Eight Evidence-Based Ingredients to Promote Immunity, Prevent Infection and Protect Your Patients

With the start of school, and as colder weather and winter approach, practitioners brace for an increase in colds, flu, respiratory infections and other ailments. (And then there’s COVID). Along with addressing nutrient deficiencies, microbiome imbalances and lifestyle factors like stress, poor sleep and lack of exercise, a strategic supplement regimen is crucial for shoring up immunity and boosting resilience.

“Supporting more robust immune activity, while balancing and ‘training’ the immune system so it does not overreact, is key,” says Ruby Tischoff, FDN-P. “Natural agents can support these areas and are an important part of any comprehensive immunity protocol.”

Eight evidence-based ingredients shown to promote balanced immunity, dampen inflammation, reinforce gut health and protect against infection all season long:

Berberine. An isoquinoline alkaloid derived from Indian barberry (B. aristata), goldenseal (Hydrastis canadensis L.) and other medicinal herbs, berberine has a long history of use in traditional medicine, and modern research validates its anti‐inflammatory and immunomodulatory activities.

“Berberine maintains a healthy inflammatory response and has antioxidant actions, two properties that make it useful in many aspects of health,” says naturopathic physician Chris Meletis, ND. “In regard to immunity, it has antiviral effects and immune-regulatory actions. Berberine also promotes lung health in animals and the health of human airway cells.” ^{1, 2}

Berberine is thought to modulate immune response by influencing the activity of immune cells, suppressing functions and differentiation of pro‐inflammatory T cells and decreasing inflammation. Other research points to berberine’s impact on the microbiome and its ability to regulate intestinal flora, support the intestinal immune system and affect the expression of intestinal immune factors. ^{3, 4}

Berberine’s antimicrobial properties guard against a variety of pathogens, inhibiting the growth of bacteria, viruses and other microorganisms, and studies suggest it may protect against several strains of influenza, strongly suppressing infection and hampering viral replication. Emerging research examining its potential role in treating COVID suggests berberine hinders the proliferation of SARS-CoV-2, attenuating associated inflammatory disorders and alleviating acute respiratory distress syndrome in patients with severe COVID -19. ^{5, 6, 7, 8}

N-acetyl cysteine (NAC). Required for the synthesis of glutathione, NAC is known for its ability to promote healthy immune response, support the respiratory system and protect against viral infection. “NAC’s primary mechanism of action involves raising levels of glutathione, the master antioxidant,” says Meletis. “It also functions as an anti-mucolytic that’s beneficial for lung health, and research in humans has found NAC treatment over six months led to a pronounced decrease in frequency and severity of influenza-like episodes, length of time spent in bed, and a significant reduction in local and systemic symptoms.” ^{9, 10}

Along with increasing glutathione levels, NAC modulates inflammation, enhances the function of various immune cells and suppresses viral replication, and newer research points to NAC as a potential therapeutic agent in the treatment or prevention of COVID-19. Mechanisms of action are thought to include blocking SARS-CoV-2 infection and replication and inhibiting the consequent cytokine storm, influencing COVID-19 progression. Studies suggest NAC may improve COVID-19 outcomes, lower hospital admission rates and reduce mechanical ventilation and mortality, and a minimum dose of 1200mg per day may significantly benefit symptomatic patients with COVID-19. ^{11, 12, 13, 14, 15}

Probiotics. Because the microbiome plays a prominent and multifaceted role in immunity, disruptions in the microbiome can trigger immune dysregulation and higher susceptibility to disease and infections. Incorporating the right kind of probiotic blend restores microbiome balance to improve immunity and boost resilience.

In studies, probiotic supplements have been shown to regulate inflammation, modulate specific immune functions, enhance overall immunity and protect against pathogens. Several strains demonstrate a broad range of antiviral activities with different mechanisms of action, improving immune cell function, forming barriers against viral infections and producing antimicrobial compounds that inhibit viral replication and attachment. Probiotics belonging to Lactobacilli and Bifidobacteria are among the most widely researched for their strong antiviral activity, and other strains show similar potential for mitigating respiratory infections. ^{16, 17, 18}

Numerous studies show the ability of probiotics to protect against influenza and respiratory tract infections, reducing the frequency of infection and decreasing the duration and severity of symptoms. New research also supports the use of probiotics in treating COVID-19, with studies suggesting probiotics can improve symptoms and clinical outcomes, alleviate long-COVID complications and lower the risk of mortality in patients with COVID-19. ^{19, 20, 21, 22, 23, 24}

Andrographis. The Andrographis paniculata plant has been used for centuries in Chinese and Ayurvedic medicine to treat colds, respiratory infections and other conditions. It contains an abundance of compounds with antioxidant and anti-inflammatory properties, and dozens of studies validate its immunomodulatory benefits. In clinical trials, andrographis supplementation was linked with an increase in T cells and T helper cells, significant increases in IFN-γ and IL-4, and decreased IL-2. Andrographolides, the primary bioactive constituents in andrographis, also exhibit powerful anti-inflammatory and cytokine-inhibiting effects, impeding pro-inflammatory pathways and suppressing the release of IL-6, TNF-α and IFN-γ and mitigating cytokine storms. ^{25, 26}

Andrographis possesses broad spectrum anti-viral activity to protect against a range of viruses, including influenza. Andrographolide and its derivatives are shown to inhibit influenza A infection, hamper viral replication and lessen the severity and duration of viral illnesses. It’s especially effective in respiratory tract infections, reducing inflammation and relieving symptoms like coughing and congestion. Published clinical studies on andrographis report both prophylactic and therapeutic benefits for upper respiratory tract infections, and 33 randomized controlled trials involving 7175 patients support the effectiveness of andrographis in alleviating respiratory tract infections caused by seasonal viruses. ^{27, 28, 29, 30, 31}

Newer research also suggests the potential of andrographis to inhibit SARS-CoV-2 and prevent and treat COVID-19 and its sequela. In one trial, andrographolide exhibited a strong binding force to SARS-CoV-2 targets. Additionally, andrographis supplementation may control cytokine storms, one of the pathogenic mechanisms leading to death in COVID-19. ^{32, 33, 34, 35, 36}

Olive leaf extract. From the leaves of the olive tree (Olea europaea), olive leaf extract is rich in oleuropein, hydroxytyrosol, oleoside and other bioactive compounds with antioxidant, anti-inflammatory and immunosupportive properties. Olive leaf extract influences immune cell activity and modulates the production and release of cytokines, and antimicrobial constituents in olive leaf extract are known to protect against a wide range of bacteria and viruses. ^{37, 38, 39}

“Oleuropein and derivatives such as elenolic acid have been found to be effective in in vitro and animal studies against numerous microorganisms, including retroviruses, coxsackie viruses, 150 influenza and parainfluenza, as well as some bacteria,” says Meletis, and other studies found olive leaf extract could impact human immunodeficiency virus (HIV), hindering the transmission of the virus into target cells.

Additionally, newer research suggests olive leaf extract may be a powerful therapeutic agent in treating COVID-19. In one clinical trial of patients hospitalized with COVID-19, olive leaf extract reduced respiratory rate, pulse rate and body temperature, increased blood oxygen saturation and decreased inflammatory markers. The study further concluded treatment with olive leaf extract can improve patient status, shorten the length of hospitalization and lead to early discharge. ^{40, 41, 42, 43}

EpiCor. Produced from a proprietary fermentation process using Saccharomyces cerevisiae yeast, EpiCor is a branded ingredient with potent antioxidant, anti-inflammatory and immunosupportive properties. EpiCor has been shown to favorably modulate immune responses without excessive suppression or stimulation of overall immune activity and is thought to enhance both innate immune response and adaptive immunity. ^{44, 45}

 “EpiCor supports mucosal immunity and increases levels of salivary secretory immunoglobulin A (sIgA), a substance coating mucosal surfaces that acts like a shield to stop unwanted substances from entering the body,” says Meletis. “I share with my patients that sIgA waterproofs or Scotch Guards the immune system by strengthening the mucosal membrane.”

In studies, EpiCor was found to decrease inflammation and enhance the function of various immune cells, including NK cells, T cells and B cells, and multiple published trials demonstrate its ability to lessen the incidence and duration of cold- and flu-like symptoms during fall and winter months. Other research validates its efficacy in reducing nasal congestion related to colds, flus and allergic rhinitis. In one randomized, double-blind, placebo-controlled trial, 500mg of EpiCor per day significantly improved the severity and duration of specific allergic rhinitis symptoms compared with placebo. Subjects who received EpiCor also experienced notably higher salivary IgA levels. ^{46, 47, 48, 49, 50}

Elderberry. From the fruit of a flowering plant native to Europe and North America, elderberry (Sambucus nigra) is a common remedy in traditional herbal medicine for treating colds, flu, respiratory conditions and a range of other ailments.

“Elderberries are an especially concentrated source of anthocyanins, known for their powerful antioxidant, anti-inflammatory and immunosupportive properties,” says Susan Hirsch, MS Herbal Medicine, CNS. “Elderberry has been shown to inhibit viral replication and boost cytokine production, crucial in mounting an effective immune response, and its antioxidant properties reduce oxidative stress, further supporting immune health.”

The anti-viral and immunosupportive benefits of elderberries are well-documented, with studies showing elderberry extracts stimulate immune response, enhance the activity of immune cells and regulate the production of cytokines. Compounds in elderberries, especially flavonoids like quercetin and anthocyanins, also exhibit strong antiviral activity against influenza A, influenza B and other viruses, inhibiting replication and blocking viral attachment. ^{51, 52, 53, 54, 55}  

A number of studies suggest elderberry supplementation is effective in treating viral infections, decreasing the duration and severity of colds and flu and relieving upper respiratory symptoms without overstimulating the immune system. In one double-blind, placebo-controlled, randomized study, elderberry syrup shortened the length of flu symptoms three to four days. Other research shows elderberry extract significantly reduces cold duration and severity and substantially lessens clinical symptoms of flu compared to placebo, with marked improvements in nasal mucus discharge, cough, fever, headache, muscle aches and nasal congestion. ^{56, 57, 58, 59, 60}

Modified citrus pectin (MCP). Made from the inner peel, or pith (white part of the inside peel), with no citrus pulp or juice components contained in the final MCP product. Made from the pulp of citrus fruits, MCP is gaining prominence for its ability to promote healthy microbiome populations, modulate inflammation and improve immune function. MCP influences the immune system in several ways, regulating the activation of T-cytotoxic cells, B cells and NK cells. One study evaluating the immunostimulatory properties of MCP on human blood samples found a ten-fold increase in NK cellular activity and a 53.6 percent increase in NK cellular functional ability. ^{61, 62, 63}

MCP products differ in efficacy, so choosing the correct form is important. Pectin is a large and complex molecule in its natural form, containing a variable degree esterification. As such, unmodified pectin is not degraded during digestion, and its large size prevents intestinal absorption. Modified pectin, on the other hand, has a low-molecular-weight degree of esterification, allowing absorption from the small intestinal epithelium into circulation. PectaSol, a proprietary form of MCP, offers the specific form of modified pectin shown in research to support immunity. Modified pectin contains galactosyl fractions that appear to bind to and block galectin-3 and are thought to be responsible for its immunosupportive effects.

“PectaSol is the original and only clinically researched form of MCP and is recognized as the most-researched galectin-3 blocker available,” says Tischoff. “PectaSol is produced from regular citrus pectin using an advanced, proprietary modification process that produces a pectin molecule with a molecular weight of 3 to 15 kilodaltons and less than 10 percent esterification, which is much smaller than regular pectin, and is what allows PectaSol to absorb into the circulation and work systemically.”

PectaSol’s effect on the immune system is attributed in part to involvement in the inflammatory response, moderating the production of pro inflammatory cytokines and immunoglobulins, addressing overactive inflammation and modulating galectin-3 driven inflammatory cascades. In addition, PectaSol supports healthy microbiome populations and can work synergistically with antibiotics against pathogenic gut microbes. In one study, PectaSol in combination with live probiotic L. acidophilus ATCC 4356 supplementation helped maintain or improve the integrity and population of the intestinal microbiota. In another study, PectaSol also inhibited E. coli adhesion and reduced Shiga toxin cytotoxicity. ^{64, 65, 66, 67}

Emerging research points to galectin-3 as a therapeutic target for treating a variety of inflammatory disorders, including pulmonary fibrosis and respiratory infections caused by COVID-19. Recent literature suggests treatment with a galectine-3 inhibitor can stem the progression of SARS-CoV-2, hinting at a potential role for MCP in COVID-19. ^{68, 69, 70, 71}

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