Commercial Mouth Wash; NOS3, NOS2, NOS Uncoupling, Colon Cancer, Hypertension, Blue Zones, POTS, Dysautonomia, and Cardiac Health

This article is not intended to be medical or healthcare advice. Before you start any health or medical related regimen, seek the advice of your Primary Care Physician or an M.D.

There are fewer more accepted practices than brushing our teeth and using mouthwash in our modern day living. It helps us be 'clean' and healthy of course.

Commercial mouth wash use has direct correlation with hypertension and elevated blood pressure.[1]

"Because antiseptic mouthwashes eradicate the oral bacterial flora, this nitric oxide-generating pathway is abolished, which may result in nitric oxide-deficient conditions potentially leading to life-threatening complications such as ischemic heart events or sepsis." [3].

"Meta-analyses and several large cohort studies have demonstrated that antiseptic mouthwashes are associated with mortality in hospitalized patients."[3]

"Meta-analyses and population-based observational studies have consistently demonstrated an inverse association of dietary nitrate with blood pressure and cardiovascular disease outcomes." [4]

NOS3 Gene - "The Heart Attack Gene", Ben Lynch

The NOS3 gene is responsible for vasodilation of blood vessels, particularly in the heart and lungs. It became well known, after Ben Lynch, in his book, Dirty Genes, named it the Heart Attack Gene. [10] For good reason. Specific mutations have been identified that are correlated with cardiac events. In more recent times, specific mutations have been identified with POTS. As you can imagine anything associated with blood flow and blood pressure may have associations with POTS. NOS3 has other mutations that are connected to dysautonomia. Seems important. NOS3 uses nitrate, and citrulline can work as well as its fuel or substrate. It is connected, like a gear, 'coupled' to NOS2 by a cofactor called BH4 - tetrahydrobiopterin.

BH4 - Tetrahydrobiopterin - Liquid Gold; Low In ME CFS Folks

BH4 is sensitive being oxidized by oxidative agents like super oxide, and such, and is often seen low in ME CFS folks [7] , as cited in a small study by Pall. There are couple of key ways to help BH4 levels: enable its production by specific genes, namely GCH1, which is controlled mainly by HSP90 (heat shock protein 90), which is stimulated by heat - sauna. [9] BH4 recycling also is a key way to maintain BH4 levels, and there are several genes involved here, perhaps most important is MTHFR 1298c, and SLC19A1 (folate metabolism). Lowering oxidative stress is also helpful to maintain BH4 levels so its not oxidized so readily. BH4 is needed for many other reasons too, and one is to process ammonia - high ammonia leads to symptoms like fatigue and brain fog. One of the key ways ammonia gets produced in the body is by the digestion of animal protein and the processing of metabolytes of candida.

Back to NOS3. So we need BH4, we need nitrate. How do we get nitrate ? Diet, and nitrate reducing bacteria in oral cavity. Ugh oh.

Nitrate is responsible for the growth of plants and assimilation of other nutrients (e.g. nitrogen rich soil) - its necessary for plants to grow and assimilate nutrients from the soil. Nitrate is highest in green leafy vegetables and root vegetables such as kale, spinach, arugula, butter leaf, celery, and beets. Its well accepted from epidemiological research that a plant based diet or eating sufficient vegetables, there is less incidence of heart disease, cancer and chronic disease. However, in the world of chronic illness, often carnivore based diets feel best to some - more on that in another blog. Its related to calming the over activation of the Aryl Hydrocarbon Receptor - which controls hundreds of genes - key among them immune pathways like IL-10. Wonder why the famous Jordan Pederson's depression went away on carnivore:). But, it highly dependent on the individual and genetics.

Some believe it is the antioxidant content of plants that were responsible for health benefits of a plant based diet. Nitrate has also been proposed as a contributor to health benefits from a plant based diet. In a recent Netflix Series, Blue Zones, where the author identifies areas that have exceedingly high concentrations of 'centarians, people over 100 years old', a plant based diet was part of each of these communities. Specifically, legumes and in one community in Japan, purple potatoes were part of the diet. Nothing is a better natural binder than legumes and skins from potatoes:). Certainly toxin removal isn't a bad thing:).

Recently clinical trials have proven nitrate can also produce benefits like reducing high blood pressure, improving exercise performance and endurance, preventing vascular inflammation, improving diabetes, obesity, Alzheimers, kidney function, etc. Studies have shown that the Japanese diet has one of the highest amounts of nitrate. In one community, the serine in the Japanese diet was very high as well, see earlier blog article on thyroid nutrition:).

The Dietary Approaches to Stop Hypertension (DASH) diet is high in nitrate content. Nitrate could explain the health benefits of a Mediterranean diet, but so could cranberries, walnuts as they raise urolithin levels, and the polyphenols in this diet (olive oil) have a variety of benefits like inhibiting a key gene (ARG1) that promotes colorectal cancer. The mechanism of action of nitrate - supports cardio vascular health - cardiac issues are one of the main causes of death for folks over 60. Why are so many Americans having heart attacks ? Could one factor be a low nitrate diet ?

How to get dietary nitrate:

1. 300 mg of nitrate in a meal is required for a clinical effect. A good sized salad. A 50 fold difference in nitrate content of the same vegetable occurs based on where and how it is grown; nitrate rich fertilizers used on conventionally grown produce are one factor why organically grown vegetables have on average about 10 times less nitrate than conventionally grown vegetables. Americans get ~ 150 mg of nitrate / day based on the Standard American diet. Now, to be clear, i am n ot suggesting you eat conventional, glyphosate isn't worth it.

2. Nitrate reducing bacteria that live in the oral cavity and convert nitrate into nitrite and nitric oxide. "Nitrate-reducing genera, such as Neisseria, Rothia, Kingella, have been reported to be associated with oral health, and they have the potential to become probiotics to stimulate nitrate metabolism, reduce oral ecological disorders, and prevent caries" [5]. "In their study, most nitrite-producing isolates obtained in the presence of oxygen were Rothia (from the tongue) and Actinomyces (from saliva and plaque), but without oxygen, most nitrite-producing bacteria were Veillonella and Actinomyces, while no Rothia was detected." [6] Lack of these bacteria is associated with higher blood pressure. ~200 million Americans use daily antiseptic mouthwash (about the same number with high blood pressure), killing these bacteria and preventing nitrate from being converted into nitrite and nitric oxide. There is an oral biome test called Bristle, that is new on the market, and various oral pro biotics by Life Extension, Allergy Research Group, and others exist. Coconut oil is a good gentle anti microbial mouthwash alternative to the more harsh alcohol based mouthwashes to promote oral cavity health. Berkley life has a lozenge that helps the process of converting nitrate into nitric oxide as well. Flouride toothpastes have similar effects on the oral biome as alcohol mouthwashes. Much less what they do to the thyroid.

3. Stomach acid is required to make nitric oxide from nitrate and nitrite, break down animal protein to liberate the minerals, like iron, copper, zinc, etc for digestion and assimilation. Nitrate is converted into nitrite by the oral bacteria, saliva becomes saturated with nitrite, and is converted into nitric oxide by the acid in the stomach. Low stomach acid can lead to low nitric oxide, low mineral assimilation. Perhaps this is one of many reasons naturopaths, even unknowingly, like stomach acid helpers, like ACV, etc.

NOS2 - Not So Fast, Literally

NOS2 is coupled to NOS3 as discussed above. What is the substrate for NOS2 ? Nitrate, and arginine. Crap. There are 3 locations on NOS2 that are upregulations. One upregulates NOS 2 by 473%. [8] This location on NOS2 is only available on the 23andme genetic test kit. NOS2 is primarily expressed in the GI Tract. Crap. A simple google search of NOS2 and colorectal cancer will tell you all you need to know. Hmm. So if NOS2 is upregulated and NOS3 is downregulated , guess what happens ? NOS Uncoupling, which produces MASSIVE amounts of super oxide, which oxidize BH4. Crap. Massive oxidative stress in the GI Tract. Surprised that folks with NOS2 upregulations have colorectal cancer, or diverticulitis?. Proof ? Nah. OJ was just going on a vacation down in Mexico never mind the 100 $ bills flying out the white bronco, never mind the blood bath left behind. He wasn't fleeing, cmon. Is it a coincidence that herbs that downregulate NOS2 also have effects on the outcomes of colon cancer. Sure. Like all of them. Damn. So, in sum, before we cram a bunch of nitrate down our throats lets look first at NOS2 - we dont want that upregulated. There are number of approaches where we can modulated NOS2 down, and modulate NOS3 up so we can maintain good NOS Coupling.

So, it appears we need to understand our genetics on NOS2 and NOS3, get away from things like alcohol mouthwash, flouride toothpaste, take care of our mouth, measure the biome there, and eat plants (for antioxidants, nitrates). In the Blue Zone series on Netflix, some of the other common characteristics of these communities were: strong meaningful connected relationships, daily movement and what we call 'exercise' - walks, gardening, etc; mental engagement; etc. Almost all of these communities were near water - which makes me think of our body's natural circadium rythms - how how the natural wave action gets our body into rythms - and how CLOCK genes are master controllers of so many functions in our body's! I do think the beans and potatoes are interesting - potentially as a way to remove toxins through the binding action of toxins in the GI tract. One community combined corn with a high legume diet. Beans are not a complete protein - they lack methionine, one of the 9 essential amino acids - and yes - corn is high in methionine. In sum, don't live like most of americans:)

Back to NOS3 / NOS2

If you have mutations that suggest this gene may have the potential to be down regulated for you (NOS3), there are specific polyphenols, and herbs that can upregulate it, as an alternative approach to Nitrate. And the same for NOS2, there are specific herbs that can downregulate this if you have mutations that make you have the potential to be upregulated here. This allows us to have alternatives to nitrate.

If you would like to explore this topic in more detail, i encourage you to check out the references below, and also the references in those articles as well.

May 2024, be the year, things start coming together for you in new ways if that serves you:).

References:

1. Over-the-counter mouthwash use, nitric oxide and hypertension risk. By Kaumudi Joshipura 1 2, Francisco Muñoz-Torres, et. al. Blood Pressure. 2020 Apr;29(2):103-112.

2. Antibacterial mouthwash blunts oral nitrate reduction and increases blood pressure in treated hypertensive men and women. By Catherine P Bondonno,  Alex H Liu, et. al. 2015 May;28(5):572-5. doi: 10.1093/ajh/hpu192. Epub 2014 Oct 30. PMID: 25359409.

3. Antiseptic mouthwash, the nitrate-nitrite-nitric oxide pathway, and hospital mortality: a hypothesis generating review. By Stijn Blot. Intensive Care Medicine. . 2021 Jan;47(1):28-38.

4. Dietary Nitrate from Plant Foods: A Conditionally Essential Nutrient for Cardiovascular Health. By Rosa M Dajani 2, M Catherine Prater, et al. PMID: 38008359. PMCID: PMC10776916. DOI: 10.1016/j.advnut.2023.100158

5. The Role of Oral Nitrate-Reducing Bacteria in the Prevention of Caries: A Review Related to Caries and Nitrate Metabolism. Dental Medicine , by Jixian Feng, Juan Liu, et al. ;JULY 25 2023. Caries Res (2023) 57 (2): 119–132. https://doi.org/10.1159/000529162. PubMed:

6. Isolation and Characterization of Nitrate-Reducing Bacteria as Potential Probiotics for Oral and Systemic Health. Bob T. Rosier Eva M. Moya-Gonzalvez Paula Corell-Escuin Alex Mira*. Front. Microbiol., 15 September 2020. Sec. Food Microbiology. Volume 11 - 2020 | https://doi.org/10.3389/fmicb.2020.555465. Department of Health and Genomics, Center for Advanced Research in Public Health, FISABIO Foundation, Valencia, Spain

7. A Study of Sauna Therapy in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Patients Shows Sauna Action via Raised Tetrahydrobiopterin and Confirms Three Predictions of the NO/ONOO− Cycle. Martin Pall, et al. Townsend Newsletter, November 2013.

8. The Role of Single-Nucleotide Variants of NOS1, NOS2, and NOS3 Genes in the Comorbidity of Arterial Hypertension and Tension-Type Headache

9. Nitric oxide synthase partial uncoupling as a key switching mechanism for the NO/ONOO- cycle. Martin L Pall 1Med Hypotheses. 2007;69(4):821-5. doi: 10.1016/j.mehy.2007.01.070. Epub 2007 Apr 19. PMID: 17448611. DOI: 10.1016/j.mehy.2007.01.070

10. Dirty Genes: A Breakthrough Program to Treat the Root Cause of Illness and Optimize Your Health, by Ben Lynch.

11. The NO/ONOO-Cycle as the Central Cause of Heart Failure. Martin L. Pall. Int J Mol Sci. 2013 Nov; 14(11): 22274–22330. Published online 2013 Nov 13. doi: 10.3390/ijms141122274