Immune health: Botanicals

Fruits and vegetables represent classic plant-based delivery of numerous nutrients and a fitting entry into plant-based ingredients for immune health. A 2010 report in the British Journal of Nutrition showed regular intake of a supplement made from fruit and vegetables (Juice Plus+®) resulted in a 20% reduction of moderate or severe common cold symptom days in health care professionals, particularly those with regular patient contact.¹ The trial involved mainly nursing staff (18 to 65 years old, n=529) from a university hospital who were randomly assigned to take either 4 capsules daily of Juice Plus+ or placebo capsules for eight months. Based on self-reporting, researchers calculated the mean number of days with moderate-to-severe common cold symptoms was 7.6 days in the Juice Plus+ group and 9.5 days in placebo group. There were no differences between the groups on number of days with any common cold symptoms.

Another supplement with roots in the produce aisle is garlic, which has long been used against bacterial, viral and parasitic infections.² Prior studies on aged garlic extract (AGE)as Kyolic®, from Wakunagashowed the supplement can increase the number and activity of NK cells, especially in patients with inoperable cancer or AIDS,³ as well as stimulate proliferation of splenocytes, cytokine release and macrophage activity.⁴ Also, chronic administration of AGE may help improve age-related immune response deterioration.⁵

Most recently, a 2010 in vitro investigation into the effects of immunomodulatory proteins from raw garlic on certain immune cells (lymphocytes, mast cells and basophils) revealed mitogenic (promotes cell duplication).⁶ Of three garlic proteins studied, QR-2 was found most potent at stimulating mitosis of human peripheral blood lymphocytes, murine spenlocytes and thymocytes, as well as inducing a two-fold higher histamine release from leukocytes. In the end, researchers concluded both QR-1 and -2 contribute to garlics immunomodulatory actions with characteristics similar to Allium sativum agglutinins I and II, respectively.

Pomegranate has demonstrated usefulness in cases of cerebral malaria, an infection by Plasmodium falciparum that is driven by inflammatory cytokines, and is marked by up-regulation and activities of metalloproteinase-9 (MMP-9) and TNF production.⁷ Researchers studied the effect of an anti-malarial formulation featuring pomegranate ellagitannins in T helper (Thp-1) cells stimulated with haemozoin (parasitic by-product) or TNF, finding the tannin preparation inhibited MMP-9 secretion and promoter activities, as well as NFkappaB-driven transcription.

Fruits like pomegranates are popularly consumed as beverages, which is a viable delivery form for the many plant compounds deemed beneficial to immune function. German researchers published results in 2010 of a study wherein a polyphenol-rich beverage showed immune-modulating effects by reducing symptoms of the common cold.⁸ In the trial, 98 patients with common cold symptoms (beginning no longer than 24 hours before the study intervention) were randomly assigned to consume either the polyphenolic beverage or a placebo twice per day for 10 days, after which researchers assessed severity of the disease as the total score of five cold symptoms: general feeling of sickness, headache and/or joint aches, sore throat and/or difficulty swallowing, hoarseness and/or cough and stuffy nose/sniffle. In the treatment group, this total score decreased from 10.2 points at baseline to 2.1 at the trials end, while the scores in the placebo group decreased only from 10.5 to 6.3 during the same period. Further, more patients in the treatment group than in the placebo group were complaint-free at the studys end. Physical examinations confirmed the significant differences between the groups symptom changes.

From the popular beverage green tea comes L-theanine, which has been studied alongside with fellow amino acid cysteine on immune challenges in endurance athletesintense exercise is associated with increased blood neutrophil counts and decreased lymphocyte counts, and can lead to inflammation and immunosuppression. A Japanese study reported in 2010 compared combined supplementation (700 mg/d cystine + 280 mg/d theanine) with placebo in long-distance runners for a week prior to and nine days during training.⁹ In those taking the combined supplement, changes in neutrophil count on the first day of training were less pronounced, but there was no such effect observed at the end of training. Similarly, the decline in lymphocyte count was less drastic in the supplement group on the first day of training, but not the last.

Botanicals have native defense systems, the components of which are considered potentially useful to human immune systems. While numerous herbal remedies have been employed for immune health over the centuries, one of the most well-known today is Echinacea, which was used traditionally by Native Americans for its antimicrobial and anti-inflammatory properties.

A 2003 review of Echinacea purpea studies by Bruce Barrett, MD, Ph.D., from University of Wisconsin, Madison, noted purpea extracts demonstrate significant immunomodulatory activities, the most convincing of which is macrophage activation.¹⁰ Activation of leukocytes and NK cells had been reasonably demonstrated, according to Barretts review, whereas alterations of T- and B-cell activities were less certain. In the end, he concluded despite the existence of some good-quality data, the effectiveness and application of E. purpurea in immune health had not been proven beyond reasonable doubt.

Barretts subsequent randomized trials on Echinacea in treatment of common cold and upper respiratory infections (URIs) yielded non-convincing results. However, he found decreased frequency of a second cold among Echinacea subjects in his trial on URIs in children.¹¹ However, the 2010 randomized trial on the common cold in 719 patients aged 12 to 80 years found only a half-day benefit in illness duration among those taking Echinacea.¹² Still, Indena reports its proprietary studies on Polinacea standardized extract of Echinacea angustifolia root (>2% echinoside) show effectiveness in reducing mortality from C. albicans infection in an animal model. The company said the key may be in removing lipopolysaccharide (LPS), which can produce a nonspecific immune response, from the extract. LPS-free Polinacea dose dependently stimulated CD3-treated isolated T lymphocytes to produce and release interferon gamma.

Fellow longtime immunomodulatory herb astragalus also impacts T-cell-mediated immunity. Past studies have shown astragalus influences TNFa production, in addition to enhancing macrophage phagocytic activity and lymphocyte response in cases of immunosuppression.^13,14 In 2010, Chinese researchers reported on their laboratory investigation of astragalus polysaccharides on dendritic cells and subsequent T cell activation, noting results showed the intervention can differentiate splenic dendritic cells and enhance T lymphocyte immune function via shifting Th2 to Th1 cells.¹⁵ Other Chinese research published in 2010 showed astragalus induced apoptosis in nasopharyngeal (upper part of pharynx) carcinoma cells;¹⁶ and astralagus polysaccharides stimulate expression of a gene (TLR4) that have been found to convey antimicrobial activities on bladder epithelial cells, in addition to secreting IL-6 and IL-8, and inhibiting bladder epithelial cell bacterial invasion (E. coli).¹⁷

Astragalus and fellow Traditional Chinese herb Andrographis paniculata were among several immunomodulatory botanical extracts including elderberryfound to induce genes involved in immune cell activation and inflammatory cytokine response.¹⁸ Researchers treated peripheral blood mononuclear cells (PMBCs)which are rich in T-cells, B-cells, NK cells, monocytes, macrophages and dendritic cellsand found astragalus treatment induced expression of several hundred cellular genes, as did elderberry; andrographis expressed fewer genes. They noted the presence of LPS in the extracts, but some evidence showed the beneficial actions charted were not just due to LPS.

Other research published in 2010 indicated andrographis extract and isolate andrographolide administered to animal metastatic tumor cells both enhanced antibody-dependent cell-mediated cytotoxicity, compared to no treatment; the treatments also increased serum IL-2 and TIMP-1 (tissue inhibitor of MMPs) , while reducing levels of pro-inflammatory cytokines including Il-1B, IL-6 and TNFa.¹⁹

Controlling inflammation is also a specialty of curcumin, which has demonstrated modulation of inflammation in several studies, according to a 2010 review.²⁰ Other 2010 study reports indicated curcumin inhibits TLR gene expression and function in human monocytes and neutrophils;²¹ interferes with colonic inflammation in inflammatory bowel disease (IBD) by inhibiting chemokine expression and neutrophil chemotaxis and chemokinesis;²² enhances T cells ability to kill cancer cells;²³ and regulates intestinal inflammation by down-regulating Th1-type immune responses and preventing bacterial translocation in the gut.²⁴

Spirulina (Arthrospira platensis), a uni-cellular microalgae, is brimming with nutrients, including vitamins, minerals, enzymes, protein/amino acids, carotenoids and fatty acids such as gamma linolenic acid (GLA). In a 2010 review of spirulina research, Bob Capeilli and Gerald Cysewski, both of Cyanotech Corp., not only explained this richness of nutrients, but also detailed the various proposed mechanisms of action for this ingredient on infection.²⁵ They reported spirulina increases resistance to infections and stimulates production of cytokines and antibodies, in addition to activating macrophages, T cells and B cells. Spirulina extracts have shown efficacy against various infections, including herpes virus, cytomegalovirus and influenza virus. They further noted Japanese scientists studying hot water spirulina extracts on cancer and viral infections reported supplementation increased NK cell gamma interferon and IL-12p40, in addition to possibly affecting signal responses via toll-like receptors (TLRs) important to the innate immune response.

The review also noted Danish in vitro and human clinical studies on spirulina (as Immunlina, from Scandinavian Clinical) found the extract strongly inhibited TT and Candida albicans infection, and enhanced several immune markers including TNFa, interferon gamma and IL-6. Phycocyanin, a highly antioxidative pigment in spirulina, also increases resistance to disease, in addition to positively impacting IgE antibodies, according to the review.

A 2010 Taiwanese in vitro trial confirmed some of these spirulina benefits, as a hot water extract of spirulina administered to shrimp enhanced innate immunity and increased resistance to Vibrio alginolyticus infection, which can cause ear infections or inflammation or wound infection.²⁶ Both shrimp injected with various doses of spirulina and those dropped into seawater containing various levels of spirulina had increased survival rates, compared to control shrimpphagocytic activity toward V. alginolyticus bacteria increased in the spirulina groups.

References

1. Roll S et al. Reduction of common cold symptoms by encapsulated juice powder concentrate of fruits and vegetables: a randomised, double-blind, placebo-controlled trial. Br J Nutr. 2011 Jan;105(1):118-22.

2. Goncagul G and Ayaz E. Antimicrobial effect of garlic (Allium sativum). Recent Pat Antiinfect Drug Discov. 2010 Jan 1;5(1):91-3.

3. Abdullah T et al. Onkologie. 1989;21:52-3.

4. Kyo E et al. Phytomedicine. 1998. 5(4):259-67.

5. Zhang Y et al. Nutraceuticals: Designer Foods III Garlic, Soy and Licorice. Food & Nutrition Press, Trumbell Conn. 1997. pp. 117-29

6. Clement F et al. Identity of the immunomodulatory proteins from garlic (Allium sativum) with the major garlic lectins or agglutinins. Int Immunopharmacol. 2010 Mar;10(3):316-24.

7. DellAgli M et al. Ellagitannins of the fruit rind of pomegranate (Punica granatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria. Malar J. 2010 Jul 19;9:208.

8. Shutz K et al. Immune-modulating efficacy of a polyphenol-rich beverage on symptoms associated with the common cold: a double-blind, randomised, placebo-controlled, multi-centric clinical study. British J Nutr. 2010;104: 1156-1164.

9. Murakami S et al. Suppression of exercise-induced neutrophilia and lymphopenia in athletes by cystine/theanine intake: a randomized, double-blind, placebo-controlled trial. J Intl Soc Sports Nutr. 2010;7:23.

10. Barrett B. Medicinal properties of Echinacea: a critical review. Phytomedicine. 2003 Jan;10(1):66-86.

11. Barrett B et al. Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial. J Pediatr. 2004 Jul;145(1):135-6.

12. Barrett B et al. Echinacea for treating the common cold: a randomized trial. Ann Intern Med. 2010 Dec 21;153(12):769-77.

13. Cho WC, Leung KN. In vitro and in vivo immunomodulating and immunorestorative effects of Astragalus membranaceus. J Ethnopharmacol. 2007 Aug 15;113(1):132-41.

14. Clement-Kruzel S et al. Immune modulation of macrophage pro-inflammatory response by goldenseal and Astragalus extracts. J Med Food. 2008 Sep;11(3):493-8.

15. Liu QY et al. Astragalus polysaccharides regulate T cell-mediated immunity via CD11c(high)CD45RB(low) DCs in vitro. J Ethnopharmacol. 2010; Published online ahead of print on July 8, 2010.

16. Song Y et al. Antitumor and immunoregulatory effects of astragalus on nasopharyngeal carcinoma In Vivo and In Vitro. Phytother Res. 2010 Dec 14. doi: 10.1002/ptr.3354.

17. Yin X et al. Enhancement of the innate immune response of bladder epithelial cells by Astragalus polysaccharides through upregulation of TLR4 expression. Biochem Biophys Res Commun. 2010 Jun 25;397(2):232-8.

18. Chao Ww et al. The production of nitric oxide and prostaglandin E2 in peritoneal macrophages is inhibited by Andrographis paniculata, Angelica sinensis and Morus alba ethyl acetate fractions. J Ethnopharmacol. 2009 Feb 25;122(1):68-75.

19. Sheeja K and Kuttan G. Andrographis paniculata downregulates proinflammatory cytokine production and augments cell mediated immune response in metastatic tumor-bearing mice. Asian Pac J Cancer Prev. 2010;11(3):723-9.

20. Svrivastava RM et al. Immunomodulatory and therapeutic activity of curcumin. Int Immunopharmacol. 2010; Published online ahead of print Sept. 8.

21. Shuto T et al. Curcumin decreases toll-like receptor-2 gene expression and function in human monocytes and neutrophils. Biochem Biophys Res Commun. 2010 Aug 6;398(4):647-52.

22. Larmonier CB et al. Modulation of neutrophil motility by curcumin: Implications for inflammatory bowel disease. Inflamm Bowel Dis. 2011 Feb;17(2):503-15.

23. Bhattacharyya S et al. Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts. Cell Mol Immunol. 2010 Jul;7(4):306-15.

24. Bereswill S et al. Anti-inflammatory effects of resveratrol, curcumin and simvastatin in acute small intestinal inflammation. PLoS One. 2010 Dec 3;5(12):e15099.

25. Capelli B and Cysewski G. Potential Health Benefits of Spirulina Microalgae: A review of Existing Literature. NUTRA foods. 2010;9(2):19-26.

26. Tayag CM et al. Administration of the hot-water extract of Spirulina platensis enhanced the immune response of white shrimp Litopenaeus vannamei and its resistance against Vibrio alginolyticus. Fish Shellfish Immunol. 2010;28(5-6):764-73