More nitrate-reducing bacteria in saliva causes Migraine

Scientists at the University of California San Diego School of Medicine have found an association between the debilitating headaches that afflict 38 million Americans, and the microbes in their mouths.

nitrite-pathway

“There is this idea out there that certain foods trigger migraines — chocolate, wine, and especially foods containing nitrates,” wrote Antonio Gonzalez, the lead author on the study published in the American Society for Microbiology’s journal mSystems. “We thought that perhaps there was a connection between someone’s microbiome [the microorganisms in their body] and what they were eating.”

So the research team analyzed 172 oral samples and nearly 2,000 fecal samples taken from the American Gut Project, and sequenced which bacteria species were found in participants who suffered migraines versus those who did not. And it turns out, the migraineurs have significantly more nitrate-reducing bacteria in their saliva than those who don’t suffer these headaches.

Having too many nitrates in the body, which can aid cardiovascular health in best case scenarios, has been linked to migraines for unlucky folks. Now this new research suggests that’s because having too much oral nitrate-reducing bacteria, which converts nitrates into nitric oxide in the body, leads to the pounding headaches.

The next step will be looking at more defined groups of patients, separated into different types of migraines, to better understand why some oral microbes could be messing with their heads.

Gonzales suggested that perhaps in the future, “We will have a magical probiotic mouthwash for everyone that helps your cardiovascular health without giving you migraines.”


The presence of nitrates and nitrites in food is associated with an increased risk of gastrointestinal cancer and, in infants, methemoglobinemia.

Despite the physiologic roles for nitrate and nitrite in vascular and immune function, consideration of food sources of nitrates and nitrites as healthful dietary components has received little attention.

Approximately 80% of dietary nitrates are derived from vegetable consumption; sources of nitrites include vegetables, fruit, and processed meats. Nitrites are produced endogenously through the oxidation of nitric oxide and through a reduction of nitrate by commensal bacteria in the mouth and gastrointestinal tract.

As such, the dietary provision of nitrates and nitrites from vegetables and fruit may contribute to the blood pressure–lowering effects of the Dietary Approaches to Stop Hypertension (DASH) diet. We quantified nitrate and nitrite concentrations by HPLC in a convenience sample of foods. Incorporating these values into 2 hypothetical dietary patterns that emphasize high-nitrate or low-nitrate vegetable and fruit choices based on the DASH diet, we found that nitrate concentrations in these 2 patterns vary from 174 to 1222 mg.

The hypothetical high-nitrate DASH diet pattern exceeds the World Health Organization’s Acceptable Daily Intake for nitrate by 550% for a 60-kg adult. These data call into question the rationale for recommendations to limit nitrate and nitrite consumption from plant foods; a comprehensive reevaluation of the health effects of food sources of nitrates and nitrites is appropriate.

In addition to the provision of nitrate and nitrite by diet or via the oxidation of nitric oxide to nitrite, vascular and gastrointestinal nitric oxide production can be enhanced through various means based on lifestyle and food choices. Physical activity, commensal bacteria, and dietary factors can influence nitric oxide production. Exercise enhances nitric oxide production in vascular endothelium (54) and postexercise plasma nitrite concentrations have been proposed as an index of exercise capacity (55). In fact, aging is associated with an impaired capacity of the vasculature to increase plasma nitrite during exercise (56). Strikingly, it has been found that dietary nitrate supplementation, at concentrations achievable by vegetable consumption, results in more efficient energy production without increasing lactate concentrations during submaximal exercise (57).

Foods can increase the generation of nitric oxide in the gastrointestinal tract via the polyphenolic content of, for example, apples or red wine (58, 59). Pomegranate juice has been shown to protect nitric oxide from oxidation while enhancing its biological activity (60). The metabolic activity of commensal bacteria in the gastrointestinal tract and probiotic bacteria also provide nitric oxide from nitrite, and to a lesser extent, from nitrate (61, 62). Whereas data estimating the contribution of the microbiota, including probiotic bacteria, to the generation of nitric oxide are speculative, they raise the possibility that the gastrointestinal production of nitric oxide and NOx is biologically plausible. These data add layers of complexity to the estimation of nitrate/nitrite exposure levels in vivo and the determination of whether specific foods or lifestyle choices can significantly affect the production and metabolic disposition of dietary and endogenous NOx species.

http://ajcn.nutrition.org/content/90/1/1.full


Nitrate Reduction to Nitrite, Nitric Oxide and Ammonia by Gut Bacteria under Physiological Conditions

The biological nitrogen cycle involves step-wise reduction of nitrogen oxides to ammonium salts and oxidation of ammonia back to nitrites and nitrates by plants and bacteria. Neither process has been thought to have relevance to mammalian physiology; however in recent years the salivary bacterial reduction of nitrate to nitrite has been recognized as an important metabolic conversion in humans.

Several enteric bacteria have also shown the ability of catalytic reduction of nitrate to ammonia via nitrite during dissimilatory respiration; however, the importance of this pathway in bacterial species colonizing the human intestine has been little studied. We measured nitrite, nitric oxide (NO) and ammonia formation in cultures of Escherichia coli, Lactobacillus and Bifidobacterium species grown at different sodium nitrate concentrations and oxygen levels.

We found that the presence of 5 mM nitrate provided a growth benefit and induced both nitrite and ammonia generation in E.coli and L.plantarum bacteria grown at oxygen concentrations compatible with the content in the gastrointestinal tract. Nitrite and ammonia accumulated in the growth medium when at least 2.5 mM nitrate was present. Time-course curves suggest that nitrate is first converted to nitrite and subsequently to ammonia. Strains of L.rhamnosus, L.acidophilus andB.longum infantis grown with nitrate produced minor changes in nitrite or ammonia levels in the cultures.

However, when supplied with exogenous nitrite, NO gas was readily produced independently of added nitrate. Bacterial production of lactic acid causes medium acidification that in turn generates NO by non-enzymatic nitrite reduction. In contrast, nitrite was converted to NO by E.coli cultures even at neutral pH. We suggest that the bacterial nitrate reduction to ammonia, as well as the related NO formation in the gut, could be an important aspect of the overall mammalian nitrate/nitrite/NO metabolism and is yet another way in which the microbiome links diet and health.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372352/


Denitrification is a type of anaerobic respiration that uses nitrate as an electron acceptor.

  • Denitrification generally proceeds through a stepwise reduction of some combination of the following intermediate forms: NO3− → NO2− → NO + N2O → N2.
    Generally, several species of bacteria are involved in the complete reduction of nitrate to molecular nitrogen, and more than one enzymatic pathway has been identified in the reduction process.
    Complete denitrification is an environmentally significant process as some intermediates of denitrification (nitric oxide and nitrous oxide) are significant greenhouse gases that react with sunlight and ozone to produce nitric acid, a component of acid rain.

electron acceptor
An electron acceptor is a chemical entity that accepts electrons transferred to it from another compound. It is an oxidizing agent that, by virtue of its accepting electrons, is itself reduced in the process.

eutrophication
The process of becoming eutrophic.

Denitrification may be deliberately used to change the composition of an environment. It’s commonly used to remove nitrogen from sewage and municipal wastewater. Denitrification is instrumental in removing excess nitrate in groundwater, which is a result of excessive fertilizer use.
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In anaerobic respiration, denitrification utilizes nitrate (NO3-) as a terminal electron acceptor in the respiratory electron transport chain. Denitrification is a widely used process; many facultative anaerobes use denitrification because nitrate, like oxygen, has a high reduction potential

Denitrification is a microbially facilitated process involving the stepwise reduction of nitrate to nitrite (NO2-) nitric oxide (NO), nitrous oxide (N2O), and, eventually, to dinitrogen (N2) by the enzymes nitrate reductase, nitrite reductase, nitric oxide reductase, and nitrous oxide reductase. The complete denitrification process can be expressed as a redox reaction: 2 NO3− + 10 e− + 12 H+ → N2 + 6 H2O.

Protons are transported across the membrane by the initial NADH reductase, quinones and nitrous oxide reductase to produce the electrochemical gradient critical for respiration. Some organisms (e.g. E. coli) only produce nitrate reductase and therefore can accomplish only the first reduction leading to the accumulation of nitrite. Others (e.g. Paracoccus denitrificans or Pseudomonas stutzeri) reduce nitrate completely. Complete denitrification is an environmentally significant process because some intermediates of denitrification (nitric oxide and nitrous oxide) are significant greenhouse gases that react with sunlight and ozone to produce nitric acid, a component of acid rain. Denitrification is also important in biological wastewater treatment, where it can be used to reduce the amount of nitrogen released into the environment, thereby reducing eutrophication.

Denitrification takes place under special conditions in both terrestrial and marine ecosystems. In general, it occurs where oxygen is depleted and bacteria respire nitrate as a substitute terminal electron acceptor. Due to the high concentration of oxygen in our atmosphere, denitrification only takes place in anaerobic environments where oxygen consumption exceeds the oxygen supply and where sufficient quantities of nitrate are present. These environments may include certain soils and groundwater, wetlands, oil reservoirs, poorly ventilated corners of the ocean, and in sea floor sediments.

The role of soil bacteria in the Nitrogen cycle

nitrogen-cycle
Denitrification is an important process in maintaining ecosystems. Generally, denitrification takes place in environments depleted of oxygen.
Denitrification is performed primarily by heterotrophic bacteria (e.g. Paracoccus denitrificans), although autotrophic denitrifiers have also been identified (e.g., Thiobacillus denitrificans). Generally, several species of bacteria are involved in the complete reduction of nitrate to molecular nitrogen, and more than one enzymatic pathway have been identified in the reduction process.

Rhizobia are soil bacteria with the unique ability to establish a N2-fixing symbiosis on legume roots. When faced with a shortage of oxygen, some rhizobia species are able to switch from O2-respiration to using nitrates to support respiration.

The direct reduction of nitrate to ammonium (dissimilatory nitrate reduction) can be performed by organisms with the nrf-gene. This is a less common method of nitrate reduction than denitrification in most ecosystems. Other genes involved in denitrification include nir (nitrite reductase) and nos (nitrous oxide reductase), which are possessed by such organisms as Alcaligenes faecalis, Alcaligenes xylosoxidans, Pseudomonas spp, Bradyrhizobium japonicum, and Blastobacter denitrificans.

Source: Boundless. “Nitrate Reduction and Denitrification.” Boundless Microbiology. Boundless, 26 May. 2016. Retrieved 19 Oct. 2016 from

https://www.boundless.com/microbiology/textbooks/boundless-microbiology-textbook/microbial-metabolism-5/anaerobic-respiration-49/nitrate-reduction-and-denitrification-314-7650/


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