Simplifying the COVID Puzzle

How Two Essential Vitamins Fortify the Immune System

COVID-19 has dominated our lives for the past year, yet there is an incredibly important topic that has not received widespread attention: the role of a healthy immune function within the context of this pandemic.

Simplifying the COVID Puzzle: How Two Essential Vitamins Fortify the Immune System by Dr. Grace McComsey and Dr. Andrew Myers

In Simplifying the COVID Puzzle, my co-author Dr. Grace McComsey and I offer a reader-friendly scientific overview of the research that has emerged in the pandemic era related to the role of nutrition—specifically vitamins K2 and D3—in immune function.

While our national focus has been on vaccinations and other measures to prevent virus spread (testing, social distancing, masks, etc.), we have overlooked the opportunity to educate to the benefits of supporting our own immune defenses.

Americans are Deficient

Americans are largely nutrient deficient, driven by poor dietary intake from a standard American diet (SAD). Deficiencies in critical nutrients like vitamin D, vitamin K2, magnesium, and others drive ramifications that include diminished immune competency to cardiovascular dysfunction and osteoporosis. The conventional medical community in the U.S. did not begin to clue into the emerging research correlating vitamin D deficiency and vitamin K2 to COVID susceptibility, and the outcome is no surprise. We are a magic-bullet medical system, and, of course, vaccinations remain the focus of our ongoing COVID response. My co-author and I are supportive of the vaccination program, just not to the exclusion of all other proactive interventions that must take into account nutritional deficiencies and the necessity for supplementation.

Disinformation and politics clearly also created significant confusion and further relegated emerging research to other more proactive countries for discussion. According to new research, the UK is considering increasing their vitamin D supplementation by five times to support the population’s immunity against respiratory tract infections. Where science and research are allowed to lead the COVID response, a broad range of treatment options and opportunities may be considered.

With all of the research and discussion surrounding vitamin D, it is even more critical to understand the synergistic relationship between vitamin D and vitamin K2.

Vitamin D3 and Vitamin K2 Synergy

From a biochemical perspective, vitamin D and vitamin K2 are distinct nutrients. From a functional perspective, their activities occur on a continuum, are synergistic, and unified.  In our body’s system of calcium management, vitamin K2 finishes the job that vitamin D started with the absorption of calcium. Vitamin K2 leads to higher protein expression than D alone and the important carboxylation of proteins to act as desired.

Vitamin K2 activates matrix Gla Proteins (MGP) that would not fulfill their expected role in the body without K2 activation (carboxylation). MGP has a high affinity for binding to calcium ions, similar to other Gla-containing proteins. The protein acts as an inhibitor of vascular mineralization and plays a role in bone organization. MGP is present in bone together with the related vitamin K2-dependent protein osteocalcin.

The synergy between vitamins D and K2 is demonstrated by the fact that sufficient K2 levels increase the number of K2-dependent proteins by up to a factor of four compared to Vitamin D alone.

In addition, without K2, many of these proteins would remain inactive.

From a supplementation perspective, vitamin K2 makes D3 products better, safer, and more effective.

Vitamin D and COVID Research

The role of vitamin D deficiency in COVID susceptibility and severity of the infection is becoming clearer as more and more research is published. Multiple research summaries and mass media articles relate to this story, and so my focus in this article is to elucidate what is happening in the Vitamin K2 research arena.

Vitamin K2 Research

Three intervention studies with all-trans MK-7 for immune health are currently ongoing.

Three to five additional intervention studies are being planned, including long-haulers with COVID-19.

Several observational studies show significant correlations between vitamin status (vitamin K2) and viral infection outcome: Dofferhoff et al. 2020, Janssen et al., 2020, Linneberg et al., 2020, Janssen and Walk, 2020.

A U.S. study conducted by my co-author, Dr. Grace McComsey (pre-print expected very soon), shows an entirely new mechanism of action and immune functions of vitamin K2 that are altogether independent of vitamin D.

Vitamin K2 (all-trans MK7) shows crucial functions in supporting the immune system.

  • Down-regulation of cytokine expression (IL-1ß, IL-6, TNF-a).
  • Activation of proteins required for thrombosis prophylaxis. These include Protein S and Protein C. It is important to note that vitamin K2 as MK7 is the extrahepatic form of vitamin K due to unique transport mechanism via LDL-particles and three days half-life compare to 2 hours of vitamins K1 and K2 as MK-4.
  • Activation of proteins for the protection of elastic fibers in the lungs.
  • In adjusted models, every one-unit increase in the log2 dp-ucMGP (a measure of vitamin K2 deficiency) nearly doubled the odds of acute critical disease or death.

It is becoming clear that optimizing vitamins K2 and D before acute COVID-19 infection may help to regulate overwhelming calcification, inflammation, and coagulopathy, which may subsequently lead to improved clinical outcomes.

Why Vitamin K2 is so Important

One of the reasons that vitamin K2 is not as well known to the scientific and supplement community is it does not have a DRI separate from vitamin K as a family. This will need to change as the research is not just about immunity; research on cardiovascular and bone health demonstrates that vitamin K2 as MK-7 has an independent and critically important role in our overall health.

From a dietary perspective, vitamin K is well represented in those who consume dark leafy greens. Vitamin K2 is very poorly represented in the American diet unless you’ve adopted the consumption of Japanese natto, which is unlikely.

Research into vitamin K2 as MK-7 is poised to explode as a greater number of researchers begin to explore the myriad benefits of this important and unique nutrient. Vitamin K2’s  synergistic relationship with vitamin D will also help extend the research field as scientists understand that they may only be examining a portion of their area by focusing exclusively on the vitamin D side of their biochemical mechanism.

Dr. McComsey and I hope that we can help bring vitamin K2 in immune health into the spotlight and help more people optimize both their immune function and their overall wellness.

  1. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. Jama. 2020;324(8):782-93.
  2. Zhang JJY, Lee KS, Ang LW, Leo YS, Young BE. Risk Factors for Severe Disease and Efficacy of Treatment in Patients Infected With COVID-19: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis. Clin Infect Dis. 2020;71(16):2199-206.
  3. Zabetakis I, Lordan R, Norton C, Tsoupras A. COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation. Nutrients. 2020;12(5).
  4. Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochimica et Biophysica Acta. 2002;1570(1):27-32.
  5. Suleiman L, Négrier C, Boukerche H. Protein S: A multifunctional anticoagulant vitamin K-dependent protein at the crossroads of coagulation, inflammation, angiogenesis, and cancer. Critical reviews in oncology/hematology. 2013;88(3):637-54.
  6. Anastasi E, Ialongo C, Labriola R, Ferraguti G, Lucarelli M, Angeloni A. Vitamin K deficiency and covid-19. Scand J Clin Lab Invest. 2020:1-3.
  7. Dofferhoff ASM, Piscaer I, Schurgers LJ, Visser MPJ, van den Ouweland JMW, de Jong PA, et al. Reduced vitamin K status as a potentially modifiable risk factor of severe COVID-19. Clin Infect Dis. 2020.
  8. Fain ME, Kapuku GK, Paulson WD, Williams CF, Raed A, Dong Y, et al. Inactive Matrix Gla Protein, Arterial Stiffness, and Endothelial Function in African American Hemodialysis Patients. Am J Hypertens. 2018;31(6):735-41.
  9. Jespersen T, Mollehave LT, Thuesen BH, Skaaby T, Rossing P, Toft U, et al. Uncarboxylated matrix Gla-protein: A biomarker of vitamin K status and cardiovascular risk. Clin Biochem. 2020;83:49-56.
  10. Piscaer I, van den Ouweland JMW, Vermeersch K, Reynaert NL, Franssen FME, Keene S, et al. Low Vitamin K Status Is Associated with Increased Elastin Degradation in Chronic Obstructive Pulmonary Disease. J Clin Med. 2019;8(8).
  11. van Ballegooijen AJ, Beulens JWJ, Kieneker LM, de Borst MH, Gansevoort RT, Kema IP, et al. Combined low vitamin D and K status amplifies mortality risk: a prospective study. Eur J Nutr. 2020.
  12. Zwakenberg SR, Burgess S, Sluijs I, Weiderpass E, consortium E-C, Beulens JWJ, et al. Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study. Clin Nutr. 2020;39(4):1131-6.
  13. Organization WH. WHO R and D Blueprint and COVID-19. 2020.
  14. Holick MF. Vitamin D deficiency. The New England journal of medicine. 2007;357(3):266-81.
  15. Simes DC, Viegas CSB, Araujo N, Marreiros C. Vitamin K as a Diet Supplement with Impact in Human Health: Current Evidence in Age-Related Diseases. Nutrients. 2020;12(1).
  16. Shen T, Bimali M, Faramawi M, Orloff MS. Consumption of Vitamin K and Vitamin A Are Associated With Reduced Risk of Developing Emphysema: NHANES 2007-2016. Front Nutr. 2020;7:47.
  17. Jamilloux Y, Henry T, Belot A, Viel S, Fauter M, El Jammal T, et al. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun Rev. 2020;19(7):102567.
  18. Pan MH, Maresz K, Lee PS, Wu JC, Ho CT, Popko J, et al. Inhibition of TNF-alpha, IL-1alpha, and IL-1beta by Pretreatment of Human Monocyte-Derived Macrophages with Menaquinone-7 and Cell Activation with TLR Agonists In Vitro. J Med Food. 2016;19(7):663-9.
  19. Ohsaki Y, Shirakawa H, Hiwatashi K, Furukawa Y, Mizutani T, Komai M. Vitamin K suppresses lipopolysaccharide-induced inflammation in the rat. Biosci Biotechnol Biochem. 2006;70(4):926-32.
  20. Reddi K, Henderson B, Meghji S, Wilson M, Poole S, Hopper C, et al. Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds. Cytokine. 1995;7(3):287-90.
  21. Ohsaki Y, Shirakawa H, Miura A, Giriwono PE, Sato S, Ohashi A, et al. Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor kappaB through the repression of IKKalpha/beta phosphorylation. J Nutr Biochem. 2010;21(11):1120-6.
  22. Ozaki I, Zhang H, Mizuta T, Ide Y, Eguchi Y, Yasutake T, et al. Menatetrenone, a vitamin K2 analog, inhibits hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of nuclear factor kappaB activation. Clin Cancer Res. 2007;13(7):2236-45.
  23. Xia J, Matsuhashi S, Hamajima H, Iwane S, Takahashi H, Eguchi Y, et al. The role of PKC isoforms in the inhibition of NF-kappaB activation by vitamin K2 in human hepatocellular carcinoma cells. J Nutr Biochem. 2012;23(12):1668-75.
  24. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA Netw Open. 2020;3(9):e2019722.
  25. Panagiotou G, Tee SA, Ihsan Y, Athar W, Marchitelli G, Kelly D, et al. Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID-19 are associated with greater disease severity. Clinical endocrinology. 2020;93(4):508-11.
  26. Liu W, Zhang L, Xu HJ, Li Y, Hu CM, Yang JY, et al. The Anti-Inflammatory Effects of Vitamin D in Tumorigenesis. Int J Mol Sci. 2018;19(9).
  27. Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients. 2013;5(7):2502-21.
  28. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ (Clinical research ed). 2017;356:i6583.
  29. Eckard AR, O’Riordan MA, Rosebush JC, Lee ST, Habib JG, Ruff JH, et al. Vitamin D supplementation decreases immune activation and exhaustion in HIV-1-infected youth. Antiviral therapy. 2018;23(4):315-24.
  30. Yancy CW. COVID-19 and African Americans. JAMA. 2020; 323(19):1891-1892.
  31. Bjørklund G, Svanberg E, Dadar M, Card DJ, Chirumbolo S, Harrington DJ, Aaseth J. The Role of Matrix Gla Protein (MGP) in Vascular Calcification. Curr Med Chem. 2020;27(10):1647-1660. doi: 10.2174/0929867325666180716104159. PMID: 30009696.
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As a successful naturopathic physician, Dr. Myers is passionate about creating solutions to the world's prominent health problems by combining the artfulness of natural medicine with the science of the human body. He has a unique ability to take complex health issues and simplify them, bringing about an understanding that health and wellness are attainable for every individual. ​ Dr. Myers has been in private medical practice since 1992. He is a graduate of Bastyr University and completed his residency at the Bastyr Center for Natural Health. ​ Speaking to audiences worldwide, Dr. Myers communicates the value of taking simple health measures to promote wellness. His genuine manner inspires his listeners to take valuable health-related information and apply it to their daily lives. ​ As a recognized authority on natural medicines, Dr. Myers is viewed as one of the world's top experts in the formulation of dietary supplements and their scientific substantiation. ​ Dr. Myers formulates complete nutritional lines for global companies and has developed many successful products. He has authored patents ranging from arthritis and weight management to cardiovascular care and pet nutrition. ​ Acting as coordinator for a number of clinical trials, Dr. Myers evaluated the effectiveness of natural products in the treatment of obesity, prostate disease and cardiovascular concerns. ​ Appearing in numerous forms of media, Dr. Myers has made repeat appearances on QVC both in the United States and the United Kingdom.