The Importance of Healthy Bacteria in Nitric Oxide Production

By Dr. Mercola

Nitric oxide (NO) is a soluble gas stored in the endothelium lining your blood vessels. NO has many exceptional health benefits, but there’s a great deal of confusion about how it’s produced in your body. While your body does produce NO naturally inside your endothelial cells from the amino acid L-arginine, the most significant source is actually dietary nitrates, found in fresh vegetables, which gut bacteria then convert into nitrite and then to NO, bypassing the classical L-arginine pathway.1

Research also suggests bacterially-derived nitrites play an important if not overriding role in NO homeostasis.2 As explained in “The Metabolic Effects of Dietary Nitrate in Health and Disease,” published earlier this month in the journal Cell Metabolism:3

“[NO], generated from L-arginine and oxygen by NO synthases, is a pleiotropic signaling molecule involved in cardiovascular and metabolic regulation. More recently, an alternative pathway for the formation of this free radical has been explored.

The inorganic anions nitrate (NO3 ) and nitrite (NO2 ), originating from dietary and endogenous sources, generate NO bioactivity in a process involving seemingly symbiotic oral bacteria and host enzymes in blood and tissues … The mechanisms underlying the salutary metabolic effects of nitrate … include interaction with mitochondrial respiration, activation of key metabolic regulatory pathways, and reduction of oxidative stress.”

Health Benefits of NO

NO promotes healthy endothelial function and heart health4 by dilating your blood vessels, thereby improving blood flow and lowering your blood pressure. The improved blood flow allows vital oxygen and nutrients to flow freely throughout your body while removing waste material and carbon dioxide. Importantly, NO infuses into areas that are hypoxic, meaning in need of oxygen, and both your heart and brain5,6 are heavy oxygen users.

NO has actually been shown to improve brain neuroplasticity by improving oxygenation of the somatomotor cortex (a brain area frequently affected in the early stages of dementia).7,8 NO also helps thin your blood and decrease its viscosity, which decreases platelet aggregation. The latter may discourage the development of blood clots that may cause a heart attack or stroke. NO also:

Plays a protective role in your mitochondrial health. Even your skeletal muscle, which is made up of only about 1 to 2 percent mitochondria, depend on these energy powerhouses to fuel your daily movements. When you exercise and your muscles ache, it’s because your muscles are depleted of oxygen, which your body compensates for by releasing NO to dilate your blood vessels making it easier for oxygen to be delivered.

This is one of the reasons why intense, short bursts of exercise are such an efficient form of exercise — it significantly boosts NO.9 When you exercise, it only takes about 90 seconds for your blood vessels to run out of stored NO and begin the process of making more. So, not only is it important to provide your body with the raw materials to produce NO, but you must also regularly work to release NO with high intensity exercises like the Nitric Oxide Dump, which:

Boosts your immune function, making your body better equipped to fight off foreign pathogens. NO also has powerful antibacterial potential in and of itself. In vitro tests show it can kill most enteric pathogens within one hour. Mycobacterium tuberculosis, Salmonella and Shigella are particularly susceptible to NO.

Helps maintain physiological homeostasis. For example, in your gut, NO regulates mucosal blood flow, intestinal motility and the thickness of mucus. NO also plays an important role in the homeostasis of reactive oxygen species, which can have a significant impact on metabolic pathways.10

Helps suppress inflammation, and in microvessels, particularly your capillaries, NO, along with growth factors, helps promote angiogenesis, the formation of new, healthy blood vessels.11

Few Scientific Discoveries Can Match the Importance of NO

When I was in medical school, NO was not even on the radar. Since its discovery in 1980,12 NO has severely challenged and updated our understanding of human biology and pathology. While Joseph Priestly discovered NO in 1772, it wasn’t until 1980 that biochemist Robert Furchgott discovered that endothelial cells release an endothelium-derived relaxing factor (EDRF), which relaxes vascular smooth muscle.

He, along with Louis J. Ignarro, Ph.D., and Dr. Ferid Murad, received the Nobel Prize in physiology or medicine in 1998 for “their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system.”13 In 1986, Furchgott and Ignarro, a pharmacologist, had independently of each other come to the identical conclusion — that EDRF is actually the NO Priestly discovered. Today, there are more than 160,000 papers detailing the physiology and pathology of NO. Here’s a quick summary of some key points:

In your body, NO is generated by three primary nitric oxide synthase (NOS) enzymes: endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS). eNOS is produced in the vascular endothelium and is typically associated with beneficial biological reactions, while nNOS and iNOS are associated with toxic effects. iNOS is readily induced in many tissues by proinflammatory cytokines, and unlike the other NOS enzymes is not regulated by changes in intracellular calcium.

NO is more than just another signaling molecule. The understanding of how it communicates reveals why NO has so many physiological roles in biological life. Importantly, local concentration of NO is not the sole determinant; it can convey information by more subtle means as well, and the fact that NO can freely cross cell membranes allows it to repeatedly diffuse into and out of a cell.

However, because NO can only diffuse over a short distance, its action is limited to the few cells closest to the source of production. This means that NO produced in the gut, for example, will not influence the central nervous system, so it’s important to encourage NO production throughout your system.

While NO has many benefits, it is also a free radical and when combined with superoxide forms the most pernicious reactive molecule in your body, peroxynitrite. In my view, it is the most damaging reactive molecule in your body contributing to a large part of oxidative damage to your DNA, cell membranes and proteins. This typically occurs when exposed to dangerous EMFs.

Most of the beneficial effects of NO are mediated through its ability to stimulate soluble guanylate cyclase, producing cGMP which acts, in turn to stimulate the cGMP-dependent protein kinase or through its ability to nitrosylate protein cysteine residues.14

One example of the therapeutic use of NO is pulsed electromagnetic field therapy or PEMF, which has been conventionally used in the treatment of nonunion bone fractures since the 1970s.15 It is likely that in this context, increased NO increases cGMP synthesis and activate protein kinase G,16 which can stimulate osteoblasts and bone growth.

We now believe the reason why PEMF is safe and EMF is not is largely a result of the frequency. PEMF is typically under 100 Hz while dangerous EMF frequencies are typically over 2000 Hz to Gigahertz.

Health Benefits of Dietary Nitrates Match Those of NO

Considering nitrates trigger the production of NO, it’s no surprise that dietary nitrates have been shown to have the same effects on health as NO, including the lowering of blood pressure, improving endothelial function, increasing exercise performance, reversing metabolic syndrome and having antidiabetic effects.17,18 Indeed, dietary nitrates have been shown to reverse metabolic syndrome in mice,19 and improve pancreatic islet blood flow and insulin secretion in rats.20

In conventional medicine, nitrates are used to treat angina and congestive heart failure, and research shows a glass of beetroot juice has the same effect as prescription nitrates.21 Raw beets — which are high in nitrates — have been shown to lower blood pressure by an average of four to five points within a few hours.22

Another study23 found drinking 8 ounces of beet juice per day lowered blood pressure by an average of nearly eight points after the first week, which is more than most blood pressure medications. Raw beets have also been shown to boost stamina during exercise by as much as 16 percent,24 courtesy of increased NO production.

Nitrites No Longer a Villain

In the past, nitrites were universally vilified as carcinogenic, regardless of the source or how they were produced. Today, we know this isn’t true, which I’ll delve into in the next section. As explained in the paper, “Nitrite in Nitric Oxide Biology,” published in 2006:25

“All life requires nitrogen compounds. Nitrite is such a compound that is naturally occurring in nature and biology. Over the years, the pharmacological stance on nitrite has undergone a surprising metamorphosis, from a vilified substance that generates carcinogenic nitrosamines in the stomach to a life-saving drug that liberates a protective agent (nitric oxide or NO) during hypoxic events.

Nitrite has been investigated as a vasodilator in mammals for over 125 years and is a known byproduct of organic nitrate metabolism. There has been a recent rediscovery of some of the vasodilator actions of nitrite in physiology along with novel discoveries which render nitrite a fundamental molecule in biology.

Until recently nitrite was thought to be an inert oxidative breakdown product of endogenous NO synthesis but the past few years have focused on the reduction of nitrite back to NO in the circulation as a possible mechanism for hypoxic vasodilatation. Nitrite has evolved into an endogenous signaling molecule and regulator of gene expression that may not only serve as a diagnostic marker but also find its role as a potential therapeutic agent of cardiovascular disease.”

Dietary Nitrates 101

As explained in “Metabolic Effects of Dietary Nitrate in Health and Disease” in the journal Cell Metabolism,26 “The relative contribution from the diet versus endogenous NO generated by NOS to the total body pool of nitrate varies, but with a moderately high intake of vegetables (200 grams of greens per day), the dietary source clearly dominates.”

In the modern diet, nitrates can be found both in nitrate-rich plant foods and in processed meats. Only one of these sources is beneficial, however. The other is known to be carcinogenic, so the devil’s in the details, as your body processes nitrates differently depending on the source.27

Dietary nitrates are converted into nitrites by oral bacteria during chewing. Once the nitrites are swallowed and come into contact with stomach acid, they can be converted into one of two things: beneficial NO, or carcinogenic N-nitroso compounds such as nitrosamines. A number of factors can influence this conversion:

1. One influencing factor is whether or not the nitrites are found in combination with protein and heme (an iron-containing compound that makes up part of the hemoglobin molecule in blood). This is what makes processed meats so detrimental to your health.28

Processed meat is actually classified as a Group 1 carcinogen, along with tobacco and asbestos.29,30 According to a review of more than 7,000 clinical studies, the World Cancer Research Fund concluded there’s no safe lower limit for processed meats31 and that they should be avoided altogether to minimize your cancer risk.

As explained by Gunter Kuhnle, professor of food and nutritional sciences at the University of Reading, U.K.,32 “What makes processed meats so ideal for forming N-nitroso compounds is that they have a combination of nitrite and proteins from the meat. And the meat’s heme seems to help convert them into N-nitroso compounds.”

2. Dietary nitrates are also more prone to converting into carcinogenic nitrosamines when heated, which is what happens during the cooking and processing of meat. Most plant foods are typically not cooked or fried at high temperatures, which minimizes the chances that harmful substances will be produced.

3. Plants contain antioxidants (such as vitamin C and polyphenols) that impede the formation of harmful nitrosamines.33 The presence of these compounds help to ensure that the nitrites are converted into beneficial NO once they reach your stomach rather than harmful N-nitroso compounds.34

4. The composition of your gut bacteria may also play a role. Research suggests beneficial bacteria help break down nitrosamines, while bad gut bacteria increase nitrosamine production.35

Foods High in Healthy Dietary Nitrates

So, in summary, a nitrate-rich diet can do wonders for your health, but only when the nitrates come from the plant kingdom. Here’s a list of the Top 10 most nitrate-rich plant foods:36,37,38

Plant source Amount of nitrates per 100 grams

Arugula

480 milligram (mg)

Rhubarb

281 mg

Cilantro

247 mg

Butter leaf lettuce

200 mg

Spring greens like mesclun mix

188 mg

Basil

183 mg

Beet greens

177 mg

Oak leaf lettuce

155 mg

Swiss chard

151 mg

Red beets

110 mg

Eating garlic also helps boost NO production via the classical L-arginine pathway. While low in nitrates, garlic increases nitric oxide synthase, which converts L-arginine to NO in the presence of cofactors such as vitamins B2 and B3.39

Beets, while on the low end of the list above, become a phenomenal trigger of NO when fermented. Fermented beets contain 2 to 3 grams of nitrates per 100 grams, which is why I regularly take our fermented beets powder in my daily smoothie. Other examples include pickled beets, beet-infused sauerkraut and fermented beet juice, known as beet kvass.

Homemade pickled beets contain higher levels of nitrates than commercial ones, a difference attributed to processing methods. According to at least one study,40 the addition of sugar in commercially made ferments “dilute” the nitrate content of the final product.

More on How NO Is Created From Dietary Nitrates

In more recent years, researchers have taken a more in-depth look at dietary nitrates, showing they play a far more important role in human health than previously thought, in large part due to their influence on NO production. As explained in a 2015 PLOS One paper:41

“… [N]itrate is first converted to nitrite and subsequently to ammonia. Strains of L.rhamnosus, L.acidophilus and B.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.”

In other words, there appears to be a very intimate relationship between dietary nitrates and various gut bacteria. The nitrate/nitrite/NO metabolism chain, and the influence of gut bacteria, can be summarized as follows:

1. In step 1, probiotic bacteria such as Lactobacillus reduce nitrate to nitrite, the latter of which becomes a substrate for NO

2. Step 2 is the conversion of nitrite to NO, which can occur via several different processes — independently of the presence of probiotic bacteria — including the following:

Acidification in the stomach or localized parts of the intestine

Other gut bacteria capable of denitrifying nitrite to NO

Gut mucosa cells with peroxidase activity

Nitrate-Rich Plant Food Plus Probiotic May Offer Greatest Benefits

When you administer a probiotic such as Lactobacillus in conjunction with dietary nitrate, you’ll gain an increase in NO, but only the first step of the process (the reduction of nitrate to nitrite) is a direct result of the probiotic. Conversely, outside the human body, such as during fermentation, the probiotics can drive the entire process, first reducing nitrate to nitrite, and then generating NO through the lactic acid produced by the fermentation process itself.

While all of this may sound frustratingly complex, the take-home message is this: If you want to support your NO pathway and boost NO production, combining probiotics with nitrate-rich plant food is likely the best way to do that, and supplements that combine both are likely to be more effective. Alternatively, if you’re taking something like fermented beet powder or some other NO supplement to boost athletic performance and/or heart42 or brain health, consider adding a high-quality probiotic, and take them together.

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