Pro-active vs re-active: Encouraging healthy immune balance

A question that has persisted through the decades is why does one person get deathly ill, another develops mild to moderate symptoms, and yet another develops no symptoms from the same virus? Dr. Robert Murphy, professor of medicine and director of the Center for Global Communicable Disease at Northwestern University, summed it up well, “that’s not the virus, that’s the host.” (1)

What actions can we take to support ongoing healthy immune function? Taking self-responsibility to cultivate your own healthy terrain is an essential step in maintaining health. Waiting for a crisis or relying only on outside sources is reactionary, removes locus of control from the individual, and is often not timely for a successful outcome. The role that a host’s terrain in the outcome of health and disease is a concept that is far from new in the world of natural health care.

The goal of this two-part article is to pick a few strategies (supplements and lifestyle) and explore some of the possible mechanisms of why and how they work.

These simple strategies for improving immune function are based on two main premises that are interrelated:

1. Lower baseline inflammatory burden
2. Support immune balance

Reduce Baseline Inflammation
The immune system has a coordinated order in managing threat. The ability to detect, signal for help, fight, and then reach resolution is an intricate balance the body knows how to co-ordinate, as long as there is minimal interference or background noise. Smoldering inflammation or inflammatory-based chronic diseases (obesity, metabolic syndrome, diabetes, cardiovascular disease) are co-morbidities that create background noise that disadvantage immune function.

The what, why and how of a few simple supplement strategies for immune health are discussed, although far from a complete list, these few cover the more researched and commonly known nutrients.

Vitamin D
The role vitamin D plays in immune function and inflammation has been a popular topic in nutritional science. Although there continues to be debate as to optimal serum levels, or daily dosing for supplementation, there is agreement that deficiency negatively affects health and is very common in today’s society.

Why: Vit D is thought to be highly pleotropic having numerous influences on health function and gene expression. The discovery of the specific molecular and signaling effects Vit D has on inhibiting the inflammatory cascade when at adequate levels was published in The Journal of Immunology in 2012.(3) More recently, the role of Vit D in both facilitating and attenuating the cellular immune response has been suggested, specifically in response to respiratory infections. Vit D deficiency may contribute to the development of acute respiratory distress syndrome (ARDS). (4)

How: When a pathogen is detected, macrophages will increase their uptake of Vit D, resulting in an increased activation of the Vit D receptor (VDR), inducing the nuclear expression of lysosomal enzymes, cathelicidin, and b defensin. Activation of these antimicrobial enzymes depend on the available level of Vit D. (5)

Vit D also assists in attenuating the immune response by reducing the production of pro-inflammatory cytokines, potentially reducing the risk of a cytokine storm. In response to infection the innate immune response generates both pro and anti-inflammatory cytokines. Vit D may help to reduce both IFNg, and TNFa inflammatory cytokines potentially quelling an overzealous immune response. (6) Vit D truly works as an immune modulator.

Gut health is a cornerstone to health. Another mechanism of immune support, Vit D incurs its role in maintaining a healthy gut barrier. Tight junctions, gap junctions, and adherens junctions rely on Vit D Viruses can disturb junction integrity and gain entry to the host. (6) Healthy gut integrity is an important physical barrier defense mechanism for the body and requires adequate Vit D to do so.

Suggested dose: 2000-5000 IU/d with food, monitor levels as a prevention strategy.

Although the recent paper by Grant et al suggests taking 10,000 IU/d for three weeks and reducing to 5000 IU/d, the goal is to raise the 25(OH)D concentrations between 100-150 nmol/L. “Test don’t guess” is always a good strategy when there is a potential for side effects. There are several factors that affect Vit D concentration variability including genetic SNP’s of VDR, and levels of Vit D binding protein, these situations could necessitate higher dosing.

Take 250mg of magnesium daily with Vit D. Magnesium is involved with many enzyme pathways in the body, as it is with most of the enzymes that metabolize Vit D.

Although the focus of this discussion is on prevention, the role of Vit D in the treatment of acute respiratory disease has been explored with positive outcomes for time spent in ICU. (6)

There are intervention trials underway looking at the role of Vit D in the treatment of COVID-19. (7)

Zinc
Although severe deficiency is rare, mild to moderate deficiency is common worldwide, unlike other minerals such as iron, zinc does not have a storage system in the body.

Why: Low zinc level is associated with severe impairment of the immune system, compromising both adaptive and innate function. Long term zinc deficiency contributes to pathological processes in chronic inflammation. (8) Zinc supplementation has been shown to reduce symptoms of the common cold; however, the real value may be in the prophylactic use of zinc. In a study looking at seniors aged 55-87, 45mg of zinc was supplemented for 12 months. There was a significant reduction in infections, inflammatory cytokines and markers of oxidative stress in the supplemented group. (9)

Zinc supplementation benefits are not limited to seniors. A study by Sazawal et al demonstrated a 45% reduction in incidence of acute lower respiratory infections in zinc supplemented children. (10)

How: During infection, the first responders of the innate system employ chemotaxis and phagocytosis as an early defense and signaling, this is reduced when there is zinc deficiency, and reversed with zinc supplementation. Zinc also induces thymulin activity, necessary for the maturation of T-cells.

Based on numerous studies suggesting multiple mechanism of action, it can be concluded zinc’s role as an antiviral fall in two categories:

1. Supplementation improves antiviral response and systemic immunity in those who are zinc deficient
2. Supplementation used as a treatment to specifically inhibit viral replication or infection related symptoms. (11)
3. zinc supplementation implemented to improve the antiviral response and systemic immunity in patients with zinc deciency, and 2)zinc treatment performed to specically inhibit viral replication or infection-related symptoms
4. zinc supplementation implemented to improve the antiviral response and systemic immunity in patients with zinc deciency, and 2)zinc treatment performed to specically inhibit viral replication or infection-related symptoms

Zinc, similar to Vit D, is important to epithelial barrier function. Zinc has a role in maintaining tight junctions and adheren junctions. When zinc is deficient, these barriers are compromised. This can also be seen in lung epithelial cells. This results in leakage cross the alveolar lung epithelium which may lead to uncontrolled neutrophil migration through disrupted junctions resulting in exacerbated inflammation leading to further mucosal damage. (12)

Suggested dose: 15-30mg/day, 45mg/day for seniors.

High dosing of zinc is not recommended and may induce a copper deficiency.

Zinc follows a U-shaped curve in its therapeutic benefit, deficiency increases risk of disease while too much zinc may also negatively affect health.

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Vitamin C
A well-known antioxidant and a commonly used nutrient, Vit C may not seem as “exciting” as other nutrients. Vit C’s role in preventing and possibly treating respiratory and systemic infection proves to be very interesting.

Why: Vitamin C deficiency is common in elderly, smokers, diabetics, and in fact it is 4th most common deficiency in the US. (13) Vit C deficiency negatively affects immune function and results in a high susceptibility to infection. Infection itself may further enhance the need for greater levels of vitamin C due to higher metabolic need during such times. (13)

How: Vit C’s role in preventing or reducing severity of the common cold has been debated. Vit C is however important in initiating the immune response. Vit C activates neutrophil migration, enhances phagocytosis, oxidant generation, and microbial killing. It also “assists in the resolution of the immune response, protecting the host from excessive damage by enhancing neutrophil apoptosis, clearance by macrophages and decreasing neutrophil necrosis”. (13) The last part of the previous statement is extremely important, if neutrophils are not properly cleared, there is a persistent ongoing stimulus for further neutrophil migration and death leading to tissue damage that can potentially be worse than the invading pathogen itself.

Vit C is likely far more sophisticated than just expressed and has a significant role in several gene regulatory enzyme pathways.

Even if Vit C does not reduce the incidence of infection, although evidence now supports this when there is added physical stress (14), the research shows prophylactic use reduces the risk of more serious infection such as pneumonia. The decrease in leukocyte Vit C levels, and urinary excretion during illness, suggests a higher demand for Vit C by the body in times of immune challenge.

Although this discussion is focused on prevention vs treatment, studies have shown using 1-3grams of oral Vit C reduced time spent in the ICU by 7.8%, and in another study it reduced the need for mechanical ventilation by 18.2%. (15) Dr. Andrew Weber, a critical care specialist affiliated with Northwell Health in New York was using 1500mg of IV Vit C three to four times/day with COVID-19 patients after hearing of successes using Vit C in China. It will be interesting to see the outcome of a clinical trial at China’s Zhongnan Hospital of Wuhan University using 12g IV Vit C with COVID-19 patients. Results are expected in September.

Suggested dose: 1000-3000mg/day in divided dose. Mild osmotic diarrhea is possible when bowel tolerance is reached (typically exceeding >3000mg/day)

Probiotics
The largest area of the body hosting immune cells is the gut mucosa immune system (MIS). Probiotics have intimate interaction with the gut mucosa immune system. Probiotics have been shown to affect the innate immune response and offered protection in gut distant mucosa such as the bronchi and urogenital mucosa. (16)

Why: A Cochrane review showed probiotics performed better than placebo in reducing the number of people experiencing episodes of acute upper respiratory tract infection by about 47%. (17). Studies looking at malnutrition models, such as undernourishment and obesity, probiotics increased the intestinal and systemic immune response. (16)

How: Probiotics interact with the intestinal epithelium stimulating a production of various cytokines and chemokines further stimulating the mucosal immune system, favoring the innate immune cells macrophages and dendritic cells. The MIS further activates immunoglobulin IgA cells of the intestine and bronchus, and also activates T cells.

Probiotics enforce intestinal barrier health by increasing production of mucins, tight junction proteins, and Goblet and Paneth cell production. (16) Probiotics also offer protection to the host by inhibiting growth of pathogens directly and through competitive inhibition for nutrients.

More studies are needed to uncover further mechanisms of action and application to health in the use of probiotics. Studies have shown probiotic benefit to be strain specific. For general immune health, using a multi-strain probiotic may offer a good overall strategy.

Suggested dose: Multi-strain probiotic (formulations that contain strains Lactobacillus (L.), Bifidobacterium (B.), and Streptococcus (S.) >40Billion CFU

There are many other strategies that advantage immune function, this reviewed just a few. Several of the mechanisms discussed cross-over affecting multiple mechanisms, and most all have a link to inflammation. Removing non-purposeful inflammation cultivates a healthier terrain resulting in improved immune function.

Listen to Episode 1 of our podcast here!

References:

1. Hamlin. Why Some People Get Sicker Than Others. The Atlantic. April 21, 2020
2. Mason, Role of Fat-Soluble Vitamins A and D in the Pathogenesis of Influence. A New Perspective. ISRN Infectious Diseases. Volume 2013, Article ID 246737, 26 pages http://dx.doi.org/10.5402/2013/246737
3. Zhang, D. Leung, B. Richers, Y. Liu, L. Remigio, D. Richesand, E. Goleva. Vit D Inhibits Monocyte/Macrophage Proinflammatory Cytokine Production by Targeting MAPK Phosphatase 1. J Immunol March 1, 2010, 188 (5) 2127-2135. https://doi.org/10.4049/jimmunol.1102412
4. Dancer, D. Parekh, S. Lax, V. D’Souza, S. Zheng, C. Bassford, D. Park, D.G. Bartis, R. Mahida, A. Turner, E. Sapey, W. Wei, B. Naidu, P. Steward, W. Fraser, K. Christopher, M. Cooper, F. Gao, D. Sansom, A. Martineau, G. Perkins, D. Thickett. Vitamin D Deficiency Contributes Direclty to the Acute Respiratory Distress Syndrome (ARDS). Thorax 2015;70:617-624. doi: 10.1136/thoraxjnl-2014-206680
5. Kim, R. Teles, S. Haile, P. Liu, R. Modlin, Vitamin D Status Contributes to the Antimicrobial Activity of Macrophages Against Mycobacterium Leprae. PLOS Neglected Tropical Disease. July 2, 2018. https://doi.org/10.1371/journal.pntd.0006608
6. Grant, H. Lahore, S. McDonnell, C. Baggerly, C. French, J. Aliano, J. Bhattoa. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 2020, 12, 988
7. Vitamin D on Prevention and Treatment of COVID-19 (COVITD-19). NIH ClinicalTrials.gov NCT04334005
8. Ishida. Review on the Role of Zn Ions in Viral Pathogenesis and the Effect of Zn Ions for Host Cell-Virus Growth Inhibition. Am J Biomed Sci & Res. 2019 -2(1). DOI: 10.34297/AJBSR.2019.02.000566
9. Prasad, Zinc in Human Health: Effect of Zinc on Immune Cells. Mol Med 12 (5-6) 353-357. May-June 2008
10. Bhan, S. Sazawal, R. Black, S. Jalla, S. Mazumdar, A. Sinha,Zinc Supplementation Reduces the Incidence of Acute Lower Respiratory Infections in Infats and Preschool Children: A Double-blind, Controlled Trial. Pediatrics. July 1998
11. Read, S. Obeid, C. Ahlenstiel, G. Ahlenstiel, The Role of Zinc in Antiviral Immunity. Adv. Nutr 2019;0:1-15
12. Gammoh, L. Rink, Zinc in Infection and Inflammation. Nutrients 2017, 9, 624
13. Carr, S. Maggini, Vitamin C and Immune Function. Nutrients 2017 Nov 3;9(11)
14. Hemila, E. Chalker, Vitamin C for Preventing and Treating the Common Cold. Cochrane Database Syst. Rev. 2013; (1).
15. Hemilä, E. Chalker, Vit C Can Shorten the Stay in the ICU: A Meta Analysis. Nutrients 2019, 11(4), 708
16. Galdeano, S. Cazorla, J. Dumit, E. Velez, G. Perdigón, Beneficial Effects of Probiotic Consumption on the Immune System. Ann Nutr Metab 2019;74:115-124
17. Hao, BR. Dong, T. Wu, Probiotics for Preventing Acute Upper Respiratory Tract Infections. Cochrane Database Syst Rev. 2015 Feb 3;(2)

Dr. Victoria Coleman is a 25-year veteran in health care delivery both clinically and in business development. A graduate of the Canadian Memorial Chiropractic College, Victoria has successfully run two wellness clinics delivering well health care from an integrative approach. Victoria is also a Certified in Functional Medicine and also  holds a Master’s degree in Human Nutrition  Encouraging proactive health care is a passion for Victoria along with a love for fitness.