not checked yetcites [178] Xu, 2015, Oral cavity contains distinct niches with dynamic microbial communities, Environ. Microbiol. source
• Supported

  The citation to this paper is attached to the general claim that oral micro-ecologies differ, not to the later examples of soft palate or regional variation on the tongue. In Results (‘Microbial community structure indicates four distinct community types’ and ‘Comparison of microbial communities from the two tooth surface-associated sites’; page not supplied), the paper reports distinct communities across oral sites, including adjacent tooth-surface niches. (LLM, conf=0.93)

  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
• Supported

  The Results and Discussion describes distinct bacterial profiles across tooth surfaces, subgingival plaque, hard and soft palates, and different regions of the tongue. It specifically reports considerable differences between the tongue dorsum and lateral tongue surface. The paper studies subgingival plaque rather than gingival tissue itself. (LLM, conf=0.92)

  cites [176] Aas, 2005, Defining the normal bacterial flora of the oral cavity, J. Clin. Microbiol. source
• Not checked yetcites [179] Krishnan, 2016, A practical guide to the oral microbiome and its relation to health and disease, Oral Dis.

In the paper

“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].”

What the sources say

• Not checked yetcites [204] Hyde, 2014, Characterization of the rat oral microbiome and the effects of dietary nitrate, Free Radic. Biol. Med. source
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [233] Tiso, 2015, Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions, PLoS One sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Introduction discusses mucosal integrity and nitrate/nitrite absorption, while the Discussion describes epithelial injury and inflammatory defects in the microcirculation. Neither section attributes those effects to elevated generation of oxidative inflammatory mediators, or says those mediators reduce nitrate/nitrite absorption or select for bacteria. Searches for oxidative mediators, impaired absorption, and antibacterial selective pressure found no passage establishing the claimed chain of effects. (LLM, conf=0.72)

  cites [321] Jädert, 2014, Preventive and therapeutic effects of nitrite supplementation in experimental inflammatory bowel disease, Redox Biol. sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [322] Chokshi, 2008, The role of nitric oxide in intestinal epithelial injury and restitution in neonatal necrotizing enterocolitis, Semin. Perinatol. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction says inflammatory reactive nitrogen species have antimicrobial activity and can give denitrifying bacteria a selective advantage at inflamed mucosal surfaces. It does not address direct effects on enterocytes or mucosal integrity, impaired NO-dependent vascular function, or reduced nitrate and nitrite absorption. It describes bacterial selection chiefly through inflammation-derived nitrate supporting bacterial growth, rather than through augmented antibacterial effects. (LLM, conf=0.87)

  cites [323] Scales, 2016, A tale of two sites: how inflammation can reshape the microbiomes of the gut and lungs, J. Leukoc. Biol. sourceExperimental — accuracy not yet measured
• Not checked yetcites [324] Petersson, 2007, Dietary nitrate increases gastric mucosal blood flow and mucosal defense, Am. J. Physiol. Gastrointest. Liver Physiol. source

In the paper

“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.”

What the sources say

• Not checked yetcites [217] Sobko, 2006, Generation of NO by probiotic bacteria in the gastrointestinal tract, Free Radic. Biol. Med. source
• Supported

  The Abstract reports NO production by bacterial cultures, including nitrite conversion to NO by E. coli. It also describes how bacterial lactic-acid production acidifies the medium and generates NO through non-enzymatic nitrite reduction, supporting the claim that gut bacteria can both produce NO and alter its production. The Discussion (Physiological significance of NO formation by bacterial nitrate reduction; page unavailable) likewise describes NO generated by gut bacteria. (LLM, conf=0.88)

  cites [233] Tiso, 2015, Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions, PLoS One source
• Not checked yetcites [271] Vermeiren, 2009, Nitric oxide production by the human intestinal microbiota by dissimilatory nitrate reduction to ammonium, J. Biomed. Biotechnol.
• Not checked yetcites [278] Sobko, 2004, Gastrointestinal nitric oxide generation in germ-free and conventional rats, Am. J. Physiol. Gastrointest. Liver Physiol. source

In the paper

“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]”

What the sources say

• ?Could not verify

  Citation [399] is attached to the U.S. GRAS-status portion of the sentence, not the Canada-and-Italy health-claims portion. The Consensus Statements table (p. 6) refers to safe probiotic species and cites the FDA’s GRAS guidance, but our copy does not say that members of Bifidobacterium or Lactobacillus have achieved GRAS status. Searches for those genera together with GRAS found no passage establishing that link. (LLM, conf=0.72)

  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. sourceExperimental — accuracy not yet measured
• Not checked yetcites [399] Gogineni, 2013, Probiotics: history and evolution, J. Anc.

In the paper

“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].”

What the sources say

• Not checked yetcites [74] Sobko, 2005, Gastrointestinal bacteria generate nitric oxide from nitrate and nitrite, Nitric Oxide source
• Partly supported

  The Results and discussion section, under “Multiple low pH tolerance mechanisms are active in Lactobacillus” (page not provided), describes lactobacilli in oral plaque and reports their acid resistance and activity at low pH, including in vitro. Our copy does not establish that they are common in the gut or that they generate nitric oxide (NO) in culture. (LLM, conf=0.88)

  cites [412] Edlund, 2015, Meta-omics uncover temporal regulation of pathways across oral microbiome genera during in vitro sugar metabolism, ISME J. sourceExperimental — accuracy not yet measured

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [1] Takahashi, 2015, Commensal microbiota-derived signals regulate host immune system through epigenetic modifications, Inflamm. Regen. source

In the paper

“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.”

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [19] Lundberg, 2015, Strategies to increase nitric oxide signalling in cardiovascular disease, Nat. Rev. Drug Discov. source
• Not checked yetcites [20] Moncada, 1993, The L-arginine-nitric oxide pathway, N. Engl. J. Med. source
• Not checked yetcites [21] Chatterjee, 2008, Endothelial nitric oxide (NO) and its pathophysiologic regulation, Vasc. Pharmacol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [28] Gaston, 1994, The biology of nitrogen oxides in the airways, Am. J. Respir. Crit. Care Med. source
• Not checked yetcites [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 yetcites [30] Ozkan, 2001, High levels of nitric oxide in individuals with pulmonary hypertension receiving epoprostenol therapy, Lung source
• Not checked yetcites [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 yetcites [32] Hsu, 2007, Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability, Blood source
• Not checked yetcites [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 yetcites [34] Tonelli, 2013, Nitric oxide deficiency in pulmonary hypertension: pathobiology and implications for therapy, Pulm. Circ. source

In the paper

“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].”

What the sources say

• Not checked yetcites [20] Moncada, 1993, The L-arginine-nitric oxide pathway, N. Engl. J. Med. source
• Not checked yetcites [22] Coggins, 2007, Nitric oxide in the pulmonary vasculature, Arterioscler., Thromb., Vasc. Biol. source

In the paper

“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.”

What the sources say

• Not checked yetcites [52] Gladwin, 2005, The emerging biology of the nitrite anion, Nat. Chem. Biol. source
• Not checked yetcites [53] Huang, 2005, Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control, J. Clin. Investig. source
• Not checked yetcites [57] Bueno, 2013, Nitrite signaling in pulmonary hypertension: mechanisms of bioactivation, signaling, and therapeutics, Antioxid. Redox Signal. source
• Not checked yetcites [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
• Not checked yetcites [51] Cosby, 2003, Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation, Nat. Med. source
• Not checked yetcites [55] Dejam, 2007, Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation, Circulation source
• Not checked yetcites [60] Gladwin, 2000, Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans, Proc. Natl. Acad. Sci. source
• Not checked yetcites [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 yetcites [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
• Not checked yetcites [63] Beier, 1995, Antihypertensive effect of oral nitrite uptake in the spontaneously hypertensive rat, Arzneimittelforschung

In the paper

“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].”

What the sources say

• Not checked yetcites [80] Licht, 1986, Mechanisms for nitrite loss from the stomach, Carcinogenesis source
• Not checked yetcites [83] McKnight, 1997, Chemical synthesis of nitric oxide in the stomach from dietary nitrate in humans, Gut source
• Not checked yetcites [89] Benjamin, 1994, Stomach NO synthesis, Nature source
• Not checked yetcites [90] Lundberg, 1994, Intragastric nitric oxide production in humans: measurements in expelled air, Gut source
• Not checked yetcites [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 yetcites [74] Sobko, 2005, Gastrointestinal bacteria generate nitric oxide from nitrate and nitrite, Nitric Oxide source

In the paper

“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].”

What the sources say

• Not checked yetcites [60] Gladwin, 2000, Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans, Proc. Natl. Acad. Sci. source
• Not checked yetcites [75] Lundberg, 2004, Inorganic nitrate is a possible source for systemic generation of nitric oxide, Free Radic. Biol. Med. source
• Not checked yetcites [76] Govoni, 2008, The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash, Nitric Oxide source
• Not checked yetcites [97] Webb, 2008, Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite, Hypertension source
• Not checked yetcites [98] Hendgen-Cotta, 2012, Dietary nitrate supplementation improves revascularization in chronic ischemia, Circulation source
• Not checked yetcites [99] Woessner, 2016, A stepwise reduction in plasma and salivary nitrite with increasing strengths of mouthwash following a dietary nitrate load, Nitric Oxide source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [68] Stokes, 2009, Dietary nitrite prevents hypercholesterolemic microvascular inflammation and reverses endothelial dysfunction, Am. J. Physiol. Heart Circ. Physiol. source
• Not checked yetcites [69] Sindler, 2011, Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging, Aging Cell. source
• Not checked yetcites [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
• Not checked yetcites [71] Lara, 2016, Effects of inorganic nitrate and beetroot supplementation on endothelial function: a systematic review and meta-analysis, Eur. J. Nutr. source
• Not checked yetcites [97] Webb, 2008, Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite, Hypertension source
• Not checked yetcites [111] Liu, 2013, Effects of a nitrate-rich meal on arterial stiffness and blood pressure in healthy volunteers, Nitric Oxide source
• Not checked yetcites [112] Lee, 2015, Effects of chronic dietary nitrate supplementation on the hemodynamic response to dynamic exercise, Am. J. Physiol. Regul. Integr. Comp. Physiol. source
• Not checked yetcites [113] Kapil, 2015, Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study, Hypertension source

In the paper

“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]”

What the sources say

• Not checked yetcites [133] Rammos, 2016, Impact of dietary nitrate on age-related diastolic dysfunction, Eur. J. Heart Fail. source
• Not checked yetcites [134] Coggan, 2015, Acute dietary nitrate intake improves muscle contractile function in patients with heart failure: a, Circ. Heart Fail. source
• Not checked yetcites [135] Coggan, 2016, Dietary Nitrate and Skeletal Muscle Contractile Function in Heart Failure, Curr. Heart Fail Rep. source
• Not checked yetcites [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
• Not checked yetcites [137] Zamani, 2015, Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction, Circulation source

In the paper

“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.”

In the paper

“Inhaled NO induces vasodilation in PAH and is capable of reversing hypoxic pulmonary vasoconstriction[139–141].”

What the sources say

• Not checked yetcites [139] Frostell, 1991, Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction, Circulation source
• Not checked yetcites [140] Pepke-Zaba, 1991, Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension, Lancet source
• Not checked yetcites [141] Totzeck, 2012, Nitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation, Circulation source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [117] Alef, 2011, Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats, J. Clin. Investig. source
• Not checked yetcites [143] Hunter, 2004, Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator, Nat. Med. source
• Not checked yetcites [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
• Not checked yetcites [147] Pankey, 2012, Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension, Nitric Oxide source
• Not checked yetcites [148] Dias-Junior, 2006, Low-dose intravenous nitrite improves hemodynamics in a canine model of acute pulmonary thromboembolism, Free Radic. Biol. Med. source
• Not checked yetcites [149] Horstman, 1998, Prolonged inhaled NO attenuates hypoxic, but not monocrotaline-induced, pulmonary vascular remodeling in rats, Anesth. Analg. source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [153] Cortazzo, 2014, Methemoglobinemia: a review and recommendations for management, J. Cardiothorac. Vasc. Anesth. source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [171] Dewhirst, 2010, The human oral microbiome, J. Bacteriol. source
• Not checked yetcites [172] Zaura, 2009, Defining the healthy “core microbiome” of oral microbial communities, BMC Microbiol. source
• Not checked yetcites [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 yetcites [174] Eren, 2014, Oligotyping analysis of the human oral microbiome, PNAS source
• Not checked yetcites [175] Bik, 2010, Bacterial diversity in the oral cavity of 10 healthy individuals, ISME J. source
• Not checked yetcites [176] Aas, 2005, Defining the normal bacterial flora of the oral cavity, J. Clin. Microbiol. source
• Not checked yetcites [177] Ahn, 2011, Oral microbiome profiles: 16S rRNA pyrosequencing and microarray assay comparison, PLoS One source

In the paper

“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].”

What the sources say

• Not checked yetcites [170] Chen, 2010, The human oral microbiome database: a web accessible resource for investigating oral microbe taxonomic and genomic information, Database source
• Not checked yetcites [171] Dewhirst, 2010, The human oral microbiome, J. Bacteriol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [180] McLean, 2014, Advancements toward a systems level understanding of the human oral microbiome, Front. Cell. Infect. Microbiol. source
• Not checked yetcites [181] Chen, 2014, Application of high-throughput sequencing in understanding human oral microbiome related with health and disease, Front. Microbiol. source
• Not checked yetcites [182] Kumar, 2016, From focal sepsis to periodontal medicine: a century of exploring the role of the oral microbiome in systemic disease, J. Physiol.

In the paper

“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].”

What the sources say

• Not checked yetcites [183] Takahashi, 2015, Oral microbiome metabolism: from "Who Are They?" to "What Are They Doing?", J. Dental Res. source

In the paper

“while more recent work has linked Porphyromonas gingivalis to atherosclerosis[185], smoking[186], and several cancers[187].”

What the sources say

• Not checked yetcites [185] Ford, 2007, Anti-P. gingivalis response correlates with atherosclerosis, J. Dent. Res. source
• Not checked yetcites [186] Morris, 2013, Comparison of the respiratory microbiome in healthy nonsmokers and smokers, Am. J. Respir. Crit. Care Med. source
• Not checked yetcites [187] Atanasova, 2014, Looking in the Porphyromonas gingivalis cabinet of curiosities: the microbium, the host and cancer association, Mol. Oral Microbiol. source

In the paper

“Amid this complexity, an ever-growing number of specific microbial taxa have been associated with both oral and systemic diseases[181,182].”

What the sources say

• Not checked yetcites [181] Chen, 2014, Application of high-throughput sequencing in understanding human oral microbiome related with health and disease, Front. Microbiol. source
• Not checked yetcites [182] Kumar, 2016, From focal sepsis to periodontal medicine: a century of exploring the role of the oral microbiome in systemic disease, J. Physiol.

In the paper

“Reduction of nitrate to nitrite by molybdenum-dependent nitrate reductases is the initial and rate-limiting step in anaerobic nitrogen metabolism[77].”

What the sources say

• Not checked yetcites [77] Sparacino-Watkins, 2014, Nitrate and periplasmic nitrate reductases, Chem. Soc. Rev. source

In the paper

“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”

What the sources say

• Not checked yetcites [77] Sparacino-Watkins, 2014, Nitrate and periplasmic nitrate reductases, Chem. Soc. Rev. source
• Not checked yetcites [195] Kox, 2015, The nitrogen cycle, Princ. Plant-Microbe Interact. source
• Not checked yetcites [196] Brittain, 1992, Bacterial nitrite-reducing enzymes, Eur. J. Biochem. source
• Not checked yetcites [197] Maia, 2014, How biology handles nitrite, Chem. Rev. source

In the paper

“Indeed, even the nitrate-nitrite-NO pathway is affected by microbial diversity[190] and oral pathology[191–193].”

What the sources say

• Not checked yetcites [190] Hyde, 2014, Metagenomic analysis of nitrate-reducing bacteria in the oral cavity: implications for nitric oxide homeostasis, PLoS One source
• Not checked yetcites [191] Doel, 2004, Protective effect of salivary nitrate and microbial nitrate reductase activity against caries, Eur. J. Oral Sci. source
• Not checked yetcites [192] Schreiber, 2010, Denitrification in human dental plaque, BMC Biol. source
• Not checked yetcites [193] Sánchez, 2014, Total salivary nitrates and nitrites in oral health and periodontal disease, Nitric Oxide source

In the paper

“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.”

In the paper

“Importantly, multiple fungal species, including the ubiquitous Candida, contain a fungal nitrate reductase enzyme and are known nitrate-reducers in the environment[229,230].”

What the sources say

• Not checked yetcites [229] Gorfer, 2011, Community profiling and gene expression of fungal assimilatory nitrate reductases in agricultural soil, ISME J. source
• Not checked yetcites [230] Shoun, 2012, Fungal denitrification and nitric oxide reductase cytochrome P450nor, Philos. Trans. R. Soc. Lond. B Biol. Sci. source

In the paper

“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].”

What the sources say

• Not checked yetcites [218] Bashan, 2016, Universality of human microbial dynamics, Nature source
• Not checked yetcites [219] Lee, 2014, Characterization of microbial associations in human oral microbiome, Biomed. Mater. Eng.

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [241] Franceschi, 2014, Helicobacter pyloriand extragastric diseases, Helicobacter source
• Not checked yetcites [242] Gobert, 2016, The immune Battle against helicobacter pylori infection: NO offense, Trends Microbiol. source
• Not checked yetcites [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 yetcites [244] Tabata, 2016, Helicobacter pylori-seropositivity along with pro-inflammatory interleukin-1 polymorphisms correlated with myocardial infarction, Ctrsc
• Not checked yetcites [245] Grabczewska, 2006, Endothelial function parameters in patients with unstable angina and infection with Helicobacter pylori and Chlamydia pneumoniae, Eur. J. Intern. Med. source

In the paper

“This may relate to the paradoxical association between nitrate-reducing oral bacteria and protection from dental caries[191,205,232,238,239].”

What the sources say

• Not checked yetcites [191] Doel, 2004, Protective effect of salivary nitrate and microbial nitrate reductase activity against caries, Eur. J. Oral Sci. source
• Not checked yetcites [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 yetcites [232] Silva Mendez, 1999, Antimicrobial effect of acidified nitrite on cariogenic bacteria, Oral Microbiol. Immunol. source
• Not checked yetcites [238] Nascimento, 2009, Correlations of oral bacterial arginine and urea catabolism with caries experience, Oral Microbiol. Immunol. source
• Not checked yetcites [239] Li, 2007, Salivary nitrate--an ecological factor in reducing oral acidity, Oral Microbiol. Immunol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [204] Hyde, 2014, Characterization of the rat oral microbiome and the effects of dietary nitrate, Free Radic. Biol. Med. source
• Not checked yetcites [232] Silva Mendez, 1999, Antimicrobial effect of acidified nitrite on cariogenic bacteria, Oral Microbiol. Immunol. source
• Not checked yetcites [233] Tiso, 2015, Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions, PLoS One source
• Not checked yetcites [234] Rowe, 1979, Nitrite inhibition of aerobic bacteria, Curr. Microbiol. source
• Not checked yetcites [235] Schlag, 2007, Inhibition of staphylococcal biofilm formation by nitrite, J. Bacteriol. source
• Not checked yetcites [236] Zemke, 2014, Nitrite modulates bacterial antibiotic susceptibility and biofilm formation in association with airway epithelial cells, Free Radic. Biol. Med. source
• Not checked yetcites [237] Arora, 2015, Nitric oxide regulation of bacterial biofilms, Biochemistry source

In the paper

“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”

What the sources say

• Not checked yetcites [248] McDonald, 2015, Continuous proton pump inhibitor therapy and the associated risk of recurrent Clostridium difficile infection, JAMA Intern. Med. source
• Not checked yetcites [249] Leonard, 2007, Systematic review of the risk of enteric infection in patients taking acid suppression, Am. J. Gastroenterol. source
• Not checked yetcites [250] Janarthanan, 2012, Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis, Am. J. Gastroenterol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [242] Gobert, 2016, The immune Battle against helicobacter pylori infection: NO offense, Trends Microbiol. source
• Not checked yetcites [246] Briskey, 2016, Microbiota and the nitrogen cycle: Implications in the development and progression of CVD and CKD, Nitric Oxide source
• Not checked yetcites [247] Kuwahara, 2000, Helicobacter pylori urease suppresses bactericidal activity of peroxynitrite via carbon dioxide production, Infect. Immun. source

In the paper

“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].”

What the sources say

• Not checked yetcites [77] Sparacino-Watkins, 2014, Nitrate and periplasmic nitrate reductases, Chem. Soc. Rev. source

In the paper

“For instance, the respiratory nitrate reductase, nar, expresses two major operons, NarGHI and NarZYW[77,256].”

What the sources say

• Not checked yetcites [77] Sparacino-Watkins, 2014, Nitrate and periplasmic nitrate reductases, Chem. Soc. Rev. source
• Not checked yetcites [256] Hille, 2014, The mononuclear molybdenum enzymes, Chem. Rev. source

In the paper

“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].”

What the sources say

• Not checked yetcites [256] Hille, 2014, The mononuclear molybdenum enzymes, Chem. Rev. source
• Not checked yetcites [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 yetcites [260] Dong, 2012, two-component system regulates nitrate and nitrite respiration in Shewanella oneidensis, PLoS One source

In the paper

“Comparatively, while the DNRA nitrate reductase, nap, shares some regulatory elements with nar such as the oxygen-dependent FNR[77,256,261–264]”

What the sources say

• Not checked yetcites [77] Sparacino-Watkins, 2014, Nitrate and periplasmic nitrate reductases, Chem. Soc. Rev. source
• Not checked yetcites [256] Hille, 2014, The mononuclear molybdenum enzymes, Chem. Rev. source
• Not checked yetcites [261] Stewart, 1994, Regulation of nitrate and nitrite reductase synthesis in enterobacteria, Antonie Van. Leeuwenhoek. source
• Not checked yetcites [262] Stewart, 1993, Nitrate regulation of anaerobic respiratory gene expression in Escherichia coli, Mol. Microbiol. source
• Not checked yetcites [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 yetcites [264] Gavira, 2002, Regulation of nap gene expression and periplasmic nitrate reductase activity in the phototrophic bacterium Rhodobacter sphaeroides DSM158, J. Bacteriol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [77] Sparacino-Watkins, 2014, Nitrate and periplasmic nitrate reductases, Chem. Soc. Rev. source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [256] Hille, 2014, The mononuclear molybdenum enzymes, Chem. Rev. source
• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [267] Espey, 2013, Role of oxygen gradients in shaping redox relationships between the human intestine and its microbiota, Free Radic. Biol. Med. source

In the paper

“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].”

What the sources say

• Not checked yetcites [233] Tiso, 2015, Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions, PLoS One source

In the paper

“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”

What the sources say

• Not checked yetcites [271] Vermeiren, 2009, Nitric oxide production by the human intestinal microbiota by dissimilatory nitrate reduction to ammonium, J. Biomed. Biotechnol.

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [193] Sánchez, 2014, Total salivary nitrates and nitrites in oral health and periodontal disease, Nitric Oxide source
• Not checked yetcites [291] Parwani, 2012, Salivary nitric oxide levels in inflammatory periodontal disease - a case-control and interventional study, Int J. Dent. Hyg. source
• Not checked yetcites [292] Wadhwa, 2013, Determination of levels of nitric oxide in smoker and nonsmoker patients with chronic periodontitis, J. Periodontal Impant Sci. source

In the paper

“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].”

What the sources say

• Not checked yetcites [84] Xia, 2003, Alterations of nitrate and nitrite content in saliva, serum, and urine in patients with salivary dysfunction, J. Oral Pathol. Med. source
• Not checked yetcites [193] Sánchez, 2014, Total salivary nitrates and nitrites in oral health and periodontal disease, Nitric Oxide source
• Not checked yetcites [231] Lundberg, 2012, Nitrate transport in salivary glands with implications for NO homeostasis, Proc. Natl. Acad. Sci. U.S.A. source
• Not checked yetcites [293] Xia, 2003, Destruction of parotid glands affects nitrate and nitrite metabolism, J. Dent. Res. source

In the paper

“Relative to the oral cavity, the gut harbors over 1kg of bacterial biomass and upwards of 1000 different species[307].”

What the sources say

• Not checked yetcites [307] Nicholson, 2005, Gut microorganisms, mammalian metabolism and personalized health care, Nat. Rev. Microbiol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [308] Maynard, 2012, Reciprocal interactions of the intestinal microbiota and immune system, Nature source
• Not checked yetcites [309] Yasuda, 2015, Biogeography of the intestinal mucosal and lumenal microbiome in the rhesus macaque, Cell Host Microbe source

In the paper

“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].”

What the sources say

• Not checked yetcites [274] Turnbaugh, 2009, A core gut microbiome in obese and lean twins, Nature source
• Not checked yetcites [310] Serino, 2009, Intestinal microflora and metabolic diseases, Diabetes Metab. source
• Not checked yetcites [311] Qin, 2012, A metagenome-wide association study of gut microbiota in type 2 diabetes, Nature source
• Not checked yetcites [312] Serino, 2014, Far from the eyes, close to the heart: dysbiosis of gut microbiota and cardiovascular consequences, Curr. Cardiol. Rep. source
• Not checked yetcites [313] Le Chatelier, 2013, Richness of human gut microbiome correlates with metabolic markers, Nature source

In the paper

“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].”

What the sources say

• Not checked yetcites [274] Turnbaugh, 2009, A core gut microbiome in obese and lean twins, Nature source
• Not checked yetcites [328] Ley, 2006, Microbial ecology: human gut microbes associated with obesity, Nature source
• Not checked yetcites [329] Turnbaugh, 2006, An obesity-associated gut microbiome with increased capacity for energy harvest, Nature source
• Not checked yetcites [330] Kassinen, 2007, The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects, Gastroenterology source
• Not checked yetcites [331] Yang, 2015, Gut dysbiosis is linked to hypertension, Hypertension source
• Not checked yetcites [276] Wen, 2008, Innate immunity and intestinal microbiota in the development of Type 1 diabetes, Nature source
• Not checked yetcites [332] Salas, 2014, Microbiome in human immunodeficiency virus infection, Clin. Lab. Med. source

In the paper

“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.”

What the sources say

• Not checked yetcites [325] Moilanen, 1995, Nitric oxide in inflammation and immune response, Ann. Med. source
• Not checked yetcites [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

In the paper

“The typically low-abundance Enterobacteraceae expand in concert with inflammation[336] and degree of dysbiosis of the Firmicutes:Bacteroidetes ratio[333,337,338].”

What the sources say

• Not checked yetcites [336] Biagi, 2010, Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians, PLoS One source
• Not checked yetcites [333] Winter, 2013, Host-derived nitrate boosts growth of E. coli in the inflamed gut, Science source
• Not checked yetcites [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 yetcites [338] Stecher, 2007, Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota, PLoS Biol. source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [337] Vázquez-Torres, 2016, Nitrate, nitrite and nitric oxide reductases: from the last universal common ancestor to modern bacterial pathogens, Curr. Opin. Microbiol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [343] Cortese-Krott, 2015, On the chemical biology of the nitrite/sulfide interaction, Nitric Oxide source
• Not checked yetcites [344] Singh, 2015, Hydrogen sulfide in physiology and diseases of the digestive tract, Microorganisms source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [344] Singh, 2015, Hydrogen sulfide in physiology and diseases of the digestive tract, Microorganisms source
• Not checked yetcites [347] Guo, 2016, Emerging roles of hydrogen sulfide in inflammatory and neoplastic colonic diseases, Front. Physiol. source
• Not checked yetcites [352] Arijs, 2013, Decreased mucosal sulfide detoxification capacity in patients with Crohn's disease, Inflamm. Bowel Dis. source
• Not checked yetcites [353] De Preter, 2012, Decreased mucosal sulfide detoxification is related to an impaired butyrate oxidation in ulcerative colitis, Inflamm. Bowel Dis. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [102] Vitturi, 2015, Convergence of biological nitration and nitrosation via symmetrical nitrous anhydride, Nat. Chem. Biol. source
• Not checked yetcites [346] Vermeiren, 2012, Sulfide- and nitrite-dependent nitric oxide production in the intestinal tract, Microb. Biotechnol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [343] Cortese-Krott, 2015, On the chemical biology of the nitrite/sulfide interaction, Nitric Oxide source
• Not checked yetcites [346] Vermeiren, 2012, Sulfide- and nitrite-dependent nitric oxide production in the intestinal tract, Microb. Biotechnol. source

In the paper

“Indeed, there remains conflicting evidence regarding the precise role of H2S in the gut[344,347].”

What the sources say

• Not checked yetcites [344] Singh, 2015, Hydrogen sulfide in physiology and diseases of the digestive tract, Microorganisms source
• Not checked yetcites [347] Guo, 2016, Emerging roles of hydrogen sulfide in inflammatory and neoplastic colonic diseases, Front. Physiol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [361] Appel, 1997, A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group, N. Engl. J. Med. source
• Not checked yetcites [363] Rouse, 1983, Blood-pressure-lowering effect of a vegetarian diet: controlled trial in normotensive subjects, Lancet source
• Not checked yetcites [364] Lindahl, 1984, A vegan regimen with reduced medication in the treatment of hypertension, Br. J. Nutr. source
• Not checked yetcites [365] Joshipura, 1999, Fruit and vegetable intake in relation to risk of ischemic stroke, JAMA source
• Not checked yetcites [366] Hung, 2004, Fruit and vegetable intake and risk of major chronic disease, J. Natl. Cancer Inst. source
• Not checked yetcites [367] Carter, 2010, Fruit and vegetable intake and incidence of type 2 diabetes mellitus: systematic review and meta-analysis, BMJ source
• Not checked yetcites [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 yetcites [369] Joshipura, 2001, The effect of fruit and vegetable intake on risk for coronary heart disease, Ann. Intern. Med. source

In the paper

“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].”

What the sources say

• Not checked yetcites [362] de Lorgeril, 2013, Mediterranean diet and cardiovascular disease: historical perspective and latest evidence, Curr. Atheroscler. Rep. source
• Not checked yetcites [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 yetcites [376] Martinez-Gonzalez, 2009, Mediterranean food pattern and the primary prevention of chronic disease: recent developments, Nutr. Rev. source
• Not checked yetcites [377] Estruch, 2013, Primary prevention of cardiovascular disease with a Mediterranean diet, N. Engl. J. Med. source