Skip to main content

Advertisement

Immunomodulatory dietary polysaccharides: a systematic review of the literature

Article metrics

Abstract

Background

A large body of literature suggests that certain polysaccharides affect immune system function. Much of this literature, however, consists of in vitro studies or studies in which polysaccharides were injected. Their immunologic effects following oral administration is less clear. The purpose of this systematic review was to consolidate and evaluate the available data regarding the specific immunologic effects of dietary polysaccharides.

Methods

Studies were identified by conducting PubMed and Google Scholar electronic searches and through reviews of polysaccharide article bibliographies. Only articles published in English were included in this review. Two researchers reviewed data on study design, control, sample size, results, and nature of outcome measures. Subsequent searches were conducted to gather information about polysaccharide safety, structure and composition, and disposition.

Results

We found 62 publications reporting statistically significant effects of orally ingested glucans, pectins, heteroglycans, glucomannans, fucoidans, galactomannans, arabinogalactans and mixed polysaccharide products in rodents. Fifteen controlled human studies reported that oral glucans, arabinogalactans, heteroglycans, and fucoidans exerted significant effects. Although some studies investigated anti-inflammatory effects, most studies investigated the ability of oral polysaccharides to stimulate the immune system. These studies, as well as safety and toxicity studies, suggest that these polysaccharide products appear to be largely well-tolerated.

Conclusions

Taken as a whole, the oral polysaccharide literature is highly heterogenous and is not sufficient to support broad product structure/function generalizations. Numerous dietary polysaccharides, particularly glucans, appear to elicit diverse immunomodulatory effects in numerous animal tissues, including the blood, GI tract and spleen. Glucan extracts from the Trametes versicolor mushroom improved survival and immune function in human RCTs of cancer patients; glucans, arabinogalactans and fucoidans elicited immunomodulatory effects in controlled studies of healthy adults and patients with canker sores and seasonal allergies. This review provides a foundation that can serve to guide future research on immune modulation by well-characterized polysaccharide compounds.

Background

Polysaccharide-rich fungi and plants have been employed for centuries by cultures around the world for their dietary and medicinal benefits [15]. Often thought to merely support normal bowel function and blood glucose and lipid levels [68], certain polysaccharides have attracted growing scientific interest for their ability to exert marked effects on immune system function, inflammation and cancers [911]. Many of these chemically and structurally diverse, non- to poorly-digestible polysaccharides have been shown to beneficially affect one or more targeted cellular functions in vitro [1116], but much of the in vivo literature consists of studies in which polysaccharides were injected [1, 2]. For clinicians and scientists interested in immunologic effects following dietary intake, the value of such studies is uncertain. Polysaccharides that elicit effects in vitro or by injection may be ineffective or have different effects when taken orally [17]. We thus decided to conduct a systematic review to evaluate the specific immunologic effects of dietary polysaccharide products on rodents and human subjects.

Methods

Literature review

Studies were identified by conducting electronic searches of PubMed and Google Scholar from their inception to the end of October 2009. The reference lists of the selected articles were checked for additional studies that were not originally found in the search.

Study selection and data extraction

The following search terms were combined with the term polysaccharide: dietary AND immune, or oral AND immune, or dietary AND inflammation, or oral AND inflammation. When specific polysaccharides or polysaccharide-rich plants and fungi were identified, further searches were conducted using their names with the same search terms. Studies were selected based on the following inclusion criteria:

1. Rodent or human studies

2. The presence of test group and control group (using either placebo, crossover, sham, or normal care)

3. Studies reporting statistically significant immunomodulatory effects

4. English language

5. Studies published up to October 2009.

Two researchers (JER, EDN) reviewed the list of unique articles for studies that fit the inclusion criteria. Uncertainties over study inclusion were discussed between the researchers and resolved through consensus. Searches were then conducted to obtain specific polysaccharide product information: safety (using the search terms: toxicity, NOAEL, LD50), composition and structure, and disposition.

Quality assessment

Each study was assessed as to whether or not it reported a significant outcome measure for the polysaccharide intervention group.

Results

A total of 62 rodent publications (Tables 1, 2 and 3) and 15 human publications (Table 4) were deemed appropriate for inclusion in this review. Available structural and compositional information for these immunomodulatory polysaccharides are provided in Table 5 and safety information is provided in Table 6. The majority of animal studies explored models in which animals were injected or implanted with cancer cells or tumors, were healthy, or were exposed to carcinogens. Other studies investigated immunodeficient, exercise-stressed, aged animals, or animals exposed to inflammatory agents, viruses, bacterial pathogens, pathogenic protozoa, radiation or mutagens. Human studies assessed immunomodulatory effects in healthy subjects, or patients with cancers, seasonal allergic rhinitis or aphthous stomatitis. Because of the limited number of human studies, we included some promising open-label controlled trials. Human study durations ranged from four days to seven years; daily doses ranging from 100-5,400 mg were reported to be well-tolerated.

Table 1 Immunomodulatory Glucan Extracts: Oral Animal Studies
Table 2 Immunomodulatory Non-Glucan Extracts: Oral Animal Studies
Table 3 Immunomodulatory Polysaccharide-Rich Plant Powders: Oral Animal Studies
Table 4 Immunomodulatory Polysaccharide Products: Oral Human Studies
Table 5 Immunomodulatory Polysaccharide Products: Composition and Structure
Table 6 Safety of Immunomodulatory Polysaccharide Products Following Oral Intake

A number of studies in healthy human adults demonstrated immune stimulating effects of oral polysaccharides. Arabinogalactans from Larix occidentalis (Western larch) were shown in RCTs to increase lymphocyte proliferation and the number of CD8+ lymphocytes [18] and to increase the IgG subtype response to pneumococcal vaccination [19]. A furanose extract from Panax quiquefolium (North American ginseng) was shown in an RCT of healthy older adults to decrease the incidence of acute respiratory illness and symptom duration [20]. Finally, an RCT of healthy adults consuming Undaria pinnatifida (wakame) fucoidans found both immune stimulating and suppressing effects, including increased stromal-derived factor-1, IFN-g, CD34+ cells and CXCR4-expressing CD34+ cells and decreased blood leukocytes and lymphocytes [21].

Studies in healthy animals showed a number of immune stimulating effects of various glucan products from Agaricus subrufescens (A. blazei) (aqueous extracts [22], aqueous extracts with standardized β-glucans [23], α-1,6 and α-1,4 glucans [24], and whole plant powders [25]); Lentinula edodes (shiitake) (lentinan [26] and β-glucans [27]); Saccharomyces cerevisiae (β-1,3-glucans [27, 28]); Laminaria digitata (laminarin [29]); Sclerotium rofsii (glucan phosphate [29]); Sclerotinia sclerotiorum (SSG [30]); and Phellinus linteus (powder [31] and aqueous, alcohol-precipitated extract [32]). A furanose extract from P. quiquefolium and pectins from Buplerum falcatum and Malus (apple) spp. have also been shown to enhance immune function in healthy young animals [3335]. Cyamopsis tetragonolobus galactomannan (guar gum) or highly methoxylated pectin feeding exerted numerous stimulating effects on antibody production in older animals [36].

Evidence for the effectiveness of oral polysaccharides against infection and immune challenges has been mainly demonstrated in animals. Immune stimulating effects have been shown in resting and exercise-stressed animals with thioglycollate, clodronate, or HSV-1 injections fed Avena (oat) spp. soluble glucans [3741]; animals injected with or fed E. vermiformis and fed Avena spp. particulate glucans [42, 43]; animals with E. coli injections fed L. digitata glucans (laminarin) [44]; animals with HSV injections fed U. pinnatifida fucoidans [45]; animals with Staphylococcus aureus or Candida albicans injections fed S. cerevisiae glucans (scleroglucan) [29]; and animals with fecal solution injections fed an aqueous extract of A. subrufescens (A. blazei Murrill) [46].

Additional controlled human and animal studies have shown anti-inflammatory and anti-allergy effects of some polysaccharide products. In an RCT of adults with seasonal allergic rhinitis, S. cerevisiae β-1,3;1-6 glucans decreased IL-4, IL-5 and percent eosinophils, and increased IL-12 in nasal fluid [47], while a placebo-controlled study of patients with recurrent aphthous stomatitis (canker sores) consuming β-1,3;1-6 glucans found increased lymphocyte proliferation and decreased Ulcer Severity Scores [48].

Animal models of inflammatory bowel disease have shown anti-inflammatory effects of Cladosiphon okamuranus Tokida fucoidans [49], Cyamopsis tetragonolobus galactomannans [50], Malus spp. pectins [51], and mixed polysaccharide supplements [52]. Animals challenged with ovalbumin have demonstrated anti-inflammatory/allergy effects of A. subrufescens aqueous extracts [22], an aqueous extract of Ganoderma tsugae [53], and Pyrus pyrifolia pectins [54]. Anti-inflammatory effects have also been seen in animals with cotton pellet implantations fed a Pholiota nameko heteroglycan (PNPS-1) [55].

Trametes versicolor glucans have demonstrated anti-cancer effects in humans. In two RCTs and five controlled trials, PSK from T. versicolor mycelia increased survival of advanced stage gastric, colon and colorectal cancer patients [5662] with one study showing increased immune parameters (including blood NK cell activity, leukocyte cytotoxicity, proportion of helper cells and lymphocyte suppressor cells) [62]. An RCT of advanced stage lung cancer patients consuming PSP from T. versicolor fruit bodies found increased IgG and IgM antibodies and total leukocyte and neutrophil counts, along with a decrease in the number of patients withdrawing from the study due to disease progression [63]. An RCT of ovarian or endometrial cancer patients consuming A. subrufescens glucans showed increased NK cell activity and fewer chemotherapy side effects [64].

In numerous animal models of cancer, a wide range of polysaccharides have shown anti-tumorogenic effects. Glucan products sourced from A. subrufescens demonstrating anti-cancer activities in animal models include an aqueous extract [65], an aqueous, acid-treated extract [66], and an aqueous extract with standardized levels of β-glucans [23]. Anti-cancer effects have been reported following intake of aqueous extracts of G. lucidum [6769]; the powder and D fraction of G. frondosa [7072]; Hordeum vulgare β-glucans [7376]; Laminaria angustata powder [77]; Lentinula edodes products (powders [70, 78, 79], SME [80], β-glucans [27], and lentinan [81, 82]); Pleurotus ostreatus powder [70], Saccharomyces cerevisiae particulate β-1,3;1,6 and β-1,3glucans[27, 73]; and a glucan from Sclerotinia sclerotiorum (SSG) [30, 83]. A glucomannan from L. edodes (KS-2) improved survival of animals with cancer cell injections [84]; apple and citrus pectins have exerted anti-cancer effects, including decreased tumor incidence [8590]. Finally, heteroglycans from Lycium barbarum (LBP3p), Lentinus lepidus (PG101) and A. subrufescens (ATOM) demonstrated a number of immune stimulating effects in animal cancer models [9193]. Interestingly, only one animal study has been performed using glucans from T. versicolor (PSP): animals with cancer cell implantations showed decreased tumor growth and vascular density [94].

Most polysaccharide products appear to be safe, based on NOAEL, acute and/or chronic toxicity testing in rodents (Table 6). As would be expected, powders, extracts and products that have not been fully characterized pose the most concerns. Other than for aloe vera gel, which was shown in a small human trial to increase the plasma bioavailability of vitamins C and E [95], the impact of polysaccharide intake on the absorption of nutrients and medications is not known. While one rat toxicity study raised concerns when guar gum comprised 15% of the daily diet [96], the product was safe in humans studies when 18-39.6 g/day was consumed for up to a year (Table 4). Product contamination may explain three case reports of hepatotoxicity and/or death following intake of an A. subrufescens aqueous extract [97]. Seven animal studies reporting positive immunologic effects of A. subrufescens extracts in healthy animals or animals with cancers found no evidence of toxicity (Tables 1 and 2). In humans, six weeks of A. subrufescens glucans intake was safe for cancer patients, and four months of 3 g/day intake by 24 healthy adults and 24 adults with liver disease reported no evidence of toxicity (Table 4). Another case report associated liver toxicity with G. lucidum intake, but the elderly subject also took an unidentified product a month previous to her admission for testing [98]. Three animal studies reported immunologic benefits and no adverse effects following intake of G. lucidum aqueous extracts; in one study intake was 5% of the diet for 5 months (Table 1). While adverse effects were also reported in a study in which 10 adults consumed 4 g/day L. edodes powder for 10 weeks [99], immunologic animal studies reported no ill effects of either L. edodes powder (5 studies, up to 5% of the diet up to nine months) or extract (7 studies, up to 40 days intake) (Tables 1 and 3). Finally, while intake of 319 mg/kg of an aqueous extract of P. ostreatus by mice for 1 month caused hemorrhages in multiple tissues [100], there was no reported toxicity when mice consumed the mushroom powder as 5% of their diet for nine months (Table 3). While ≥1 gram/day of T. versicolor glucan products were safely consumed by cancer patients for up to 10 years, the long-term effects of ingestion of the other polysaccharide products discussed in this review is also not known.

Discussion

The majority of studies that qualified for inclusion in this review employed models investigating immune stimulation; fewer explored anti-inflammatory effects. Animal studies reported immune system effects in the gut, spleen, bone marrow, liver, blood, thymus, lungs, and saliva; controlled human studies reported evidence of immune stimulation in the blood, anti-inflammatory effects in nasal lavage fluid and improved survival in cancer patients. The literature is highly heterogenous and is not sufficient to support broad structure/function generalizations. For the limited number of studies that investigated well-characterized, isolated products (primarily glucan products), effects can be unequivocally attributed to polysaccharides. Such associations are certainly more tenuous when considering product powders or products obtained by extraction methods designed to isolate polysaccharides, but without complete compositional analyses.

Dietary polysaccharides are known to impact gut microbial ecology [101, 102], and advances in microbial ecology, immunology and metabolomics indicate that gut microbiota can impact host nutrition, immune modulation, resistance to pathogens, intestinal epithelial development and activity, and energy metabolism [103107]. Other than fucoidans, the polysaccharides discussed in this review appear to be at least partially degraded by bacterial enzymes in the human digestive tract (Table 7). Arabinogalactans, galactomannans, a glucan (laminarin), glucomannans, and mixed polysaccharide products (Ambrotose® products) have been shown to be metabolized by human colonic bacteria. Orally ingested fucoidans, glucans and mannans (or their fragments) have been detected in numerous tissues and organs throughout the body [73, 108, 109], (Carrington Laboratories, personal communication). We know of no study that has determined the specific identity of orally-ingested polysaccharide end products in animal or human tissues.

Table 7 Fate of Immunomodulatory Polysaccharide Products Following Oral Intake

One can only speculate upon the mechanisms by which the polysaccharides discussed in this review influence immunologic function, particularly when one considers the exceedingly complex environment of the GI tract. It is possible that fragments of polysaccharides partially hydrolyzed by gut bacteria may either bind to gut epithelia and exert localized and/or systemic immune system effects, or be absorbed into the bloodstream, with the potential to exert systemic effects. Current studies investigating the link between the bioconversion of dietary polysaccharides, their bioavailability and their downstream effects on the host metabolism and physiology are utilizing metabolomic and metagenomic approaches that can detect and track diverse microbial metabolites from immunomodulatory polysaccharides [103]. These and other innovative approaches in the field of colonic fermentation are providing novel insights into gut microbial-human mutualism [110, 111], its impact on regulating human health and disease, and the importance of dietary modulation [112115].

Additional RCTs of well-characterized products are needed to more completely understand the immunomodulatory effects and specific applications of oral polysaccharides. Such studies will need to better investigate the optimal timing and duration for polysaccharide ingestion. That is, should they be consumed continuously, before, at the time of, or after exposure to a pathogen or environmental insult? Only a few studies have actually investigated the impact of timing of polysaccharide intake to achieve optimal benefits. Daily feeding with some polysaccharides appears to result in tolerance (and diminished benefits); this has been demonstrated for some mushroom β-glucans [3, 26]. For those polysaccharides whose immunologic effects are dependent on their prebiotic activities, regular feeding would be presumed necessary.

Conclusions

The dietary polysaccharides included in this review have been shown to elicit diverse immunomodulatory effects in animal tissues, including the blood, GI tract, and spleen. In controlled human trials, polysaccharide intake stimulated the immune system in the blood of healthy adults, dampened the allergic response to a respiratory inflammatory agent, and improved survival in cancer patients. Additional RCTs of well-characterized products are needed to more completely understand the immunomodulatory effects and specific applications of oral polysaccharides

Abbreviations

♀:

female

♂:

male

Ab:

antibody

AIDS:

autoimmune deficiency syndrome

AOM:

azoxymethane

BBN:

N-butyl-N'-butanolnitrosamine

BLCL:

Burkitt's Lymphoma Cell Line

BW:

body weight

CBC:

complete blood count

CD:

cluster of differentiation

CFU:

colony forming unit

ConA:

concanavalin A

CXCR:

CXC chemokine receptor

DMBA:

7,12-dimethylbenz(a)anthracene

DMH:

N-N'-dimethylhydrazine

DMN:

dimethylhydrazine

DSS:

dextran sulfate sodium

EBV:

Epstein-Barr virus

GALT:

gut-associated lymphoid tissue

GI:

gastrointestinal

HSV:

herpes simplex virus

ICR:

imprinting control region

ID:

intradermal

IEL:

intraepithelial lymphocytes

IFN-λ:

interferon gamma

IG:

intragastric

IgA:

immunoglobulin A

IgE:

immunoglobulin E

IgG:

immunoglobulin G

IgM:

immunoglobulin M

IL:

interleukin

IMC:

invasive micropapillary carcinoma

IN:

intranasally

IP:

intraperitoneal

IV:

intravenous

LPS:

lipopolysaccharide

Mø:

macrophage

mAb:

monoclonal antibody

3-MCA:

methylcholanthrene

MLN:

mesenteric lymph nodes

MM-46 carcinoma:

mouse mammary carcinoma

MW:

molecular weight

NK:

natural killer

NOAEL:

no observable adverse effect level

OVA:

ovalbumin

PBL:

peripheral blood leukocytes

PBMC:

peripheral blood mononuclear cells

PHA:

phytohaemagglutinin

PMA:

phorbol 12-myristate 13-acetate

PML:

polymorphonuclear lymphocyte

RCT:

randomized, controlled trial

RNA:

ribonucleic acid

SC:

subcutaneous

SD rats:

Sprague Dawley

TCR:

T cell receptor

TLR:

toll like receptor

TNF-α:

tumor necrosis factor alpha

UC:

ulcerative colitis

WT:

wild type.

References

  1. 1.

    Paulsen BS: Plant polysaccharides with immunostimulatory activities. Curr Org Chem. 2001, 5: 939-950. 10.2174/1385272013374987.

  2. 2.

    Yamada H, Kiyohara H: Complement-activating polysaccharides from medicinal herbs. Immunomodulatory Agents from Plants. Edited by: Wagner H Basel. 1999, Switzerland: Birkhauser Verlag

  3. 3.

    Hobbs C: Medicinal Mushrooms: An Exploration of Tradition, Healing and Culture. 2003, Summertown, Tenn: Botanica Press

  4. 4.

    Kusaykin M, Bakunina I, Sova V, Ermakova S, Kuznetsova T, Besednova N, et al: Structure, biological activity, and enzymatic transformation of fucoidans from the brown seaweeds. Biotechnol J. 2008, 3: 904-915. 10.1002/biot.200700054.

  5. 5.

    Aloes. The genus aloe. 2003, Boca Raton, Fla.: CRC Press

  6. 6.

    Anderson JW, Smith BM, Gustafson NJ: Health benefits and practical aspects of high-fiber diets. Am J Clin Nutr. 1994, 59: 1242S-1247S.

  7. 7.

    Weickert MO, Pfeiffer AF: Metabolic effects of dietary fiber consumption and prevention of diabetes. J Nutr. 2008, 138: 439-442.

  8. 8.

    Estruch R, Martinez-Gonzalez MA, Corella D, Basora-Gallisa J, Ruiz-Gutierrez V, Covas MI, et al: Effects of dietary fibre intake on risk factors for cardiovascular disease in subjects at high risk. J Epidemiol Community Health. 2009, 63: 582-588. 10.1136/jech.2008.082214.

  9. 9.

    Pelley RP, Strickland FM: Plants, polysaccharides, and the treatment and prevention of neoplasia. Crit Rev Oncog. 2000, 11: 189-225.

  10. 10.

    Lull C, Wichers HJ, Savelkoul HF: Antiinflammatory and immunomodulating properties of fungal metabolites. Mediators Inflamm. 2005, 2005: 63-80. 10.1155/MI.2005.63.

  11. 11.

    Chan GC, Chan WK, Sze DM: The effects of beta-glucan on human immune and cancer cells. J Hematol Oncol. 2009, 2: 25-10.1186/1756-8722-2-25.

  12. 12.

    Schepetkin IA, Quinn MT: Botanical polysaccharides: macrophage immunomodulation and therapeutic potential. Int Immunopharmacol. 2006, 6: 317-333. 10.1016/j.intimp.2005.10.005.

  13. 13.

    Ma Y, Hebert JR, Li W, Bertone-Johnson ER, Olendzki B, Pagoto SL, et al: Association between dietary fiber and markers of systemic inflammation in the Women's Health Initiative Observational Study. Nutrition. 2008, 24: 941-949. 10.1016/j.nut.2008.04.005.

  14. 14.

    Hua KF, Hsu HY, Chao LK, Chen ST, Yang WB, Hsu J, et al: Ganoderma lucidum polysaccharides enhance CD14 endocytosis of LPS and promote TLR4 signal transduction of cytokine expression. J Cell Physiol. 2007, 212: 537-550. 10.1002/jcp.21050.

  15. 15.

    Ho YW, Yeung JSL, Chiu PKY, Tang WM, Lin ZB, Man RYK, et al: Ganoderma lucidum polysaccharide peptide reduced the production of proinflammatory cytokines in activated rheumatoid synovial fibroblast. Mol Cell Biochem. 2007, 301: 173-179. 10.1007/s11010-006-9409-y.

  16. 16.

    Kim MH, Joo HG: Immunostimulatory effects of fucoidan on bone marrow-derived dendritic cells. Immunol Lett. 2008, 115: 138-143. 10.1016/j.imlet.2007.10.016.

  17. 17.

    Boh B, Berovic M, Zhang J, Zhi-Bin L: Ganoderma lucidum and its pharmaceutically active compounds. Biotechnol Annu Rev. 2007, 13: 265-301. full_text.

  18. 18.

    Nantz MP, Parker AR, McGill C, Percival SS: Evaluation of arabinogalactan's effect on human immunity. FASEB Journal. 2001, 15 (4): A633-

  19. 19.

    Udani JK, Singh BB, Barrett ML, Singh VJ: Immunomodulatory effects of a proprietary arabinogalactan extract: a randomized, double-blind, placebo-controlled, parallel group study. Presented at the 50th Annual American College of Nutrition Meeting, Resort Lake Buena Vista, Florida, October 1-4, 2009. 2009

  20. 20.

    McElhaney JE, Goel V, Toane B, Hooten J, Shan JJ: Efficacy of COLD-fX in the prevention of respiratory symptoms in community-dwelling adults: a randomized, double-blinded, placebo controlled trial. J Altern Complement Med. 2006, 12: 153-157. 10.1089/acm.2006.12.153.

  21. 21.

    Irhimeh MR, Fitton JH, Lowenthal RM: Fucoidan ingestion increases the expression of CXCR4 on human CD34+ cells. Exp Hematol. 2007, 35: 989-994. 10.1016/j.exphem.2007.02.009.

  22. 22.

    Chan Y, Chang T, Chan CH, Yeh YC, Chen CW, Shieh B, et al: Immunomodulatory effects of Agaricus blazei Murill in Balb/cByJ mice. J Microbiol Immunol Infect. 2007, 40: 201-208.

  23. 23.

    Takimoto H, Wakita D, Kawaguchi K, Kumazawa Y: Potentiation of cytotoxic activity in naive and tumor-bearing mice by oral administration of hot-water extracts from Agaricus blazei fruiting bodies. Biol Pharm Bull. 2004, 27: 404-406. 10.1248/bpb.27.404.

  24. 24.

    Mizuno M, Morimoto M, Minato K, Tsuchida H: Polysaccharides from Agaricus blazei stimulate lymphocyte T-cell subsets in mice. Biosci Biotechnol Biochem. 1998, 62: 434-437. 10.1271/bbb.62.434.

  25. 25.

    Yuminamochi E, Koike T, Takeda K, Horiuchi I, Okumura K: Interleukin-12- and interferon-gamma-mediated natural killer cell activation by Agaricus blazei Murill. Immunology. 2007, 121: 197-206. 10.1111/j.1365-2567.2006.02558.x.

  26. 26.

    Hanaue H, Tokuda Y, Machimura T, Kamijoh A, Kondo Y, Ogoshi K, et al: Effects of oral lentinan on T-cell subsets in peripheral venous blood. Clin Ther. 1989, 11: 614-622.

  27. 27.

    Vetvicka V, Vashishta A, Saraswat-Ohri S, Vetvickova J: Immunological effects of yeast- and mushroom-derived beta-glucans. J Med Food. 2008, 11: 615-622. 10.1089/jmf.2007.0588.

  28. 28.

    Tsukada C, Yokoyama H, Miyaji C, Ishimoto Y, Kawamura H, Abo T: Immunopotentiation of intraepithelial lymphocytes in the intestine by oral administrations of beta-glucan. Cell Immunol. 2003, 221: 1-5. 10.1016/S0008-8749(03)00061-3.

  29. 29.

    Rice PJ, Adams EL, Ozment-Skelton T, Gonzalez AJ, Goldman MP, Lockhard BE, et al: Oral delivery and gastrointestinal absorption of soluble glucans stimulate increased resistance to infectious challenge. J Pharmacol Exp Ther. 2005, 314: 1079-1086. 10.1124/jpet.105.085415.

  30. 30.

    Suzuki I, Hashimoto K, Ohno N, Tanaka H, Yadomae T: Immunomodulation by orally administered beta-glucan in mice. Int J Immunopharmacol. 1989, 11: 761-769. 10.1016/0192-0561(89)90130-6.

  31. 31.

    Lim BO, Yamada K, Cho BG, Jeon T, Hwang SG, Park T, et al: Comparative study on the modulation of IgE and cytokine production by Phellinus linteus grown on germinated brown rice, Phellinus linteus and germinated brown rice in murine splenocytes. Biosci Biotechnol Biochem. 2004, 68: 2391-2394. 10.1271/bbb.68.2391.

  32. 32.

    Oh GS, Lee MS, Pae HO, Kwon J, Lee SS, Jeong JG, et al: Effects of oral administration of Phellinus linteus on the production of Th1- and Th2-type cytokines in mice. Immunopharmacol Immunotoxicol. 2006, 28: 281-293. 10.1080/08923970600809363.

  33. 33.

    Biondo PD, Goruk S, Ruth MR, O'Connell E, Field CJ: Effect of CVT-E002 (COLD-fX) versus a ginsenoside extract on systemic and gut-associated immune function. Int Immunopharmacol. 2008, 8: 1134-1142. 10.1016/j.intimp.2008.04.003.

  34. 34.

    Lim BO, Lee SH, Park DK, Choue RW: Effect of dietary pectin on the production of immunoglobulins and cytokines by mesenteric lymph node lymphocytes in mouse colitis induced with dextran sulfate sodium. Biosci Biotechnol Biochem. 2003, 67: 1706-1712. 10.1271/bbb.67.1706.

  35. 35.

    Sakurai MH, Matsumoto T, Kiyohara H, Yamada H: B-cell proliferation activity of pectic polysaccharide from a medicinal herb, the roots of Bupleurum falcatum L. and its structural requirement. Immunology. 1999, 97: 540-547. 10.1046/j.1365-2567.1999.00774.x.

  36. 36.

    Yamada K, Tokunaga Y, Ikeda A, Ohkura K, Kaku-Ohkura S, Mamiya S, et al: Effect of dietary fiber on the lipid metabolism and immune function of aged Sprague-Dawley rats. Biosci Biotechnol Biochem. 2003, 67: 429-433. 10.1271/bbb.67.429.

  37. 37.

    Murphy EA, Davis JM, Brown AS, Carmichael MD, Ghaffar A, Mayer EP: Oat beta-glucan effects on neutrophil respiratory burst activity following exercise. Med Sci Sports Exerc. 2007, 39: 639-644. 10.1249/mss.0b013e3180306309.

  38. 38.

    Davis JM, Murphy EA, Brown AS, Carmichael MD, Ghaffar A, Mayer EP: Effects of oat beta-glucan on innate immunity and infection after exercise stress. Med Sci Sports Exerc. 2004, 36: 1321-1327. 10.1249/01.MSS.0000135790.68893.6D.

  39. 39.

    Murphy EA, Davis JM, Carmichael MD, Mayer EP, Ghaffar A: Benefits of oat beta-glucan and sucrose feedings on infection and macrophage antiviral resistance following exercise stress. Am J Physiol Regul Integr Comp Physiol. 2009, 297: R1188-R1194.

  40. 40.

    Murphy EA, Davis JM, Brown AS, Carmichael MD, Carson JA, Van RN, et al: Benefits of oat beta-glucan on respiratory infection following exercise stress: role of lung macrophages. Am J Physiol Regul Integr Comp Physiol. 2008, 294: R1593-R1599.

  41. 41.

    Davis JM, Murphy EA, Brown AS, Carmichael MD, Ghaffar A, Mayer EP: Effects of moderate exercise and oat beta-glucan on innate immune function and susceptibility to respiratory infection. Am J Physiol Regul Integr Comp Physiol. 2004, 286: R366-R372.

  42. 42.

    Yun CH, Estrada A, Van Kessel A: Immunomodulatory effects of oat beta-glucan administered intragastrically or parenterally on mice infected with Eimeria vermiformis. Microbiol Immunol. 1998, 42: 457-465.

  43. 43.

    Yun CH, Estrada A, Van KA, Park BC, Laarveld B: Beta-glucan, extracted from oat, enhances disease resistance against bacterial and parasitic infections. FEMS Immunol Med Microbiol. 2003, 35: 67-75. 10.1016/S0928-8244(02)00460-1.

  44. 44.

    Neyrinck AM, Mouson A, Delzenne NM: Dietary supplementation with laminarin, a fermentable marine beta (1-3) glucan, protects against hepatotoxicity induced by LPS in rat by modulating immune response in the hepatic tissue. Int Immunopharmacol. 2007, 7: 1497-1506. 10.1016/j.intimp.2007.06.011.

  45. 45.

    Hayashi K, Nakano T, Hashimoto M, Kanekiyo K, Hayashi T: Defensive effects of a fucoidan from brown alga Undaria pinnatifida against herpes simplex virus infection. Int Immunopharmacol. 2008, 8: 109-116. 10.1016/j.intimp.2007.10.017.

  46. 46.

    Bernardshaw S, Hetland G, Grinde B, Johnson E: An extract of the mushroom Agaricus blazei Murill protects against lethal septicemia in a mouse model of fecal peritonitis. Shock. 2006, 25: 420-425. 10.1097/01.shk.0000209526.58614.92.

  47. 47.

    Kirmaz C, Bayrak P, Yilmaz O, Yuksel H: Effects of glucan treatment on the Th1/Th2 balance in patients with allergic rhinitis: a double-blind placebo-controlled study. Eur Cytokine Netw. 2005, 16: 128-134.

  48. 48.

    Koray M, Ak G, Kurklu E, Tanyeri H, Aydin F, Oguz FS, et al: The effect of beta-glucan on recurrent aphthous stomatitis. J Altern Complement Med. 2009, 15: 111-113. 10.1089/acm.2008.0118.

  49. 49.

    Matsumoto S, Nagaoka M, Hara T, Kimura-Takagi I, Mistuyama K, Ueyama S: Fucoidan derived from Cladosiphon okamuranus Tokida ameliorates murine chronic colitis through the down-regulation of interleukin-6 production on colonic epithelial cells. Clin Exp Immunol. 2004, 136: 432-439. 10.1111/j.1365-2249.2004.02462.x.

  50. 50.

    Naito Y, Takagi T, Katada K, Uchiyama K, Kuroda M, Kokura S, et al: Partially hydrolyzed guar gum down-regulates colonic inflammatory response in dextran sulfate sodium-induced colitis in mice. J Nutr Biochem. 2006, 17: 402-409. 10.1016/j.jnutbio.2005.08.010.

  51. 51.

    Lim BO, Lee SH, Park DK, Choue RW: Effect of dietary pectin on the production of immunoglobulins and cytokines by mesenteric lymph node lymphocytes in mouse colitis induced with dextran sulfate sodium. Biosci Biotechnol Biochem. 2003, 67: 1706-1712. 10.1271/bbb.67.1706.

  52. 52.

    Koetzner L, Grover G, Boulet J, Jacoby H: Plant-derived polysaccharide dietary supplements inhibits dextran sulfate sodium-induced colitis in the rat. Dig Dis Sci. 2010, 55: 1278-1285. 10.1007/s10620-009-0848-7.

  53. 53.

    Lin JY, Chen ML, Lin BF: Ganoderma tsugae in vivo modulates Th1/Th2 and macrophage responses in an allergic murine model. Food Chem Toxicol. 2006, 44: 2025-2032. 10.1016/j.fct.2006.07.002.

  54. 54.

    Lee JC, Pak SC, Lee SH, Na CS, Lim SC, Song CH, et al: Asian pear pectin administration during presensitization inhibits allergic response to ovalbumin in BALB/c mice. J Altern Complement Med. 2004, 10: 527-534. 10.1089/1075553041323867.

  55. 55.

    Li H, Lu X, Zhang S, Lu M, Liu H: Anti-inflammatory activity of polysaccharide from Pholiota nameko. Biochemistry (Mosc). 2008, 73: 669-675. 10.1134/S0006297908060060.

  56. 56.

    Mitomi T, Tsuchiya S, Iijima N, Aso K, Suzuki K, Nishiyama K, et al: Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. The Cooperative Study Group of Surgical Adjuvant Immunochemotherapy for Cancer of Colon and Rectum (Kanagawa). Dis Colon Rectum. 1992, 35: 123-130. 10.1007/BF02050666.

  57. 57.

    Ito K, Nakazato H, Koike A, Takagi H, Saji S, Baba S, et al: Long-term effect of 5-fluorouracil enhanced by intermittent administration of polysaccharide K after curative resection of colon cancer. A randomized controlled trial for 7-year follow-up. Int J Colorectal Dis. 2004, 19: 157-164. 10.1007/s00384-003-0532-x.

  58. 58.

    Ohwada S, Ikeya T, Yokomori T, Kusaba T, Roppongi T, Takahashi T, et al: Adjuvant immunochemotherapy with oral Tegafur/Uracil plus PSK in patients with stage II or III colorectal cancer: a randomised controlled study. Br J Cancer. 2004, 90: 1003-1010. 10.1038/sj.bjc.6601619.

  59. 59.

    Nakazato H, Koike A, Saji S, Ogawa N, Sakamoto J: Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Study Group of Immunochemotherapy with PSK for Gastric Cancer. Lancet. 1994, 343: 1122-1126. 10.1016/S0140-6736(94)90233-X.

  60. 60.

    Tsujitani S, Kakeji Y, Orita H, Watanabe A, Kohnoe S, Baba H, et al: Postoperative adjuvant immunochemotherapy and infiltration of dendritic cells for patients with advanced gastric cancer. Anticancer Res. 1992, 12: 645-648.

  61. 61.

    Torisu M, Hayashi Y, Ishimitsu T, Fujimura T, Iwasaki K, Katano M, et al: Significant prolongation of disease-free period gained by oral polysaccharide K (PSK) administration after curative surgical operation of colorectal cancer. Cancer Immunol Immunother. 1990, 31: 261-268. 10.1007/BF01740932.

  62. 62.

    Nio Y, Tsubono M, Tseng CC, Morimoto H, Kawabata K, Masai Y, et al: Immunomodulation by orally administered protein-bound polysaccharide PSK in patients with gastrointestinal cancer. Biotherapy. 1992, 4: 117-128. 10.1007/BF02171756.

  63. 63.

    Tsang KW, Lam CL, Yan C, Mak JC, Ooi GC, Ho JC, et al: Coriolus versicolor polysaccharide peptide slows progression of advanced non-small cell lung cancer. Respir Med. 2003, 97: 618-624. 10.1053/rmed.2003.1490.

  64. 64.

    Ahn WS, Kim DJ, Chae GT, Lee JM, Bae SM, Sin JI, et al: Natural killer cell activity and quality of life were improved by consumption of a mushroom extract, Agaricus blazei Murill Kyowa, in gynecological cancer patients undergoing chemotherapy. Int J Gynecol Cancer. 2004, 14: 589-594. 10.1111/j.1048-891X.2004.14403.x.

  65. 65.

    Murakawa K, Fukunaga K, Tanouchi M, Hosokawa M, Hossain Z, Takahashi K: Therapy of myeloma in vivo using marine phospholipid in combination with Agaricus blazei Murill as an immune respond activator. J Oleo Sci. 2007, 56: 179-188.

  66. 66.

    Kobayashi H, Yoshida R, Kanada Y, Fukuda Y, Yagyu T, Inagaki K, et al: Suppressing effects of daily oral supplementation of beta-glucan extracted from Agaricus blazei Murill on spontaneous and peritoneal disseminated metastasis in mouse model. J Cancer Res Clin Oncol. 2005, 131: 527-538. 10.1007/s00432-005-0672-1.

  67. 67.

    Zhang Q-H, Lin Z-B: The antitumor activity of Ganoderma lucidum (Curt.:Fr.) P. Karst. (LingZhi) (Aphyllophoromycetidease) polysaccharides is related to tumor necrosis factor-alpha and interferon-gamma. Int J Medicinal Mushrooms. 1999, 207-215.

  68. 68.

    Lu H, Kyo E, Uesaka T, Katoh O, Watanabe H: A water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia suppresses azoxymethane-induction of colon cancers in male F344 rats. Oncol Rep. 2003, 10: 375-379.

  69. 69.

    Lu H, Kyo E, Uesaka T, Katoh O, Watanabe H: Prevention of development of N,N'-dimethylhydrazine-induced colon tumors by a water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia in male ICR mice. Int J Mol Med. 2002, 9: 113-117.

  70. 70.

    Kurashige S, Akuzawa Y, Endo F: Effects of Lentinus edodes, Grifola frondosa and Pleurotus ostreatus administration on cancer outbreak, and activities of macrophages and lymphocytes in mice treated with a carcinogen, N-butyl-N-butanolnitrosoamine. Immunopharmacol Immunotoxicol. 1997, 19: 175-183. 10.3109/08923979709007657.

  71. 71.

    Hishida I, Nanba H, Kuroda H: Antitumor activity exhibited by orally administered extract from fruit body of Grifola frondosa (maitake). Chem Pharm Bull (Tokyo). 1988, 36: 1819-1827.

  72. 72.

    Nanba H, Kubo K: Effect of Maitake D-fraction on cancer prevention. Ann N Y Acad Sci. 1997, 833: 204-207. 10.1111/j.1749-6632.1997.tb48611.x.

  73. 73.

    Hong F, Yan J, Baran JT, Allendorf DJ, Hansen RD, Ostroff GR, et al: Mechanism by which orally administered (beta)-1,3-glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models. J Immunol. 2004, 173: 797-806.

  74. 74.

    Modak S, Koehne G, Vickers A, O'Reilly RJ, Cheung NK: Rituximab therapy of lymphoma is enhanced by orally administered (1-->3),(1-->4)-D-beta-glucan. Leuk Res. 2005, 29: 679-683. 10.1016/j.leukres.2004.10.008.

  75. 75.

    Cheung NK, Modak S, Vickers A, Knuckles B: Orally administered beta-glucans enhance anti-tumor effects of monoclonal antibodies. Cancer Immunol Immunother. 2002, 51: 557-564.

  76. 76.

    Cheung NK, Modak S: Oral (1-->3),(1-->4)-beta-D-glucan synergizes with antiganglioside GD2 monoclonal antibody 3F8 in the therapy of neuroblastoma. Clin Cancer Res. 2002, 8: 1217-1223.

  77. 77.

    Teas J, Harbison ML, Gelman RS: Dietary seaweed (Laminaria) and mammary carcinogenesis in rats. Cancer Res. 1984, 44: 2758-2761.

  78. 78.

    Nanba H, Mori K, Toyomasu T, Kuroda H: Antitumor action of shiitake (Lentinus edodes) fruit bodies orally administered to mice. Chem Pharm Bull (Tokyo). 1987, 35: 2453-2458.

  79. 79.

    Sugui MM, ves de Lima PL, Delmanto RD, da Eira AF, Salvadori DM, Ribeiro LR: Antimutagenic effect of Lentinula edodes (BERK.) Pegler mushroom and possible variation among lineages. Food Chem Toxicol. 2003, 41: 555-560. 10.1016/S0278-6915(02)00306-X.

  80. 80.

    deVere White RW, Hackman RM, Soares SE, Beckett LA, Sun B: Effects of a mushroom mycelium extract on the treatment of prostate cancer. Urology. 2002, 60: 640-644. 10.1016/S0090-4295(02)01856-3.

  81. 81.

    Yap AT, Ng M-L: Immunopotentiating properties of lentinan (1-3)-b-D-glucan extracted from culinary-medicinal Shiitake mushroom. Int J Medicinal Mushrooms. 2003, 5: 19-39.

  82. 82.

    Ng ML, Yap AT: Inhibition of human colon carcinoma development by lentinan from shiitake mushrooms (Lentinus edodes). J Altern Complement Med. 2002, 8: 581-589. 10.1089/107555302320825093.

  83. 83.

    Suzuki I, Sakurai T, Hashimoto K: Inhibition of experimental pulmonary metastasis of Lewis lung carcinoma by orally administered beta-glucan in mice. Chem Pharm Bull (Tokyo). 1991, 39: 1606-1608.

  84. 84.

    Fujii T, Maeda H, Suzuki F, Ishida N: Isolation and characterization of a new antitumor polysaccharide, KS-2, extracted from culture mycelia of Lentinus edodes. J Antibiot (Tokyo). 1978, 31: 1079-1090.

  85. 85.

    Ohkami H, Tazawa K, Yamashita I: Effects of apple pectin on fecal bacterial enzymes in azoxymethane- induced rat colon carcinogenesis. Jpn J Cancer Res. 1995, 86: 523-529.

  86. 86.

    Watanabe K, Reddy BS, Weisburger JH, Kritchevsky D: Effect of dietary alfalfa, pectin, and wheat bran on azoxymethane- or methylnitrosourea-induced colon carcinogenesis in F344 rats. J Natl Cancer Inst. 1979, 63: 141-145.

  87. 87.

    Hayashi A, Gillen AC, Lott JR: Effects of daily oral administration of quercetin chalcone and modified citrus pectin on implanted colon-25 tumor growth in Balb-c mice. Altern Med Rev. 2000, 5: 546-552.

  88. 88.

    Pienta KJ, Naik H, Akhtar A: Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst. 1995, 87: 348-353. 10.1093/jnci/87.5.348.

  89. 89.

    Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, et al: Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. J Natl Cancer Inst. 2002, 94: 1854-1862.

  90. 90.

    Tazawa K, Okami H, Yamashita I: Anticarcinogenic action of apple pectin on fecal enzyme activities and mucosal or portal prostaglandin E2 levels in experimental rat colon carcinogenesis. J Exp Clin Cancer Res. 1997, 16: 33-38.

  91. 91.

    Gan L, Hua ZS, Liang Y, Bi XH: Immunomodulation and antitumor activity by a polysaccharide-protein complex from Lycium barbarum. Int Immunopharmacol. 2004, 4: 563-569. 10.1016/j.intimp.2004.01.023.

  92. 92.

    Jin M, Jeon H, Jung HJ, Kim B, Shin SS, Choi JJ, et al: Enhancement of repopulation and hematopoiesis of bone marrow cells in irradiated mice by oral administration of PG101, a water-soluble extract from Lentinus lepideus. Exp Biol Med (Maywood). 2003, 228: 759-766.

  93. 93.

    Ito H, Shimura K, Itoh H, Kawade M: Antitumor effects of a new polysaccharide-protein complex (ATOM) prepared from Agaricus blazei (Iwade strain 101) Himematsutake and its mechanisms in tumor-bearing mice. Anticancer Res. 1997, 17: 277-284.

  94. 94.

    Ho JC, Konerding MA, Gaumann A, Groth M, Liu WK: Fungal polysaccharopeptide inhibits tumor angiogenesis and tumor growth in mice. Life Sci. 2004, 75: 1343-1356. 10.1016/j.lfs.2004.02.021.

  95. 95.

    Vinson JA, Al Kharrat H, Andreoli L: Effect of Aloe vera preparations on the human bioavailability of vitamins C and E. Phytomedicine. 2005, 12: 760-765. 10.1016/j.phymed.2003.12.013.

  96. 96.

    Graham SL, Arnold A, Kasza L, Ruffin GE, Jackson RC, Watkins TL, et al: Subchronic effects of guar gum in rats. Food Cosmet Toxicol. 1981, 19: 287-290. 10.1016/0015-6264(81)90386-2.

  97. 97.

    Mukai H, Watanabe T, Ando M, Katsumata N: An alternative medicine, Agaricus blazei, may have induced severe hepatic dysfunction in cancer patients. Jpn J Clin Oncol. 2006, 36: 808-810. 10.1093/jjco/hyl108.

  98. 98.

    Yuen MF, Ip P, Ng WK, Lai CL: Hepatotoxicity due to a formulation of Ganoderma lucidum (lingzhi). J Hepatol. 2004, 41: 686-687. 10.1016/j.jhep.2004.06.016.

  99. 99.

    Levy AM, Kita H, Phillips SF, Schkade PA, Dyer PD, Gleich GJ, et al: Eosinophilia and gastrointestinal symptoms after ingestion of shiitake mushrooms. J Allergy Clin Immunol. 1998, 101: 613-620. 10.1016/S0091-6749(98)70168-X.

  100. 100.

    Al Deen IH, Twaij HA, Al Badr AA, Istarabadi TA: Toxicologic and histopathologic studies of Pleurotus ostreatus mushroom in mice. J Ethnopharmacol. 1987, 21: 297-305. 10.1016/0378-8741(87)90105-X.

  101. 101.

    Flint HJ, Duncan SH, Scott KP, Louis P: Interactions and competition within the microbial community of the human colon: links between diet and health. Environ Microbiol. 2007, 9: 1101-1111. 10.1111/j.1462-2920.2007.01281.x.

  102. 102.

    Macfarlane GT, Steed H, Macfarlane S: Bacterial metabolism and health-related effects of galacto-oligosaccharides and other prebiotics. J Appl Microbiol. 2008, 104: 305-344.

  103. 103.

    Jacobs DM, Gaudier E, van DJ, Vaughan EE: Non-digestible food ingredients, colonic microbiota and the impact on gut health and immunity: a role for metabolomics. Curr Drug Metab. 2009, 10: 41-54. 10.2174/138920009787048383.

  104. 104.

    Ishizuka S, Tanaka S, Xu H, Hara H: Fermentable dietary fiber potentiates the localization of immune cells in the rat large intestinal crypts. Exp Biol Med (Maywood). 2004, 229: 876-884.

  105. 105.

    Garrett WS, Gordon JI, Glimcher LH: Homeostasis and inflammation in the intestine. Cell. 2010, 140: 859-870. 10.1016/j.cell.2010.01.023.

  106. 106.

    Segain JP, Raingeard de la BD, Bourreille A, Leray V, Gervois N, Rosales C, et al: Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease. Gut. 2000, 47: 397-403. 10.1136/gut.47.3.397.

  107. 107.

    Mazmanian SK, Kasper DL: The love-hate relationship between bacterial polysaccharides and the host immune system. Nat Rev Immunol. 2006, 6: 849-858. 10.1038/nri1956.

  108. 108.

    Irhimeh MR, Fitton JH, Lowenthal RM, Kongtawelert P: A quantitative method to detect fucoidan in human plasma using a novel antibody. Methods Find Exp Clin Pharmacol. 2005, 27: 705-710. 10.1358/mf.2005.27.10.948919.

  109. 109.

    Sakurai MH, Matsumoto T, Kiyohara H, Yamada H: Detection and tissue distribution of anti-ulcer pectic polysaccharides from Bupleurum falcatum by polyclonal antibody. Planta Med. 1996, 62: 341-346. 10.1055/s-2006-957898.

  110. 110.

    Arasaradnam RP, Pharaoh MW, Williams GJ, Nwokolo CU, Bardhan KD, Kumar S: Colonic fermentation--more than meets the nose. Med Hypotheses. 2009, 73: 753-756. 10.1016/j.mehy.2009.04.027.

  111. 111.

    Possemiers S, Grootaert C, Vermeiren J, Gross G, Marzorati M, Verstraete W, et al: The intestinal environment in health and disease - recent insights on the potential of intestinal bacteria to influence human health. Curr Pharm Des. 2009, 15: 2051-2065. 10.2174/138161209788489159.

  112. 112.

    Liu J, Gunn L, Hansen R, Yan J: Yeast-derived beta-glucan in combination with anti-tumor monoclonal antibody therapy in cancer. Recent Pat Anticancer Drug Discov. 2009, 4: 101-109. 10.2174/157489209788452858.

  113. 113.

    Tuohy KM, Gougoulias C, Shen Q, Walton G, Fava F, Ramnani P: Studying the human gut microbiota in the trans-omics era--focus on metagenomics and metabonomics. Curr Pharm Des. 2009, 15: 1415-1427. 10.2174/138161209788168182.

  114. 114.

    Schiffrin EJ, Morley JE, Donnet-Hughes A, Guigoz Y: The inflammatory status of the elderly: The intestinal contribution. Mutat Res. 2010, 690: 50-56.

  115. 115.

    Leung MY, Liu C, Koon JC, Fung KP: Polysaccharide biological response modifiers. Immunol Lett. 2006, 105: 101-114. 10.1016/j.imlet.2006.01.009.

  116. 116.

    Noda H, Amano H, Arashima K, Hashimoto S, Nisizawa K: Antitumor activity of polysaccharides and lipids from marine algae. Nippon Suisan Gakkaishi. 1989, 5: 1265-1271.

  117. 117.

    Wasser SP: Medicinal mushrooms as a source of antitumor and immunomodulating polysaccharides. Appl Microbiol Biotechnol. 2002, 60: 258-274. 10.1007/s00253-002-1076-7.

  118. 118.

    Firenzuoli F, Gori L, Lombardo G: The medicinal mushroom Agaricus blazei Murrill: Review of literature and pharmaco-toxicological problems. Evid Based Complement Alternat Med. 2008, 5: 3-15. 10.1093/ecam/nem007.

  119. 119.

    Luta G, McAnalley B: Aloe vera: chemical composition and methods used to determine its presence in commercial products. GlycoScience & Nutrition. 2005, 6: 1-12.

  120. 120.

    Qiu Z, Jones K, Wylie M, Jia Q, Orndorff S: Modified Aloe barbadensis polysaccharide with immunoregulatory activity. Planta Med. 2000, 66: 152-156. 10.1055/s-2000-11125.

  121. 121.

    Yagi A, Nakamori J, Yamada T, Iwase H, Tanaka T, Kaneo Y, et al: In vivo metabolism of aloe mannan. Planta Med. 1999, 65: 417-420. 10.1055/s-1999-14018.

  122. 122.

    Pugh N, Ross SA, ElSohly MA, Pasco DS: Characterization of Aloeride, a new high-molecular-weight polysaccharide from Aloe vera with potent immunostimulatory activity. J Agric Food Chem. 2001, 49: 1030-1034. 10.1021/jf001036d.

  123. 123.

    Final report on the safety assessment of Aloe andongensis extract, Aloe andongensis leaf juice, Aloe arborescens leaf extract, Aloe arborescens leaf juice, Aloe arborescens leaf protoplasts, Aloe barbadensis flower extract, Aloe barbadensis leaf, Aloe barbadensis leaf extract, Aloe barbadensis leaf juice, Aloe barbadensis leaf polysaccharides, Aloe barbadensis leaf water, Aloe ferox leaf extract, Aloe ferox leaf juice, and Aloe ferox leaf juice extract. Int J Toxicol. 2007, 26 (Suppl 2): 1-50.

  124. 124.

    Akramiene D, Kondrotas A, Didziapetriene J, Kevelaitis E: Effects of beta-glucans on the immune system. Medicina (Kaunas). 2007, 43: 597-606.

  125. 125.

    Kidd PM: A new approach to metastatic cancer prevention: modified citrus pectin (MCP), a unique pectin that blocks cell surface lectins. Alt Med Rev. 1996, 1: 4-10.

  126. 126.

    Nagaoka M, Shibata H, Kimura-Takagi I, Hashimoto S, Kimura K, Makino T, et al: Structural study of fucoidan from Cladosiphon okamuranus TOKIDA. Glycoconj J. 1999, 16: 19-26. 10.1023/A:1006945618657.

  127. 127.

    Akaki J, Matsui Y, Kojima H, Nakajima S, Kamei K, Tamesada M: Structural analysis of monocyte activation constituents in cultured mycelia of Cordyceps sinensis. Fitoterapia. 2009, 80: 182-187. 10.1016/j.fitote.2009.01.007.

  128. 128.

    Whistler RL, BeMiller JN: Carbohydrate Chemistry for Food Scientists. 1999, St. Paul, Minn.: American Association of Cereal Chemists, Inc, 2

  129. 129.

    Ohkuma T, Otagiri K, Ikekawa T, Tanaka S: Augmentation of antitumor activity by combined cryo-destruction of sarcoma 180 and protein-bound polysaccharide, EA6, isolated from Flammulina velutipes (Curt. ex Fr.) Sing. in ICR mice. J Pharmacobiodyn. 1982, 5: 439-444.

  130. 130.

    Wasser SP: Reishi or Ling Zhi (Ganoderma lucidum). Encyclopedia of Dietary Supplements. Edited by: Coates PM, Blackman MR, Cragg GM, Levine M, Moss J, White JD. 2005, New York, New York: Marcel Dekker, 603-622.

  131. 131.

    Song G, Xu A, Chen H, Wang X: Component analysis on polysaccharides in exocarp of Ginkgo biloba. Zhong Yao Cai. 1997, 20: 461-463.

  132. 132.

    Kubo K, Nanba H, Kuroda H: Modification of cellullar immune responses in experimental autoimmune hepatitis in mice by maitake (Grifola frondosa). Mycoscience. 1998, 39: 351-360. 10.1007/BF02460895.

  133. 133.

    Berteau O, Mulloy B: Sulfated fucans, fresh perspectives: structures, functions, and biological properties of sulfated fucans and an overview of enzymes active toward this class of polysaccharide. Glycobiology. 2003, 13: 29R-40R. 10.1093/glycob/cwg058.

  134. 134.

    D'Adamo P: Larch arabinogalactan. J Neuropath Med. 1990, 6: 33-37.

  135. 135.

    Chihara G, Maeda Y, Hamuro J, Sasaki T, Fukuoka F: Inhibition of mouse sarcoma 180 by polysaccharides from Lentinus edodes (Berk.) sing. Nature. 1969, 222: 687-688. 10.1038/222687a0.

  136. 136.

    Chihara G: The antitumor polysaccharide Lentinan: an overview. Manipulation of Host Defence Mechanisms. Edited by: Aoki T, Ichiro U, Eiro T. 1981, Excerpta Medica, 1-16.

  137. 137.

    Trnovec T, Hrmova M: Immunomodulatory polysaccharides: chemistry, disposition and metabolism. Biopharm Drug Dispos. 1993, 14: 187-198. 10.1002/bdd.2510140302.

  138. 138.

    Jin M, Jung HJ, Choi JJ, Jeon H, Oh JH, Kim B, et al: Activation of selective transcription factors and cytokines by water-soluble extract from Lentinus lepideus. Experimental Biology and Medicine. 2003, 228: 749-758.

  139. 139.

    Wasser SP: Shiitake (Lentinus edodes). Encyclopedia of Dietary Supplements. Edited by: Coates PM, Blackman MR, Cragg GM, Levine M, Moss J, White JD. 2005, New York, New York: Marcell Dekker, 653-664.

  140. 140.

    Oshima Y, Sato K, Hikino H: Isolation and hypoglycemic activity of quinquefolans A, B, and C, glycans of Panax quinquefolium roots. J Nat Prod. 1987, 50: 188-190. 10.1021/np50050a010.

  141. 141.

    Zhu T, Kim SH, Chen CY: A medicinal mushroom: Phellinus linteus. Curr Med Chem. 2008, 15: 1330-1335. 10.2174/092986708784534929.

  142. 142.

    Matsuba S, Matsuno H, Sakuma M, Komatsu Y: Phellinus linteus extract augments the immune response in mitomycin C-induced immunodeficient mice. Evid Based Complement Alternat Med. 2008, 5: 85-90. 10.1093/ecam/nem001.

  143. 143.

    Refaie FM, Esmat AY, Daba AS, Taha SM: Characterization of polysaccharopeptides from Pleurotus ostreatus mycelium: assessment of toxicity and immunomodulation in vivo. Micologia Aplicada International. 2009, 21: 67-75.

  144. 144.

    Babicek K, Cechova I, Simon RR, Harwood M, Cox DJ: Toxicological assessment of a particulate yeast (1,3/1,6)-beta-D-glucan in rats. Food Chem Toxicol. 2007, 45: 1719-1730. 10.1016/j.fct.2007.03.013.

  145. 145.

    Lehne G, Haneberg B, Gaustad P, Johansen PW, Preus H, Abrahamsen TG: Oral administration of a new soluble branched beta-1,3-D-glucan is well tolerated and can lead to increased salivary concentrations of immunoglobulin A in healthy volunteers. Clin Exp Immunol. 2006, 143: 65-69. 10.1111/j.1365-2249.2005.02962.x.

  146. 146.

    Ng TB: A review of research on the protein-bound polysaccharide (polysaccharopeptide, PSP) from the mushroom Coriolus versicolor (Basidiomycetes: Polyporaceae). Gen Pharmacol. 1998, 30: 1-4.

  147. 147.

    Tsukagoshi S, Hashimoto Y, Fujii G, Kobayashi H, Nomoto K, Orita K: Krestin (PSK). Cancer Treat Rev. 1984, 11: 131-155. 10.1016/0305-7372(84)90005-7.

  148. 148.

    Lee JB, Hayashi K, Hashimoto M, Nakano T, Hayashi T: Novel antiviral fucoidan from sporophyll of Undaria pinnatifida (Mekabu). Chem Pharm Bull (Tokyo). 2004, 52: 1091-1094. 10.1248/cpb.52.1091.

  149. 149.

    Katsube T, Yamasaki Y, Iwamoto M, Oka S: Hyaluronidase-inhibiting polysaccharide isolated and purified from hot water extract of sporophyll of Undaria pinnatifida. Food Sci Technol. 2003, 9: 25-29. 10.3136/fstr.9.25.

  150. 150.

    Koo JG, Jo KS, Do JR, Woo SJ: Isolation and purification of fucoidans from Laminara religiosa and Undaria pinnatifida in korea. J Korean Fish Soc. 1995, 28: 227-236.

  151. 151.

    Tamboli S, Arora S, Bhatnagar U, Vishwase G, Singh M: Reproductive and developmental toxicity evaluation of a purified Arabinogalactan-Protein (AGP) composition in Wistar rats. Fitoterapia. 2010, 81: 276-283. 10.1016/j.fitote.2009.10.001.

  152. 152.

    Kim KJ, Lee OH, Lee HH, Lee BY: A 4-week repeated oral dose toxicity study of fucoidan from the Sporophyll of Undaria pinnatifida in Sprague-Dawley rats. Toxicology. 2010, 267: 154-158. 10.1016/j.tox.2009.11.007.

  153. 153.

    Track NS, Cawkwell ME, Chin BC, Chiu SS, Haberer SA, Honey CR: Guar gum consumption in adolescent and adult rats: short- and long-term metabolic effects. Can J Physiol Pharmacol. 1985, 63: 1113-1121.

  154. 154.

    Simons LA, Gayst S, Balasubramaniam S, Ruys J: Long-term treatment of hypercholesterolaemia with a new palatable formulation of guar gum. Atherosclerosis. 1982, 45: 101-108. 10.1016/0021-9150(82)90175-7.

  155. 155.

    McIvor ME, Cummings CC, Van Duyn MA, Leo TA, Margolis S, Behall KM, et al: Long-term effects of guar gum on blood lipids. Atherosclerosis. 1986, 60: 7-13. 10.1016/0021-9150(86)90081-X.

  156. 156.

    Koujitani T, Oishi H, Kubo Y, Maeda T, Sekiya K, Yasuba M, et al: Absence of detectable toxicity in rats fed partially hydrolyzed guarm gum (K-13) for 13 weeks. Int J Toxicol. 1997, 16: 611-623. 10.1080/109158197226928.

  157. 157.

    Takahashi H, Yang S, Fujiki M, Kim M, Yamamoto T, Greenberg N: Toxocity studies of partially hydrolyzed guar gum. J Am Coll Toxicol. 1994, 13: 273-278.

  158. 158.

    Kuroiwa Y, Nishikawa A, Imazawa T, Kanki K, Kitamura Y, Umemura T, et al: Lack of subchronic toxicity of an aqueous extract of Agaricus blazei Murrill in F344 rats. Food Chem Toxicol. 2005, 43: 1047-1053. 10.1016/j.fct.2005.02.007.

  159. 159.

    The safety of extended consumption of freezing dryness Agaricus blazei (lwade strain 101) himematsutake. Yakuri to Chiryo. 2006, 34: 103-117.

  160. 160.

    Tsuneo K, Takahiko N, Takashi F, Masaaki O, Michitaka S, Ahikiro S, et al: Single dose toxicity study of powdered Grifola frondosa by oral administration in rats. Pharmacometrics. 2003, 65: 39-41.

  161. 161.

    Han YS, Park SY, Choi BK, Choung SY: Acute oral toxicity studies of extract of sanghwang mushroom (Phellinus linteus). J Appl Pharmacol. 2001, 9: 46-50.

  162. 162.

    Cheng K-F, Leung P-C: General review of polysaccharopeptides (PSP) from C. versicolor: pharmacological and clinical studies. Cancer Therapy. 2008, 6: 117-130.

  163. 163.

    Sinnott RA, Ramberg J, Kirchner JM, Oubre C, Duncan C, Boyd S, et al: Utilization of arabinogalactan, aloe vera gel polysaccharides, and a mixed saccharide dietary supplement by human colonic bacteria in vitro. Int J Probiotics Prebiotics. 2007, 2: 97-104.

  164. 164.

    Salyers AA, Arthur R, Kuritza A: Digestion of larch arabinogalactan by a strain of human colonic Bacteroides growing in continuous culture. J Agric Food Chem. 1981, 29: 475-480. 10.1021/jf00105a009.

  165. 165.

    Salyers AA, Vercellotti JR, West SE, Wilkins TD: Fermentation of mucin and plant polysaccharides by strains of Bacteroides from the human colon. Appl Environ Microbiol. 1977, 33: 319-322.

  166. 166.

    Salyers AA: Breakdown of polysaccharides by human intestinal bacteria. J Environ Pathol Toxicol Oncol. 1985, 5: 211-231.

  167. 167.

    Crociani F, Alessandrini A, Mucci MM, Biavati B: Degradation of complex carbohydrates by Bifidobacterium spp. Int J Food Microbiol. 1994, 24: 199-210. 10.1016/0168-1605(94)90119-8.

  168. 168.

    Degnan BA, Macfarlane GT: Arabinogalactan utilization in continuous cultures of Bifidobacterium longum: Effect of co-culture with Bacteroides thetaiotaomicron. Anaerobe. 1995, 1: 103-112. 10.1006/anae.1995.1005.

  169. 169.

    Imamura L, Murai K, Zhao C-J, Takebe S, Kobashi K: Metabolism of arabinogalactan by rat and human intestinal microflora. BIFIDUS Flores, Fructus et Semina. 1992, 6: 19-29.

  170. 170.

    Michel C, Lahaye M, Bonnet C, Mabeau S, Barry JL: In vitro fermentation by human faecal bacteria of total and purified dietary fibres from brown seaweeds. Br J Nutr. 1996, 75: 263-280. 10.1079/BJN19960129.

  171. 171.

    Okubo T, Ishihara N, Takahashi H, Fujisawa T, Kim M, Yamamoto T, et al: Effects of partially hydrolyzed guar gum intake on human intestinal microflora and its metabolism. Biosci Biotech Biochem. 1994, 58: 1364-1369. 10.1271/bbb.58.1364.

  172. 172.

    Deville C, Gharbi M, Dandrifosse G, Peulen O: Study on the effects of laminarin, a polysaccharide from seaweed, on gut characteristics. J Sci Food Agric. 2007, 87: 1717-1725. 10.1002/jsfa.2901.

  173. 173.

    Ikuzawa M, Matsunaga K, Nishiyama S, Nakajima S, Kobayashi Y, Andoh T, et al: Fate and distribution of an antitumor protein-bound polysaccharide PSK (Krestin). Int J Immunopharmacol. 1988, 10: 415-423. 10.1016/0192-0561(88)90128-2.

  174. 174.

    Yagi A, Hamano S, Tanaka T, Kaneo Y, Fujioka T, Mihashi K: Biodisposition of FITC-labeled aloemannan in mice. Planta Med. 2001, 67: 297-300. 10.1055/s-2001-14314.

  175. 175.

    Marzorati M, Verhelst A, Luta G, Sinnott R, Verstraete W, Van de Wiele T, et al: In vitro modulation of the human gastrointestinal microbial community by plant-derived polysaccharide-rich dietary supplements. Int J Food Microbiol. 2010, 139: 168-176. 10.1016/j.ijfoodmicro.2010.02.030.

  176. 176.

    Salyers AA, West SE, Vercellotti JR, Wilkins TD: Fermentation of mucins and plant polysaccharides by anaerobic bacteria from the human colon. Appl Environ Microbiol. 1977, 34: 529-533.

Download references

Acknowledgements

The authors would like to thank Barbara K. Kinsey, Ward Moore and Mrs. Jennifer Aponte for their assistance with the preparation of this manuscript, and Dr. Azita Alavi and Mrs. Christy Duncan for their editorial assistance.

Author information

Correspondence to Jane E Ramberg.

Additional information

Competing interests

The authors are employees of the Research & Development Department at Mannatech, Incorporated, which sells two of the polysaccharide products (Ambrotose® powder and Advanced Ambrotose® powder) discussed in this review.

Authors' contributions

JER and EDN conducted literature searches and wrote the manuscript. RAS provided technical guidance. All authors read and approved the final manuscript.

Authors’ original submitted files for images

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Keywords

  • Polysaccharide
  • Pectin
  • Glucan
  • Aqueous Extract
  • Seasonal Allergic Rhinitis