Todd Runestad, Content Director,, Sr. Supplements Editor

November 1, 2008

27 Min Read
The latest advances in immune health

Maintaining healthy immune systems has moved decidedly toward intestinal fortitude, with gut-health ingredients such as probiotics and prebiotics leading the way. The other avenue suppliers are pursuing is through unique branded ingredients. Todd Runestad investigates the changing immune-health landscape

The traditional nutritional-supplements method to address immune health has been via a vitamin, a mineral and herbs — namely, vitamin C, zinc, echinacea and garlic. Vitamin C sales have been steady since 2002, rising about 2.5 per cent in 2007 to about $850 million in the US. But zinc sales have decreased from their 2000 high of $85 million to about $72 million last year, a 15 per cent decline. Echinacea's fortunes are off by about 25 per cent from their high of more than $200 million in 1999 sales. The demand for garlic has steadily declined since 1997 — partly because of its renowned efficacy for cardiovascular conditions, which has been usurped by newer and more novel ingredients.1

Today's immune market has moved on, and is finding good growth in two separate and distinct areas: gut health and unique branded ingredients. Gut-health ingredients are predicated on the function of the digestive system, which extracts and absorbs nutrients from foods, and also attacks harmful organisms that may be present in foods. Branded ingredients address the gamut of the highly complex innate and adaptive immune response, from boosting natural killer (NK) cell counts to enhancing cytokine production.

Gut response
It is estimated that three quarters of the cells necessary for the immune system to function effectively are connected to the gastrointestinal tract. In addition, without proper digestive function, basic metabolic processes break down, leading to various disease states.

Probiotics — intestinal microbes — are a key factor in the development of the post-natal immune system and in acquired immune response and inflammation. The intestinal flora in the large intestine plays an important role in protecting against pathogens. The beneficial bacteria line the lumenal wall of the intestine and guard against infection. These probiotics produce the natural antibiotic-like substance acidophilin, and inhibit or reduce the proliferation and adhesion to intestinal cells of undesirable bacteria, known as the barrier effect.2

One 2008 study found the probiotic species Bifidobacterium infantis normalised gut permeability and improved disease in an animal model of colitis.3 In addition, microflora modulate the immune system, thereby reinforcing the body's natural defence.4

Much company-sponsored research takes specific probiotic strains and works on "delivering efficacious doses to the appropriate gastrointestinal tract location," according to Bob Berman, senior marketing manager at DSM, which supplies the Lafti range of probiotics.

While the conventional use of probiotics is aimed at modulating gastrointestinal health by increasing natural resistance to infectious diseases, other potential applications include menopause, cholesterol and hypertension with various specific strains.5

On the immunity front, though, a 2008 randomised, double-blind, placebo-controlled study of 77 HIV-infected children (ages 2-12 years) supplemented one group with a probiotic formula containing Bifidobacterium bifidum and Streptococcus thermophilus (1010 CFUs) for two months. The probiotics group experienced increased CD4 cell counts and reduced liquid-stool episodes, which researchers concluded was positive "immunostimulatory properties" of probiotics.6 CD4 cells are T-helper lymphocytes with CD4 cell-surface markers, and are used to assess immune status and susceptibility to opportunistic infections.

A 2008 five-month human study with the L. casei Shirota strain showed it modulates the immune response to grass pollen, and helps those with hay fever. Hay fever is an allergic reaction to pollen spores whereby the immune system is confused by the spores, making white blood cells produce cytokines to oppose them. The probiotics reduced production of the cytokines and "significantly reduced the production of molecules associated with allergy," according to the study authors.7 The probiotic came in the form of Yakult drinks, a popular consumer beverage in Japan.

A recent study involving more than 500 one- to three-year-old children indicated that a year's consumption of Howaru Bifido (B. lactis HN019) and Howaru Rhamnosus (L. rhamnosus HN001), combined with a prebiotic, reduced the number of days of severe illness or fever and the incidence of ear infections. Three other trials using Howaru Bifido and Howaru Rhamnosus, supplied by Danisco showed enhanced NK cell activity as well as enhanced phagocytic activity of peripheral blood mononucleocytes.8,9,10

Prebiotic fibres — primarily inulin, fructo-oligosaccharides (FOS), and galacto-oligosaccharides (GOS) with resistant starch as an emerging prebiotic option — are benefiting from research showing a true synergistic effect when combined with probiotics.11 This is a vital point that should interest all product developers. Robert Hutkins, PhD, a researcher and renowned probiotics expert at the University of Nebraska, asserts that while research with E. coli finds it attaches to FOS instead of the receptors lining the intestinal-tract lining, GOS is the better anti-adhesive prebiotic.

Still, the burning question among researchers is which prebiotic matches up best with probiotic strains to give the best health benefit. Answers to this question should drive commercialisation of the most potent consumer product. It is now no longer just a question of providing sufficient numbers of viable bacteria in a product; industry must also provide proof of efficacy for each strain.12

The increasing knowledge of the metabolism of prebiotics by probiotics is allowing researchers and suppliers to consider specifically targeting such dietary intervention tools at specific population groups, and specific disease states beyond mere immunity.13

Enzyme supplements: These can increase the absorption and usage of nutrients, decrease stomach discomfort, and lead to a stronger immune system. Enzyme supplements typically consist of lipase, protease and amylase. Lipase breaks down fats found in butter, meat and cheese. Protease assists in the digestion of proteins found in meats and nuts. Because proteins are a key part of food allergies, proteases should aid in that part of immune function. And amylase breaks down the carbohydrates, sugars and starches present in potatoes and other vegetables, fruits, and snack foods.

Of the three categories of enzymes, proteases are vital to the immune system because most types of illness are composed of or enveloped by proteins. Protease enzymes can act upon the protein coating of viruses or any protein that is harmful to the body or does not belong, with one study showing that a mixture of papain and pancreatin was more effective than either alone.14

Proteases act as raw material from which the lymph system and bone marrow can manufacture additional white blood cells.15 Finally, proteases can break down undigested food proteins and toxins in the blood, thus freeing up the immune system from this task.16

Digestive enzymes can help with digestive problems, but because they help strengthen your body's immune system, their uses are much broader than just digestion-related illnesses and discomforts. There is a connection between the strength of the body's immune system and its enzyme level — the greater the amount of enzymes, the stronger the immune system will be. Digestive enzymes have been shown to help with wound healing, tissue repair, food allergies and other applications.17,18,19

Branded leaders
AHCC: Active Hexose Correlated Compound is a mushroom extract supplied by Quality of Life Labs. It is a mixture of polysaccharides, amino acids, lipids and minerals derived from cocultured mycelia of several species of Basidiomycete mushrooms. AHCC has been implicated to modulate immune functions and plays a protective role against infection. In a 2006 animal study, it was shown to increase NK cells, killer T-cells and macrophages — all immune-enhancing lymphocytes that regulate both innate and adaptive immune responses.20 Natural killer cells are the white blood cells of the immune system that are critical in host defence and immune regulation. NK cells are the first line of cellular defence against invading micro-organisms, bacteria, virusus and other pathogens. They carry cytotoxic granules that oppose invading cells, and play significant roles in viral infections, auto-immunity and adaptive immunity.

T-cells are white blood cells responsible for 'cell-mediated immunity' — the integrated response required for the successful defence of one's health. Macrophages produce cytokines, start the process of antibody production and, through phagocytosis, directly destroy invaders.

In a 2008 double-blind, placebo-controlled, randomised human clinical trial in Japan, the 10 subjects taking 3g/day AHCC for four weeks experienced improvements in some immunity markers — specifically elevated circulating dendritic cells and clusters of differentiation and allogeneic mixed-leukocyte reaction — while no change was observed in NK cell activity and the proliferative response of T lymphocytes toward mitogen.21

In a December 2007 study to assess AHCC's safety and tolerability, 26 human subjects were given 9g AHCC/day for 14 days in a liquid format. The dosage well exceeds the normal dose, and it was well tolerated by 85 per cent of subjects, with transient adverse effects of nausea, diarrhoea and bloating.22

Of note, a 2007 study in rats found AHCC to possess both anti-inflammatory as well as prebiotic properties. Rats receiving AHCC showed greater colonic bifidobacteria counts and lower incidence of clostridia bacteria.23 Other published studies in the past two years indicate efficacy in animal models in enhancing resistance to infection after surgery, increasing innate immune response to primary influenza infection, and even enhanced immunity while in outer space.24,25,26

In all, AHCC has been the subject of more than 80 clinical trials. It is said that more than 700 hospitals and medical clinics in Japan recommend AHCC as part of an immune-maintenance regimen. It received the NutrAward in 2002 for best new product of the year at the Nutracon conference. The recognition was based on the product's scientific merit, efficacy, safety, innovation, market potential and ability to advance the industry. As a patented ingredient, AHCC can be exclusively licensed to select manufacturers.

Maitake D-Fraction: There actually are thousands of known mushroom varieties, and several have been studied for their ability to enhance the human immune system and fight infections. Some of the more well-known varieties include reishi (Ganoderma lucidum), shiitake (Lentinus edodes), cordyceps (Cordyceps sinensis), and maitake (Grifola frondosa).

Maitake is also a premier culinary mushroom. The active proteoglucan in maitake, called the D-fraction, is a unique beta-glucan conjugated with protein. Beta-glucans are naturally occurring polysaccharides that enhance macrophages and NK cell function. The induction of cellular responses by mushrooms and other beta-glucans is likely to involve their specific interaction with several cell-surface receptors.27

Much research with D-fraction involves antitumour effects, specifically its ability to inhibit cancer cell growth.28 Through animal models of cancer, it has been discovered that D-fraction also reduces immunosuppression in tumour-bearing mice. It appears to do this by activating T-cells, macrophages and NK cells.29,30 NK cells are directly cytotoxic for tumour cells, as well as play a primary role in regulating immune response. Even 20 days after D-fraction ended, NK cells were being activated at an elevated rate. Researchers also found D-fraction increased macrophage-derived interleukin-12, which activates NK cells.31

As well as its anticarcinogenic potential, maitake is being investigated as an adjunct to HIV therapy. (It may also provide some benefit in treating hyperlipidaemia, hypertension, hepatitis and diabetes.)32,33 EpiCor: The story of the discovery of this unique immune-boosting ingredient is a great one. An administrative actuary at the Diamond V plant, which manufactured animal-nutrition ingredients, noticed that those employees who worked directly with a unique brewer's/baker's yeast had far fewer sick days and fewer health-insurance claims.

The scientists stepped in and discovered that those healthier employees had higher NK cell activity and higher antioxidant levels. The ingredient is a dried, complex fermentation product derived from Saccharomyces cerevisiae, which came to be known as EpiCor. It also has been found to activate B cells, which support antibody production specific to an invading pathogen. It also acts as an anti-inflammatory.

Two 2008 published human clinical studies vouch for EpiCor's anecdotes. In one, on markers of immune health, EpiCor supported the health of red blood cells and mucosal immune protection.34

The problem with many nutritional studies is that they look at markers and not bottom-line consumer benefit. So what if taking a supplement enhanced cellular markers of immunity? Did a person get sick less often?

With EpiCor, the answer is yes. A 2008 double-blind, placebo-controlled, randomised clinical trial with 116 humans gave half 500mg/day EpiCor. Participants receiving EpiCor had significantly fewer cold and flu symptoms and significantly shorter duration of symptoms as compared to those taking placebo. Cold and flu symptoms were 21 per cent less likely to occur overall, and observable symptom duration was reduced by 14 per cent, with 32 per cent fewer annual sick days.35

Cold-fX: CV Technologies, a Canadian company, has developed a unique product that ranks as the top-selling cold and flu remedy in Canada, according to ACNielsen's rating for the 52 weeks ending July 5, 2008. A proprietary extract of the roots of North American ginseng (Panax quinquefolium), which is rich in polysaccharides, Cold-fX is the subject of five published human clinicals since 2004.

In one, 42 people between the ages of 18 and 65 with more than two respiratory infections in the previous year were enrolled. After taking Cold-fX 200mg twice daily for four months, the supplementing group had increased proportion of T-helper and NK cells and decreased IgA levels in plasma compared to placebo.36

Cold-fX also addresses that same issue of markers vs real-world results. In a double-blind, placebo-controlled, randomised human clinical trial of 43 community-dwelling adults older than 65, there was no difference between groups for the first two months. But for the last two months of the study — November and December — the treatment group experienced 32 per cent fewer incidences of acute respiratory illness compared to placebo. Plus, the duration of symptoms during this time was significantly shorter — 5.6 days vs 12.6 days in the placebo group.37

Two larger studies — on 323 and 198 humans, respectively — found similar results.38,39 The larger of the two was included in the "National Institutes of Health Office of Dietary Supplements Annual Bibliography of Significant Advances in Dietary Supplements Research for 2005."

Research continues on Cold-fX. One is a Canadian multi-centre study among 720 community-dwelling seniors. Two others aim at delineating the product's precise molecular mechanism of action.

Wellmune WGP — More than a dozen published studies have assessed the safety and efficacy of this yeast-derived beta-glucan ingredient from Biothera. It, too, was the winner of the NutrAward competition at Nutracon, for best new product of 2005. It also received the 2007 IFT Food Expo Innovation Award.

It has been shown to activate innate immune cells to move faster to the site of a challenge and more quickly recognize and destroy foreign intruders. In one study, it increased phagocytic capacity — the ability of the innate immune cells to eat and destroy foreign intruders — from 64 per cent to 83 per cent, and increased the number of highly phagocytic cells from 37 per cent to 50 per cent.40 In another study, it elevated NK cell and T-cell counts over placebo participants from 9.8 per cent to 12.5 per cent, as a percentage of all lymphocytes.41 Another study found it enhanced the ability of neutrophils to more rapidly respond to an infection site.42

Finally, a human study presented at the 2008 American College of Sports Medicine annual meeting showed that wildland firefighters who took the supplement had 23 per cent fewer upper respiratory tract infections compared to a placebo group.43 An animal study found it to be well tolerated.44

1. Nutrition Business Journal's Raw Materials & Ingredient Supply Report 2008.
2. Lodemann U, et al. Effects of Bacillus cereus var toyoi as probiotic feed supplement on intestinal transport and barrier function in piglets. Arch Anim Nut 2008 Apr;62(2):87-106.
3. Ewaschuk JB, et al. Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol. 2008 Sep 11. [Epub ahead of print]
4. Fanaro S, Vigi V. Infant formulas supplemented with prebiotics: intestinal microbiota and immune responses. Minerva Pediatr 2008 Jun;60(3):327-35.
5. Liong MT. Probiotics: a critical review of their potential role as antihypertensives, immune modulators, hypocholesterolemics, and perimenopausal treatments. Nutr Rev 2007 Jul;65(7):316-28.
6. Trois L, et al. Use of probiotics in HIV-infected children: a randomized double-blind controlled study. J Trop Pediatr 2008 Feb;54(1):19-24.
7. Ivory K, et al. Oral delivery of Lactobacillus casei Shirota modifies allergen-induced immune responses in allergic rhinitis. Clin Exp Allergy 2008 Aug;38(8):1282-9.
8. Gill H, et al. Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019. Am J Clin Nutr 2001;74:833-9.
9. Gill HS, Rutherfurd KJ. Probiotic supplementation to enhance natural immunity in the elderly: effects of a newly characterized immunostimulatory strain Lactobacillus rhamnosus HN001 (DR20?) on leucocyte phagocytosis. Nutr Res 2001;21:183-9.
10. Sazawal S, et al. Efficacy of milk fortified with a probiotic Bifidobacterium lactis (DR-10) and prebiotic galacto-oligosaccharides in prevention of morbidity and on nutritional status. Asia Pac J Clin Nutr 2004;13:S28.
11. Van Loo J, Jonkers N. Evaluation in human volunteers of the potential anticarcinogenic activities of novel nutritional concepts: prebiotics, probiotics and synbiotics (the SYNCAN project QLK1-1999-00346). Nutr Metab Cardiovasc Dis 2001 Aug;11(4 Suppl):87-93.
12. Dekker J, et al. Functionality of probiotics - potential for product development. Forum Nutr 2007;60:196-208.
13. Rastall RA, et al. Modulation of the microbial ecology of the human colon by probiotics, prebiotics and synbiotics to enhance human health: an overview of enabling science and potential applications. FEMS Microbiol Ecol 2005 Apr 1;52(2):145-52.
14. Steffen C, Menzel J. Enzyme breakdown of immune complexes. Z Rheumatol 1983 Sep-Oct;42(5):249-55.
15. Ernst E, Matrai A. Oral therapy with proteolytic enzymes for modifying blood rheology. Klin Wschr 1987;65:994.
16. Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci 2001 Aug;58(9):1234-45.
17. Parks WC. Matrix metalloproteinases in wound repair. Wound Rep Regen 1999;7:423-32.
18. Mangipudy RS, et al. Tissue repair response as a function of dose in thioacetamide hepatotoxicity. Environ Health Perspect 1995 Mar;103(3):260—7.
19. McCann M. Pancreatic enzyme supplement for treatment of multiple food allergies. Ann Allerg 1993;71:269.
20. Gao Y, et al. Active hexose correlated compound enhances tumor surveillance through regulating both innate and adaptive immune responses. Cancer Immunol Immunother 2006 Oct;55(10):1258-66.
21. Terakawa N, et al. Immunological effect of active hexose correlated compound (AHCC) in healthy volunteers: a double-blind, placebo-controlled trial. Nutr Cancer 2008;60(5):643-51.
22. Spierings EL, et al. A phase I study of the safety of the nutritional supplement, active hexose correlated compound, AHCC, in healthy volunteers. J Nutr Sci Vitaminol (Tokyo) 2007 Dec;53(6):536-9.
23. Daddaoua A, et al. Active hexose correlated compound acts as a prebiotic and is anti-inflammatory in rats with hapten-induced colitis. J Nutr 2007 May;137(5):1222-8.
24. Aviles H, et al. Active hexose correlated compound (AHCC) enhances resistance to infection in a mouse model of surgical wound infection. Surg Infect (Larchmt) 2006 Dec;7(6):527-35.
25. Ritz BW, et al. Supplementation with active hexose correlated compound increases the innate immune response of young mice to primary influenza infection. J Nutr 2006 Nov;136(11):2868-73.
26. Aviles H, et al. Active hexose correlated compound enhances the immune function of mice in the hindlimb-unloading model of spaceflight conditions. J Appl Physiol 2004 Oct;97(4):1437-44.
27. Akramiene D, et al. Effects of beta-glucans on the immune system. Medicina (Kaunas) 2007;43(8):597-606.
28. Konno S. Potential growth inhibitory effect of maitake D-fraction on canine cancer cells. Vet Ther 2004 Winter;5(4):263-71.
29. Kodama N, et al. Maitake D-fraction enhances antitumor effects and reduces immunosuppression by mitomycin-C in tumor-bearing mice. Nutrition 2005 May;21(5):624-9.
30. Kodama N, et al. Effect of Maitake (Grifola frondosa) D-fraction on the activation of NK cells in cancer patients. J Med Food 2003 Winter;6(4):371-7.
31. Kodama N, et al. Effects of D-fraction, a polysaccharide from Grifola frondosa on tumor growth involve activation of NK cells. Biol Pharm Bull 2002 Dec;25(12):1647-50.
32. Mayell M. Maitake extracts and their therapeutic potential. Altern Med Rev 2001 Feb;6(1):48-60.
33. Hong L, et al. Anti-diabetic effect of an alpha-glucan from fruit body of maitake (Grifola frondosa) on KK-Ay mice. J Pharm Pharmacol 2007 Apr;59(4):575-82.
34. Jensen GS. A double-blind placebo-controlled, randomized pilot study: consumption of a high-metabolite immunogen from yeast culture has beneficial effects on erythrocyte health and mucosal immune protection in health subjects. Open Nutr J 2008;2:68-75.
35. Moyad MA. Brewer's/baker's yeast (Saccharomyces cerevisiae) and preventive medicine: Part II. Urol Nurs 2008 Feb;28(1):73-5.
36. Predy GN, et al. Immune modulating effects of daily supplementation of COLD-fX (a proprietary extract of North American ginseng) in healthy adults. J Clin Biochem Nutr 2006;39:162-7.
37. McElhaney JE, et al. Efficacy of COLD-fX in the prevention of respiratory symptoms in community-dwelling adults: a randomized, double-blinded, placebo-controlled trial. J Alt Complemen Med 2006 Mar;12(2):153-7.
38. Predy G, et al. Efficacy of an extract of North American ginseng containing poly-furanosyl-pyranosyl-saccharides for preventing upper respiratory tract infections: a randomized controlled trial. Canadian Med Assoc J 2005;173(9):1043-8.
39. McElhaney J, et al. A placebo-controlled trial of a proprietary extract of North American ginseng (CVT-E002) to prevent acute respiratory illness in institutionalized older adults. J Am Geriatr Soc 2004;52:13-9.
40. Li B, et al. Yeast ß-glucan amplifies phagocyte killing of iC3b-opsonized tumor cells via CR3-Syk-PI3-kinase pathway J Immun 2006 Aug 1;177(3):1661-9.
41. Salvador C, et al. Yeast-derived ß-glucan augments the therapeutic efficacy mediated by anti—vascular endothelial growth factor monoclonal antibody in human carcinoma xenograft models. Canc Res 2007;67:7421-30.
42. Li B, et al. Combined yeast ß-glucan and antitumor monoclonal antibody therapy requires C5a-mediated neutrophil chemotaxis via regulation of decay-accelerating factor CD55. Clin Canc Res 2008;14(4):1239.
44. Babicek K, et al. Toxicological assessment of a particulate yeast (1,3/1,6)-beta-D-glucan in rats. Food Chem Toxicol 2007 Sep;45(9):1719-30.

About the Author(s)

Todd Runestad

Content Director,, Sr. Supplements Editor, Natural Products Insider

I've been writing on nutrition science news since 1997. I'm The content director for NaturalProductsInsidercom and digital magazines. Other incarnations: supplements editor for, Delicious Living and Natural Foods Merchandiser. Former editor-in-chief of Functional Ingredients magazine and still cover raw material innovations and ingredient science.

Connect with me here

My daily vitamin regime includes a morning smoothie with a range of powders including protein, collagen and spirulina; a quality multi, B complex, C with bioflavonoids, >2,000IU vitamin D, E, magnesium, high-selenium yeast, PQQ, choline, alpha-lipoic acid with carnitine, coQ10, fish oil concentrate, probiotics and some adaptogenic herbs. 

Subscribe and receive the latest updates on trends, data, events and more.
Join 57,000+ members of the natural products community.

You May Also Like