Over the past month, there have been circulating concerns regarding the safety of certain dietary supplements in the context of the current immunity challenge we are facing as a global community.
Some healthcare professionals have advised patients to avoid supplemental vitamins A and D, as well as the traditional herb elderberry, arguing that these supplements may increase the severity of immune threats and potentially even cause an intimidating-sounding phenomenon called a “cytokine storm.” Unfortunately, these concerns, and advice to avoid supplemental vitamins A and D and elderberry, are based on a misunderstanding of how these nutrients impact the immune system and inflammatory processes. In this blog, we would like to clear up the confusion regarding supplementing with vitamins A, D, and elderberry, and instead, strongly encourage you to include them as part of your immune support protocol.
The Beginning of the Controversy: ACE2 and Cytokine Storms
The controversy surrounding the use of vitamins A and D and elderberry to address immune challenges begins with an enzyme called ACE2 and a biological phenomenon called a “cytokine storm.”
Let’s start by discussing the system within which the ACE2 receptor functions, the renin-angiotensin system (RAS), followed by a discussion of what cytokine storms are and how they may or may not be impacted by elderberry.
What is the Renin-Angiotensin System?
The renin-angiotensin system (RAS) is a hormonal system that regulates blood pressure, fluid and electrolyte balance, and the function of your circulatory system that carries blood throughout your body. When your body experiences a drop in blood volume or blood pressure, the RAS activates a cascade of hormones and other signaling molecules that work together to constrict blood vessels and raise blood pressure back to a healthy level.
Angiotensin II is a primary molecule in the RAS that has a variety of effects on the human body. It raises systemic arterial blood pressure and causes the release of aldosterone by your adrenal glands. Aldosterone causes the kidneys to reabsorb more sodium and water from urine, thus raising blood pressure.
Angiotensin-converting enzyme (ACE) is a crucial enzyme in the RAS that converts a peptide called angiotensin I into angiotensin II, promoting blood vessel constriction and raising blood pressure. ACE2, the sister enzyme to ACE, counters the activity of ACE, reducing the formation of angiotensin II and initiating the formation of angiotensin (1-7), which have inflammation-modulating and blood pressure lowering effects on the body.
ACE inhibitors prevent ACE activity, which relax the vascular system and lower blood pressure. ACE inhibitors are thus used for the treatment of high blood pressure and cardiovascular disease. However, research shows ACE inhibitors also upregulate ACE2, and ACE2 receptors have been found to facilitate the entry of certain foreign invaders into human cells. This is where the controversy and confusion begin regarding nutrients that increase ACE2 expression.
ACE2 Is an Entry Portal for Foreign Invaders, But There’s More to the Story
Angiotensin-converting enzyme 2 (ACE2) recently came into the spotlight when it was discovered that it serves as an entry portal for harmful foreign invaders into the cells of our bodies.1 Once these intruders enter cells via ACE2 receptors, they can replicate and establish an infection. This has led some people to believe that decreasing the level of ACE2 receptors in cells might help reduce risk of infection. However, it is important to also consider that ACE2 is shown to have protective effects against invader-induced lung damage by increasing the production of peptides that dilate blood vessels.2,3
Increasing ACE2 expression can actually help promote healthy inflammatory levels which may counteract the negative effects precipitated by harmful foreign invaders.
Still, some healthcare professionals believe that patients should discontinue supplements that increase ACE2 expression, including vitamins A and D, because in theory, these substances could increase the receptors through which foreign invaders get into cells.5 However, scientists point out that we currently have no data proving a causal relationship between ACE2 activity and foreign invader-induced mortality so it is premature to make recommendations to avoid supplements that boost ACE2 expression.6
In our opinion, it is a gross oversimplification to suggest that, simply because vitamins A and D upregulate ACE2, they may increase our risk of immune threats. Vitamins A and D offer multi-faceted support for healthy immune and inflammatory balance, supporting a healthy RAS and optimal ACE2 levels. Vitamins A and D also support the immune system in our gut, which, when compromised, may make us more susceptible to immune threats.7
Overall, the relationship between ACE2 and immunity is complicated. However, what is clear is that ACE2 appears to play dual roles in influencing both our susceptibility and immunity to foreign invaders. Reducing ACE2 expression may come at a cost – increased susceptibility to pathogen-induced problems, increasing our risk of invader-induced damage. Avoiding micronutrients that upregulate ACE2 expression, such as vitamins A and D, will likely have adverse, rather than protective effects on immune function and susceptibility to harmful intruders
Vitamins A and D, ACE2, and Immunity
Vitamin A influences the activity of the renin-angiotensin-aldosterone system, including upregulating ACE2 expression.5 The upregulation of ACE2 by vitamin A helps promote a healthy blood pressure, suggesting that it supports normal functioning of the body.8 If vitamin A can promote a healthy blood pressure via ACE2, it follows that it may reduce susceptibility to harmful bugs by decreasing ACE2 expression.
In addition to balancing the RAS, vitamin A supplementation supports a robust immune response to invaders. Animals that are deficient in vitamin A have been found to be more susceptible to these threats than those who have healthy levels of vitamin A.9
Vitamin D also helps support the body’s defense against invaders by increasing ACE2 expression, particularly in the lungs. 10,11 In the presence of harmful bugs, lung epithelial cells convert inactive vitamin D into active vitamin D, increasing the expression of a peptide called cathelicidin, which has microbial-balancing effects.
Furthermore, vitamin D deficiency is independently associated with an increased risk of suffering from seasonal microbial threats.12 Vitamin D receptors (VDR) are present on most immune cells, indicating their indispensability as components of the immune system.13 Vitamin D modulates both the innate and adaptive immune responses to unwanted bugs, offering comprehensive support for immunity.12
Vitamins A and D may increase ACE2 but, as you can see, this effect appears to help support the body’s defenses against seasonal microbial threats, rather than cause harm to the body. While we are not suggesting that vitamins A and D are a proverbial ‘magic bullet’, we firmly believe that they should be a central part of your immune support protocol.
Our Position on Elderberry
Elderberry (Sambucus nigra) is a small dark purple berry that has been used for centuries in traditional herbalism as an aid to the immune system. However, this herb has unfortunately been featured in an unfavorable light in the context of recent immune threats. Some people have expressed concerns over whether elderberry may induce a “cytokine storm” and worsen health. We would like to clear the air and reassure you that elderberry can, and should, be a central part of your immune support protocol and that fears regarding its purported potential to trigger a cytokine storm are unfounded.
Can Elderberry Cause a Cytokine Storm?
What exactly is a cytokine storm, and should you stop taking elderberry for fear of experiencing this reaction? Let’s take a look at this concern in more detail.
A cytokine storm is an overproduction of immune cells and their activating products, cytokines. Cytokine storms occur in the end stages of severe infection, particularly those that are viral in origin. The cytokine storm causes extreme lung inflammation and fluid buildup in the lungs, sickening, and sometimes even causing death.14
Some people have taken the concept of a cytokine storm entirely out of context, claiming that anything stimulating to the immune system, such as elderberry, can cause a “cytokine storm.”
It bears repeating, a cytokine storm is a massive immunological reaction triggered in the end stages of a severe viral infection, not something that can be triggered by an herb or dietary supplement.
In fact, elderberry is an immune modulator, meaning it can balance immune activity. This enables it to help the immune system target invaders while promoting healthy inflammatory levels. Elderberry has been shown to help defend cells from entry by foreign invaders.15 It helps coordinate a more efficient immune response against invaders through the induction of cytokines such as IL-6 and IL-8. Furthermore, the antioxidant anthocyanin found in elderberry, may support a normal inflammatory response against invaders and, finally, supports the growth of beneficial gut bacteria, many of which have immune-bolstering properties.16,17,18 A meta-analysis of randomized control trials has also found that elderberry supplementation effectively supports respiratory health, which can be compromised by foreign invaders.19
Our opinion at Quicksilver Scientific is that you can safely take vitamins A and D and elderberry at this time, without worrying about increasing health risks. We believe these substances will help bolster the activity of your immune system and support your body’s defenses against the health threats our communities are facing.
- Zhang H, et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020. [online].
- Imai Y, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005; 436 (7047): 112-116.
- Michely D. Re: Preventing a covid-19 pandemic. BMJ. https://www.bmj.com/content/368/bmj.m810/rr-33. Published 19 March 2020. Accessed 24 March 2020.
- Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020. 1-4.
- Zhong JC, et al. Upregulation of angiotensin-converting enzyme 2 by all-trans retinoic acid in spontaneously hypertensive rats. Hypertension. 2004; 44(6): 907-912.
- Tucker ME. ESC says continue hypertension meds despite COVID-19 concern. Medscape. https://www.medscape.com/viewarticle/926838. Published 16 March 2020. Accessed 24 March 2020.
- Mora JR, et al. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol. 2008; 8(9): 685-698.
- Wu Z, et al. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020. [online].
- West CE, et al. Epithelia-damaging virus infections affect vitamin A status in chickens. J Nutr. 1992; 122(2): 333-339.
- Hansdottir S, et al. Respiratory epithelial cells convert inactive vitamin D to its active form: Potential effects on host defense. J Immunol. 2008; 181(10): 7090-7099.
- Xu J, et al. Vitamin D alleviates lipopolysaccharide‑induced acute lung injury via regulation of the renin‑angiotensin system. Molec Med Rep. 2017; 16(5). [online].
- Greiller CL and Martineau AR. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients. 2015; 7(6): 4240-4270.
- Lin R. Crosstalk between vitamin D metabolism, VDR signalling, and innate immunity. Biomed Res Int. 2016; 2016: 1375858.
- Tisoncik JR, et al. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012; 76(1): 16-32.
- Torabian G, et al. Anti-influenza activity of elderberry (Sambucus nigra). J Funct Foods. 2019; 54: 353-360.
- Ho GTT, et al. Elderberry and elderflower extracts, phenolic compounds, and metabolites and their effect on complement, RAW 264.7 macrophages and dendritic cells. Int J Mol Sci. 2017; 18(3): [online].
- Simonyi A, et al. Inhibition of microglial activation by elderberry extracts and its phenolic components. Life Sci. 2015; 128: 30-38.
- Lavefve L, et al. Berry polyphenols metabolism and impact on human gut microbiota and health. Food & Funct. 2020: [online].
- Hawkins J, et al. Black elderberry (Sambucus Nigra) supplementation effectively treats upper respiratory symptoms: A meta-analysis of randomized, controlled clinical trials. Complement Ther Med. 2019; 42: 361-365.