Lesson 15: Science-backed Nutraceutical Support for Hyperinflammation
Lesson 15 Protocol 4
Understand how each of eight nutraceuticals can help you de-escalate a hyperinflammatory response to SARS-CoV-2 infection and COVID-19 disease.
Review the benefits attributable to each nutraceutical, and consume those that best address your vulnerability to getting infected with SARS-CoV-2 and risk getting health-threatening COVID-19 symptoms; given your age, lifestyle behaviors, and comorbidities.
If, given the comorbidities discussed throughout this course, you're vulnerable to getting a SARS-CoV-2 infection and resulting COVID-19, consider taking this nutraceuticals before getting infected and sick.
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Ding S, Xu S, Ma Y, Liu G, Jang H, Fang J. Modulatory mechanisms of the NLRP3 inflammasomes in diabetes. Biomolecules. 2019;9(12):E850. doi:10.3390/biom9120850.
Chen IY, Moriyama M, Chang MF, Ichinohe T. Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Front Microbiol. 2019;10:50. doi:10.3389/fmicb.2019.00050.
Tőzsér J, Benkő S. Natural compounds as regulators of NLRP3 inflammasome-mediated IL-1β production. Mediators Inflamm. 2016;2016:5460302. doi:10.1155/2016/5460302.
Covid-19: Functional Medicine Resources. The Functional Medicine Approach to COVID-19: Virus-Specific Nutraceutical and Botanical Agents. The Institute for Functional Medicine. April 7, 2020.
Di A, Xiong S, Ye Z, et al. The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation. Immunity. 2018;49(1):56-65.e4. doi:10.1016/j.immuni.2018.04.032.
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Moghadamtousi SZ, Kadir HA, et al. A review on antibacterial, antiviral, and antifungal activity of curcumin. Biomed Res Int. 2014;2014:186864.
Yin H, Guo Q, et al. Curcumin Suppresses IL-1β Secretion and Prevents Inflammation through Inhibition of the NLRP3 Inflammasome. J Immunol. 2018 Apr 15;200(8):2835-2846. doi: 10.4049/jimmunol.1701495. Epub 2018 Mar 16. PMID: 29549176.
Utomo RY, Ikawati M, Meiyanto E. Revealing the Potency of Citrus and Galangal Constituents to Halt SARS-CoV-2 Infection. Preprints 2020, 2020030214.
Secor ER Jr, Carson WF IV, et al. Bromelain exerts anti-inflammatory effects in an ovalbumin-induced murine model of allergic airway disease. Cell Immunol (2005) 237 68–75.
Rathnavelu V, Alitheen NB, et al. Potential role of bromelain in clinical and therapeutic applications. Biomed Rep. 2016;5(3):283-288. doi:10.3892/br.2016.720.
Müller S, März R, Schmolz M, Drewelow B, Eschmann K, Meiser P. Placebo-controlled randomized clinical trial on the immunomodulating activities of low- and high-dose bromelain after oral administration - new evidence on the antiinflammatory mode of action of bromelain. Phytother Res. 2013 Feb;27(2):199-204.
Misawa T, Saitoh T, Akira S. Resveratrol inhibits the acetylated α-tubulin-mediated assembly of the NLRP3-inflammasome. Int Immunol. September, 2015 (9): 425-34.
Yang SJ, Lim Y. Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation. Metabolism. May, 2014; 63(5): 693-701.
Li YQ, Li ZL, Zhao WJ, et al. Synthesis of stilbene derivatives with inhibition of SARS coronavirus replication. Eur J Med Chem. 2006; 41(9):1084-1089. doi:10.1016/j.ejmech.2006.03.024.
Wang H, Syrovets T, Kess D, et al: Targeting NF-kappa B with a natural triterpenoid alleviates skin inflammation in a mouse model of psoriasis. J Immunol. 2009.183:4755-4763.
Moussaieff A, Shohami E, Kashman Y, et al. Incensole acetate, a novel anti-inflammatory compound isolated from Boswellia resin, inhibits nuclear factor-kappa B activation. Mol Pharmacol. 2007. 72(6):1657-1664. doi:10.1124/mol.107.038810.
Shahenvaz Alam, Syeda Warisul, et al. Unravelling promise of Indian herbal compounds as potential COVID-19 therapeutic agent. Research Square. July 16, 2020. DOI:10.21203/rs.3.rs-41688/v1.
T?zsér J, Benk? S. Natural compounds as regulators of NLRP3 inflammasome-mediated IL-1β production. Mediators Inflamm. 2016:5460302. doi:10.1155/2016/5460302.
Lee HE, Yang G, Park YB, et al. Epigallocatechin-3-gallate prevents acute gout by suppressing NLRP3 inflammasome activation and mitochondrial DNA synthesis. Molecules. 2019; 24(11):E2138. doi:10.3390/molecules24112138.
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Li S, Yang H, Chen X. Protective effects of sulforaphane on diabetic retinopathy: activation of the Nrf2 pathway and inhibition of NLRP3 inflammasome formation. Exp Anim. 2019 May 8;68(2):221-231.
Yang G, Yeon SH, et al. Suppression of NLRP3 inflammasome by oral treatment with sulforaphane alleviates acute gouty inflammation. Rheumatology (Oxford). April, 2018. 57(4):727-736.
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Dias IH, Chapple IL, et al. Sulforaphane restores cellular glutathione levels and reduces chronic periodontitis neutrophil hyperactivity in vitro. PLoS One. June, 2013.8(6):e66407.
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In Lesson 14 you learned that two molecules that can be responsible for a hyperinflammatory reaction to SARS-CoV-2 and COVID-19 are NLRP3 and Nuclear factor kappa ?.
In this lesson, Lesson 15, we cover eight nutracueticals that studies indicate may be helpful to prevent or reduce this hyperinflammation.
Those with the comorbidities reviewed in Lesson 10, or over the age of 50, may elect to take these nutraceuticals at the first sign of infection, even if symptoms are Mild or Moderate.
Should symptoms escalate to Severe or Critical, everyone should consider using these nutraceurtcials; however, at this stage you should be under a doctor's care and he or she can guide you.
Science-backed Nutraceutical Support For Hyperinflammation
Here’s a possible scenario you could face: You have one or more of the comorbidities described earlier in Lesson 10, or you’re over 50. Your symptoms are getting progressively worse, and you’ve done Protocols one through three. But you got infected anyway, and now you’re really sick and in a hyperinflammatory state.
As I said before, in this scenario you should probably be in a hospital. Certainly, you should be under a doctor’s care. But just in case you’re not, the burning question is, What can you do to tamp down this escalating inflammation?
The answer is to consume the nutraceuticals covered in this lesson that can help downregulate NLRP3 and Nuclear factor kappa ?
Remember from the last lesson that NLRP3 drives inflammation in the lung and Nuclear factor kappa Beta drives pro-inflammatory cytokines. So, we want to inhibit NLRP3 and Nuclear factor kappa ? activation.
You know by now that a coronavirus such as SARS-CoV-2 can be deadly because of its ability to stimulate a part of the innate immune response called the inflammasome, which can cause uncontrolled release of pro-inflammatory cytokines, leading to cytokine storm and severe, sometimes irreversible, damage to your lungs. 
We reviewed that one reason why the SARS-CoV-2 virus can be so harmful, even deadly, is because it can activate the NLRP3 inflammasome. [2,3]
A 2016 review of many studies about regulators of NLRP3 identifies the nutraceuticals useful for this purpose, as well as being helpful for regulating Nuclear factor kappa ? in some cases.
[“... polyphenols like resveratrol, curcumin, EGCG [a green tea catechin], and quercetin are potent inhibitors of NLRP3 inflammasome-mediated IL-1β [interleukin beta] production, typically acting at more than one element of the involved pathways. However, it should be noted that these polyphenols have an even much broader biological effect, as they influence a variety of pathways.”
The research reviewed by the Institute of Functional Medicine supports the use of those polyphenols, and adds a few more to help prevent activation of the NLRP3 inflammasome, to decrease Nuclear factor kappa ? activation, and to potentially inhibit SARS-CoV-2 replication. 
Research studies support the following eight nutraceuticals to potentially be helpful to prevent or reduce the hyperinflammation caused by NLRP3 and Nuclear factor kappa ?:
Let’s examine each nutraceutical in terms of its potential to tamp down hyperinflammation.
Potassium is one of seven essential macrominerals. The human body requires at least 100 milligrams of potassium daily to support key biological processes, although that is the bare minimum, not a healthy amount.
Maintaining blood potassium levels is important to prevent potassium cellular efflux, which is a condition where the potassium content of cells flow out of them.
Potassium cellular efflux upregulates inflammasome assembly, which is a fancy way of saying that insufficient potassium in cells are responsible for the activation of inflammatory responses. 
Because potassium is easily obtained from foods, such as apricots, beans, squash and potatoes, deficiencies in the macromineral are uncommon unless you:
- Use certain medicines, such as diuretics.
- Have physically demanding jobs.
- Athletes exercising in hot climates and sweating excessively.
- Have health conditions that affect their digestive absorption, such as Crohn's disease.
- Have an eating disorder.
- Abuse alcohol or drugs.
Curcumin is a compound in turmeric, the common Indian spice. It has well-documented beneficial health effects, such as antiviral and anti-inflammatory activity. [7,8]
It’s also been shown to suppress NLRP3 activation, and is thought to have the potential to halt viral entry into host cells. [9,10]
Although you can get curcumin from eating the Indian spice turmeric, it's highly unlikely you'll get sufficient quantities to have a therapeutic effect, especially given that curcumin is poorly absorbed. Your best bet is to supplement with a curcumin formulation that enhances bioavailability. Check the Nutraceutical Guide for recommendations.
Bromelain is an enzyme extract derived from the stems of pineapples. Many studies have documented the ability of bromelain to reduce inflammation and inflammatory diseases.
Of particular importance here is bromelain’s documented ability to decrease tissue edema and inflammation. Several studies have shown that bromelain is effective in respiratory conditions such as asthma, bronchitis, and sinusitis that are characterized by increased mucus production and inflammation. [11,12]
Research also shows that bromelain decreases cytokines. A placebo-controlled randomized clinical trial found that high-dose oral bromelain showed immunomodulation of both Th-1 and Th-2 cytokines. 
Resveratrol is a natural chemical (a stilbenoid) produced by several plants in response to injury or when the plant is under attack by pathogens. Sources of resveratrol in food include the skin of grapes, blueberries, raspberries, peanuts and coca.
Resveratrol has been shown to reduce inflammation, as well as to inhibit the mitochondrial damage in macrophages, which can happen when the NLRP3 inflammasome is initiated. [15-17]
If you choose to supplement with resveratrol, choose the trans resveratrol formulation. As I wrote in a post about trans-resveratrol:
“Trans-resveratrol is the best resveratrol supplement you can take simply because your body can absorb it better. Regular resveratrol is not very bioavailable, thus compromising its potential health benefits.”
Boswellia, also called Indian frankincense, is a resin herbal extract from the boswellia tree that exerts a number of anti-inflammatory effects. It’s been shown to significantly inhibit NFKB signaling, although I should point out that these were in mice models. [17,18]
Nonetheless, boswellia is on our list of inflammatory-suppressing nutraceuticals, because even though you’re not a mouse, boswellia has been used for centuries to treat chronic inflammatory illnesses. Moreover, a July 2020 study not yet peered reviewed found that:
“Out of eleven compounds, β-boswellic acid (Boswellia serrata) was found to be best suitable along with Glycyrrhizic acid (Glycyrrhiza glabra). Being medicinal compounds, their efficacy was found to be higher than conventionally available anti-viral, anti-inflammatory and anti-malarial drugs. With the advantage of being natural source, it features no harmful side effects, these novel compounds make a great choice to be used for the treatment of COVID patients.” 
As you may recall from Lesson 13, Glycyrrhiza glabra is Licorice root. Combining it with boswellia appears to be a potent combination against the potentially unregulated inflammatory reaction of the immune system to viral infection.
EGCG (epigallocatechin gallate) is a polyphenol with potent health protective effects against several chronic diseases, but here our focus is to tamp down the immune system’s potential lingering and accelerating inflammatory response to Covid. To that end, EGCG can help modulate the NLRP3 inflammasome, potentially targeting the SARS-CoV-2 main protease (a type of protein) to reduce viral replication, and has also been shown to prevent influenza in healthcare workers. [20-22]
You can supplement with an EGCG extract, but getting it from high-EGCG content tea may be a better, more natural source. Brewed tea contains the highest concentration of EGCG, and its concentration increases with brewing time. To maximize EGCG content, pour boiling water (not just hot water) over a green tea bag, and let steep for ten minutes before drinking it.
EGCG, like other catechins, binds to proteins in our food and make them less absorbable into your bloodstream; thus, drink the tea between meals rather than directly with food to get the most benefit. EGCG can also bind with minerals in food such as iron; this also reduces its absorption, and provides an additional reason to consume green tea separately from other foods.
Sulforaphane is a well-studied anti-inflammatory phytochemical found in cruciferous vegetables, such as broccoli (especially the sprouts), cabbage, cauliflower, Brussels sprouts, Swiss chard and bok choy.
Sulforaphane inhibits NLRP3 inflammasome biology. [23,24] It also activates an antioxidant pathway [Nrf2] pathway and upregulates glutathione levels. [25,26]
What that translates to is that sulforaphane helps to tamp down excess inflammation, while improving the ability of our body to produce more of its “Master Antioxidant”, glutathione, as reviewed in Lesson 9.
It’s noteworthy that curcumin, resveratrol, quercetin, and berberine have all been shown to promote AMPK (adenosine 5′ monophosphate-activated protein kinase). 
AMPK is an enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It’s also a promoter of SIRT2 (one of seven sirtuin genes in mammals involved in ageing, energy production and lifespan extension) that is known to inhibit NLRP3 inflammasome assembly. 
PEA (Palmitoylethanolamide) is a naturally occurring food component that is an anti-inflammatory palmitic acid derivative that interfaces with the endocannabinoid system.
(Palmitic acid is the most common saturated fatty acid found in animals, plants and microorganisms. The endocannabinoid system is one composed of endogenous lipid-based neurotransmitters that bind to cannabinoid receptors and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system.)
PEA has emerged as a useful nutraceutical, because this compound is naturally produced in many plant and animal food sources, as well as in cells and tissues of mammals, and is endowed with important neuroprotective, anti‐inflammatory and analgesic actions. 
A 2013 study published in the International Journal of Inflammation found a significantly favorable outcome in five of six double blind placebo-controlled trials looking at acute respiratory disease due to influenza. 
There are multiple mechanisms of action associated with PEA that result in attenuating the potentially fatal cytokine storm , as well as being an effective agent in relieving inflammatory and neuropathic pain. 
If you have the misfortune of getting into this hyperinflammatory phase, consider taking the nutraceuticals I just reviewed. That said, at this point, hopefully you’ll also be under your doctor’s care.
In Lesson 14 you learned that two molecules that can be responsible for a hyperinflammatory reaction to SARS-CoV-2 and COVID-19 are NLRP3 and Nuclear factor kappa ?. In this lesson we covered eight nutracueticals that studies indicate may be helpful to prevent or reduce this hyperinflammation.
Those with the comorbidities reviewed in Lesson 10, or over the age of 50, may elect to take these nutraceuticals at the first sign of infection, even if symptoms are Mild or Moderate. Should symptoms escalate to Severe or Critical, everyone should consider using the nutraceurtcials; however, at this stage you should be under a doctor's care and he or she can guide you.
And that ends this Covid Immunity Course. I now I leave you to put into practice all that you've learned.