The potential of vitamins D and K2 for the immune system

Overcoming micronutrient deficiencies such as zinc and vitamins C, D and K2 has gained attention as a potential part of building a strategic response to the COVID-19 pandemic. Research supporting vitamin D supplementation is already compelling and quickly gaining government and public notice. Vitamin K has long remained in the shadows, but recent studies suggest it might benefit the immune system.

Vitamin D for immunity

Several meta-analyses have already demonstrated vitamin D benefits against respiratory tract infections; low levels of vitamin D were associated with a higher risk for infection and symptoms severity.^1-4 Similar findings have been published regarding an association of low vitamin D levels and a higher risk for SARS-CoV-2 infection.^5-12

D, K2: A common connection to calcium

Vitamin D intake is generally regarded as safe, but high doses of vitamin D could induce short-term hypercalcemia, a transient increase in serum calcium levels.¹³ Calcium, although vital for the normal function of the human body, may have deleterious consequences when it cannot be properly absorbed into the bone matrix.¹⁴ Deposition of calcium in the blood vessels, or on elastic fibers in the lungs, can lead to damages.^15,16,17 Co-supplementation of D with vitamin K2 may minimize this calcification risk.¹⁴

Through their common connection to calcium metabolism, vitamin D and K may work in pair for bone, vascular and immune health. But scientists postulate that vitamin D intake in a vitamin K deficiency state could endanger both pulmonary and vascular health.^13,18,19 This may be even more relevant in COVID-19 patients, whose lungs and vascular health are already compromised. Hence, taking adequate amounts of the circulating form of vitamin K2 along with D may be a better strategy. Furthermore, research points to the potential involvement of vitamin K in COVID-19 coagulopathy, which goes beyond mitigating the calcification risk induced by high vitamin D intake.¹³

Vitamin K2: The underrated vitamin

Insufficiency of vitamin K2 is thought to be common in Western populations due to dietary reasons.¹⁴ Because of their structural differences, vitamins K1 and K2 have different metabolic outcomes.^20,21 K1 is directly taken by the liver, where it is used to activate vital coagulation factors. K2 on the other hand is left available for the rest of the body to activate different, yet equally crucial, proteins. In bones, they incorporate calcium into the bone matrix. In soft tissues like blood vessels or the lungs, they prevent calcium deposition, elastic fiber degradation, thrombosis and inflammation.¹³

K2 implications in COVID-19

The latest research shows that poor COVID-19 outcomes correlate with low vitamin K status.²² A recent study evaluating serum vitamin K levels in COVID-19 hospitalized patients showed that those with poor outcomes of COVID-19 had the lowest levels of vitamin K. In comparison, people who tested negative for SARS-CoV-2 infection showed adequate vitamin K levels. Surprisingly, unpublished research showed patients with sufficient D levels had accelerated elastic fiber degradation, compared to those with mild deficiency. The study authors explained that by promoting K-dependent proteins' production, vitamin D might have unfavorable pro-calcification effects, and that vitamin K may compensate for the latter.

A second unpublished study later confirmed this correlation; K2 status was significantly lower among COVID-19 patients, and a statistical analysis showed mortality among COVID-19 patients to be strongly dependent on vitamin K status. “This suggests that vitamin K plays a role in the disease mechanisms,” the authors noted.

The ‘missing link’ in COVID-19

The British Journal of Nutrition published a review of the available scientific literature on vitamin K metabolism and its connection to COVID-19.¹³ The authors presented vitamin K deficiency as the potential missing link between lung damage and thromboembolism, two of the most severe outcomes observed in COVID-19.

Vitamin K2 has also been described as one of the best potential ligands to the recently discovered fatty acid binding site in SARS-CoV-2 spike protein.²³ Research suggests its binding would stabilize the locked spike conformation, thus reducing the opportunity of interaction with ACE2 receptor (through which SARS-CoV-2 enters host cells), limiting infection risks.

K2 for the immune system

Vitamin K may also play a role in the body’s response to inflammation.²⁴ Scientific support points to vitamin K’s role in the modulation of the cell signaling complex, nuclear factor kappa-B (NF-kB).²⁵ This major transcription factor helps regulates genes responsible for both the innate and adaptive immune response. Vitamin K can regulate the activation of the NF-kB pathway, modulating the immune and inflammatory responses. Similarly, vitamin K inhibits cytokine release, among which the potent cytokine interleukin (IL)-6,²⁶ which is used as an inflammatory marker for severe COVID-19 infection with poor prognosis, noted several presenters at a virtual cardiovascular conference hosted in April 2020 by Imperial College London.

Research is ongoing

A clinical trial investigating possible benefits of vitamin K2 supplementation in COVID-19 patients has been initiated by the Canisius Wilhelmina Hospital, Nijmegen, Netherlands. Funded by Kappa Bioscience, the randomized, double-blind, placebo-controlled “KOVIT” trial aims to evaluate whether vitamin K status affects elastic fibers degradation in the lungs. Research will be led by two doctors—pulmonologist Rob Janssen, Ph.D., and coordinating investigator Jona Walk, Ph.D., resident in internal medicine.

“There is a need for further experimental evidence to link vitamin K deficiency with the pathology of COVID-19 and determine whether vitamin K2 supplementation has a place in treatment protocols,” Janssen detailed. “The potential role of vitamin K2 supplementation to prevent development of severe COVID-19 in subjects who have not yet contracted COVID-19, but are at risk for the infection, is also very relevant to assess.”

Kappa Bioscience AS is entering research agreements with several research centers in Europe and the U.S. The company aims to support research to generate a better understanding around vitamin K2 deficiency and COVID-19 pathogenesis.

Based on the recently published science, it is important to seek more understanding about the potential role of vitamin K2 in COVID-19 and immune health through research collaborations with experts in the field.

Trygve Bergeland is the vice president of science at Kappa Bioscience.

To read related content, click the following link to access the “Immune health rising” digital magazine.

References

1 Bergman P et al. “Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials.” PloS One. 2013;8(6):e65835.

2 Martineau AR et al. “Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.” BMJ. 2017;356:i6583.

3 Pham H et al. “Acute respiratory tract infection and 25-hydroxyvitamin D concentration: a systematic review and meta-analysis.” Int J Environ Res Public Health. 2019;16(17):3020.

4 Zhou YF, Luo BA, Qin LL. “The association between vitamin D deficiency and community-acquired pneumonia: A meta-analysis of observational studies.” Medicine. 2019;98(38).

5 Ali N. “Role of Vitamin D in Preventing of COVID-19 Infection, Progression and Severity.” J Infect Public Health. 2020;13(10):1373-1380.

6 D’Avolio A et al. “25-hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2.” Nutrients. 2020;12(5):1359.

7 Ilie PC, Stefanescu S, Smith L. “The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality.” Aging Clin Exp Res. 2020:1-4.

8 Im JH et al. “Nutritional status of patients with COVID-19.” Int J Infect Dis. 2020;100:390-393.

9 Kaufman HW et al. “SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels.” PLoS One. 2020;15(9):e0239252.

10 Meltzer DO et al. “Association of vitamin D status and other clinical characteristics with COVID-19 test results.” JAMA Netw Open. 2020;3(9):e2019722-e2019722.

11 Panagiotou G et al. “Low serum 25‐hydroxyvitamin D (25 [OH] D) levels in patients hospitalized with COVID‐19 are associated with greater disease severity.” Clin Endocrinol. 2020;93(4):508-511.

12 Radujkovic A et al. “Vitamin D Deficiency and Outcome of COVID-19 Patients.” Nutrients. 2020;12(9):2757.

13 Janssen R et al. “Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Covid-19.” Br J Nutr. 2020;1-25.

14 Maresz K. “Proper calcium use: vitamin K2 as a promoter of bone and cardiovascular health.” Integr Med: Clin J. 2015;14(1):34.

15 Lutsey PL, Michos ED. “Vitamin D, calcium, and atherosclerotic risk: evidence from serum levels and supplementation studies.” Curr Atheroscler Rep. 2013;15(1):293.

16 Sung KC et al. “High levels of serum vitamin D are associated with a decreased risk of metabolic diseases in both men and women, but an increased risk for coronary artery calcification in Korean men.” Cardiovasc Diabetol. 2016;15(1):112.

17 Wang J et al. “Vitamin D in vascular calcification: a double-edged sword?” Nutrients. 2018;10(5):652.

18 Price PA, Buckley JR, Williamson MK. “The amino bisphosphonate ibandronate prevents vitamin D toxicity and inhibits vitamin D-induced calcification of arteries, cartilage, lungs and kidneys in rats.” J Nutr. 2001;131(11):2910-2915.

19 Van Ballegooijen AJ et al. “Joint association of vitamins D and K status with long-term outcomes in stable kidney transplant recipients.” Nephrol Dial Transplant. 2020;35(4):706-714.

20 Vermeer CV. “Vitamin K: the effect on health beyond coagulation – an overview.” Food Nutr Res. 2012;56(1):5329.

21 Schurgers LJ, Vermeer CV. “Differential lipoprotein transport pathways of K-vitamins in healthy subjects.” Biochim Biophys Acta Gen Subj. 2002;1570(1):27-32.

22 Dofferhoff ASM et al. “Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019.” Clin Infect Dis. 2020:ciaa1258.

23 Shoemark DK et al. “Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS‐CoV‐2 Spike Protein.” Angewandte Chemie. 2021;60(13):7098-7110.

24 Reddi K et al. “Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds.” Cytokine. 1995;7(3):287-290.

25 Ghosh S, Dass JFP. “Study of pathway cross-talk interactions with NF-κB leading to its activation via ubiquitination or phosphorylation: A brief review.” Gene. 2016;584(1):97-109.

26 Rossol M et al. “LPS-induced cytokine production in human monocytes and macrophages.” Crit Rev Immunol. 2011;31(5):379-446.