Immunomodulatory dietary polysaccharides: a systematic review of the literature

  • Jane E Ramberg1Email author,

    Affiliated with

    • Erika D Nelson1 and

      Affiliated with

      • Robert A Sinnott1

        Affiliated with

        Nutrition Journal20109:54

        DOI: 10.1186/1475-2891-9-54

        Received: 6 May 2010

        Accepted: 18 November 2010

        Published: 18 November 2010

        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. 1.

          Rodent or human studies

           
        2. 2.

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

           
        3. 3.

          Studies reporting statistically significant immunomodulatory effects

           
        4. 4.

          English language

           
        5. 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

        Source

        Extract

        Animal

        Dose/day

        Duration of study

        Treatment

        Effects

        Reference

        Agaricus

        (A. blazei) subrufescens

        α-1,6 and

        α-1,4 glucans

        8-week ♀ C3H/He mice (5/group)

        100 mg/kg IG every 3 days

        1 month

        Healthy animals

        ↑ #s splenic T lymphocytes (Thy1.2, CD4+ and CD8+)

        [24]

         

        Aqueous

        7-9-week ♂ Balb/cByJ mice (40/group)

        1 ml 0.45N, 0.6N, or 3N aqueous extract

        2 months

         

        All doses ↑ serum IgG levels, CD3+ T cell populations and PML phagocytic activity

        [22]

          

        7-9-week male Balb/cByJ mice (40/group)

        1 ml 0.45N, 0.6N, or 3N aqueous extract

        10 weeks

        IP injection of OVA at 4 weeks

        0.6N and 3N ↑ levels of OVA-specific serum IgG 28 days post-immunization; all doses ↑ delayed-type hypersensitivity and TNF-α secreted from splenocytes at 10 weeks; 0.6N ↑ splenocyte proliferation at 10 weeks

         
          

        5-6 -week ♀ BALB/cHsdOla mice (8/group × 2)

        One 200 μl extract day 1, orogastric intubation

        1 week

        Injected IP fecal solution day 2

        ↓ CFU in blood of mice with severe peritonitis & improved overall survival rate in all peritonitis groups

        [46]

          

        6-week BALB/c nu/nu mice (7/group)

        2.5 mg extract days 20-41, drinking water

        41 days

        Injected SC Sp-2 myeloma cells day 1

        ↓ tumor size & weight after 21 days treatment

        [65]

         

        Aqueous, acid treated

        6-week ♀ C57BL/6 mice (10/group)

        20, 100 or 500 μg/ml, drinking water

        9 days

        Injected IP human ovarian cancer cells day 1

        500 μg/ml ↓ tumor weight

        [66]

           

        20, 100 or 500 μg/ml, drinking water

        3 weeks

        Injected IV murine lung cancer (3LL) cells

        100 & 500 μg/ml ↓ #s metastatic tumors

         
         

        Aqueous, with 200 ng/day

        β-glucan

        6-week ♀ BALB/c mice (10/group)

        200 ng days 5-21

        3 weeks

        Injected Meth A tumor cells day 1

        ↓ tumor size & weight

        [23]

            

        2 weeks

        Injected Meth A tumor cells

        ↑ cytotoxic T lymphocyte activity & spleen cell IFN-α protein

         
           

        300 mg

        5 days

        Healthy animals

        ↑ splenic NK cell activity

         

        Avena spp.

        β-glucans (particulate)

        6-7 -week ♀ C57BL/6 mice (7/group)

        3 mg every 48 h, days 1-3

        1 month

        Oral E. vermiformis oocytes day 10

        E. vermiformis fecal oocyte #s; increased intestinal anti-merozoite IgA; ↓ # of IL-4-secreting MLN cells

        [42]

           

        3 mg on alternating days, days 1-10

        22 days

        Injected IP Eimeria vermiformis day 10

        E. vermiformis fecal oocyte #s; ↑ anti-merozoite intestinal IgA

        [43]

         

        β-glucans (soluble)

        4-week ♂ CD-1 mice (24/group)

        0.6 mg/ml 68% β-glucan, drinking water

        1 month

        Resting or exercise-stressed (days 8-10) animals administered HSV-1 IN

        day 10

        ↓ morbidity in resting and exercise-stressed animals; ↓ mortality in exercise-stressed animals; pre-infection, ↑ Mø anti-viral resistance in resting and exercise-stressed animals

        [38]

           

        ~3.5 mg days

        1-10, drinking water

         

        Resting or exercise-stressed (days 5-10) animals administered HSV-1 IN

        day 10

        Pre-infection, ↑ Mø antiviral resistance in resting animals

        [41]

          

        4-week ♂ CD-1 mice (10/group)

        0.6 mg/ml 68% β-glucan, drinking water

        10 days

        Resting animals or animals exposed to a bout of fatiguing exercise days 8-10 or moderate exercise days 5-10, injected IP with thioglycollate on day 10

        ↑ neutrophil mobilization in resting & moderately exercised animals; ↑ neutrophil respiratory burst activity in resting and fatiguing exercised animals

        [37]

          

        4-week ♂ CD-1 mice (19-30/group)

        0.8 mg/ml 50% β-glucan, days

        1-10, drinking water

        1 month

        Resting or exercise-stressed (days 8-10) animals administered IN clodronate-filled liposomes to deplete Mø days 8 & 14 & infected IN with HSV-1 day 10

        ↓ morbidity, mortality, symptom severity in exercise-stressed animals, without Mø depletion

        [40]

          

        4-week ♂ CD-1 mice (20/group)

          

        Resting or exercise-stressed (days 8-10) animals administered HSV-1 IN day 10

        ↓ morbidity in exercise-stressed & resting animals; ↓ mortality in exercise-stressed animals

        [39]

        Ganoderma lucidum

        Aqueous

        7-week ♂ CD-1 mice (26/group)

        5% of diet

        5 months

        Injected IM DMH once a week, weeks 1-10

        ↓ aberrant crypt foci per colon, tumor size, cell proliferation, nuclear staining of β-catenin

        [69]

          

        4-8-week BALB/c mice (10/group)

        50, 100 or 200 mg/kg, oral

        10 days

        Injected SD Sarcoma 180 cells

        ↓ of tumor weight was dose dependent: 27.7, 55.8, 66.7%, respectively

        [67]

        Ganoderma lucidum (mycelia)

        Aqueous

        7-week ♂ F344/Du Crj rats (16/group)

        1.25% or 2.5% of diet

        6 months

        Injected SC AOM once a week, weeks2-5

        Both doses ↓ colonic adenocarcinoma incidence; 2.5% ↓ total tumor incidence; both doses ↓ nuclear staining of β-catenin and cell proliferation

        [68]

        Ganoderma tsugae

        Aqueous

        8-week ♀ BALB/cByJNarl mice (14/group)

        0.2-0.4% of diet (young fungi); 0.33 or 0.66% of diet (mature fungi)

        5 weeks

        Injected IP OVA days 7, 14, 21; aerosolized OVA twice during week 4

        In splenocytes, both doses of both extracts ↑ IL-2 and IL-2/IL-4 ratios, 0.2% young extract and 0.66% mature extract ↓ IL-4; in Mø, 0.66% mature extract ↑ IL-1β, both doses of both extracts ↑ IL-6

        [53]

        Grifola frondosa

        D fraction

        Mice: 1) ICR, 2) C3H/HeN, 3) CDF1 (10/group)

        1.5 mg every other day, beginning day 2

        13 days

        Implanted SC: 1) Sarcoma-180, 2) MM-46 carcinoma, or 3) IMC carcinoma cells

        ↓ tumor weight & tumor growth rate: 1) 58%, 2) 64%, and 3) 75%, respectively

        [71]

          

        5-week ♂ BALB/c mice (10/group)

        2 mg,

        days 15-30

        45 days

        Injected in the back with 3-MCA, day 1

        ↓ (62.5%) # of animals with tumors; ↑ H202 production by plasma Mø; ↑ cytotoxic T cell activity

        [72]

        Hordeum vulgare

        β-1,3;1,4 or β-1,3;1,6-D-glucans

        Athymic nu/nu mice

        (4-12/group)

        40 or 400 μg IG for 4 weeks

        31 weeks

        Mice with human xenografts (SKMel28 melanoma, A431 epidermoid carcinoma, BT474 breast carcinoma, Daudi lymphoma, or LAN-1 neuroblastoma) ± mAb (R24, 528, Herceptin, Rituximab, or 3F8, respectively) therapy twice weekly

        400 μg + mAb ↓ tumor growth & ↑ survival; higher MW ↓ tumor growth rate for both doses

        [75]

         

        β-1,3;1,4-D-glucans

        Athymic BALB/c mice

        4, 40, or 400 μg for 3-4 weeks

        1 month

        Mice with neuroblastoma (NMB7, LAN-1, or SK-N-ER) xenografts, ± 3F8 mAb therapy twice weekly

        40 and 400 μg doses + mAB ↓ tumor growth; 400 μg dose ↑ survival. Serum NK cells required for effects on tumor size

        [76]

          

        C57BL/6 WT and CR3-deficient mice (10/group)

        0.4 mg for 3 weeks

        100 days

        Injected SC RMA-S-MUC1 lymphoma cells day 1 ± IV 14.G2a or anti-MUC1 mAb every 3rd day

        ±mAB ↓ tumor diameter; ↑ survival

        [73]

         

        β-glucans

        ♀ Fox Chase ICR immune-deficient (SCID) mice (9/group)

        400 μg days 1-29

        50 days

        Mice with human (Daudi, EBV-BLCL, Hs445, or RPMI6666) lymphoma xenografts, ± Rituximab mAb therapy twice weekly

        +mAB ↓ tumor growth and ↑ survival

        [74]

        Laminaria digitata

        Laminarin

        ♂ ICR/HSD mice (3/group)

        1 mg

        1 day

        Healthy animals

        ↑ Mø expression of Dectin-1 in GALT cells; ↑ TLR2 expression in Peyer's patch dendritic cells

        [29]

          

        ♂ Wistar rats (7/group)

        5% of diet days 1-4, 10% of diet days 5-25

        26 days

        Injected IP E. coli LPS day 25

        ↓ liver ALT, AST, and LDH enzyme levels; ↑ ED2-positive cells, .↓ peroxidase-positive cells in liver; ↓ serum monocytes, TNF-α, PGE2, NO2

        [44]

        Lentinula edodes

        SME

        6-week nude mice

        0.1 ml water with10% SME/10 g body weight days 1-19, 33-50

        50 days

        Injected SC prostate cancer (PC-3) cells day 1

        ↓ tumor size

        [80]

         

        β-glucans

        ♀ 3- and 8-week BALB/c mice (15/group)

        50, 100 or 250 μg

        1-2 weeks

        Healthy animals

        250 μg dose ↑ spleen cell IL-2 secretion

        [27]

          

        ♀ 3- and 8-week BALB/c mice (15/group)

        50, 100 or 250 μg

        1-2 weeks

        Injected murine mammary carcinoma (Ptas64) cells into mammary fat pads 2 weeks before treatment

        ↓ tumor weight

         
         

        Lentinan

        6-week ♂ Wistar-Imamichi specific-pathogen free rats (10/group)

        1 mg twice weekly

        1-2 months

        Healthy animals

        ↑ T cell #s, helper-cell #s & helper/suppressor ratio, ↓ suppressor cell level at 4, but not 8 weeks

        [26]

          

        5-6-week ♂

        pre-leukemic AKR mice (10/group)

        3 mg, days 1-7

        3 weeks

        Injected SC K36 murine lymphoma cells day 7

        ↓ tumor weight; ↑ tumor inhibition rate (94%)

        [82]

          

        5-6-week athymic mice (10/group)

         

        5 weeks

        Injected SC colon cancer (LoVo and SW48, SW480 and SW620, or SW403 and SW1116) cells day 7

        ↓ tumor weight, ↑ tumor inhibition rate (>90%)

         
          

        ♂ AKR mice

        3 mg

        1 day

        Pre-leukemic mice

        ↑ serum IFN-α and TNF-α, peak at 4 h and then back to normal at 24 h; ↑ IL-2 and IL-1α, peak at 2 h and back to normal at 24 h; ↑ CD3+ T, CD4+ T, CD8+ T, B lymphocytes

        [81]

        Phellinus linteus

        Aqueous, alcohol-precipitated

        6-7-week C57BL/6 mice (10-50/group)

        200 mg/kg in drinking water

        1 month

        Healthy animals

        ↑ production and secretion of IFN-γ by con A stimulated T cells

        [32]

        Saccharomyces cerevisiae

        Scleroglucan

        ♂ ICR/HSD mice (3/group)

        1 mg one day before challenge (day 1)

        6 days

        IV Staphylococcus aureus or Candida albicans day 2

        ↑ long-term survival

        [29]

         

        β-1,3;1,6 glucans (particulate)

        3 and 8-week ♀ BALB/c mice (15/group)

        50, 100 or 250 μg

        1-2 weeks

        Injected murine mammary carcinoma (Ptas64) cells into mammary fat pads 2 weeks before treatment

        ↓ tumor weight

        [27]

         

        β-1,3-glucan

           

        Healthy animals

        All 3 doses ↑ phagocytic activity of blood monocytes & neutrophils & ↑ spleen cell IL-2 secretion

         
          

        WT or CCD11b-/- C57BL/6 mice (2/group)

        0.4 mg for 3 weeks

        100 days

        Injected SC RMA-S-MUC1 lymphoma cells ± 14.G2a or anti-MUC1 mAb IV injection every 3rd day

        ↓ tumor diameter when included with mAb; ↑ survival with and without mAb

        [73]

          

        C57BL/6mice (4/group)

        25 mg

        1 week

        Healthy animals

        ↑ # intestinal IELs; ↑ # TCRαβ+, TCR γδ+, CD8+, CD4+, CD8αα+, CD8αβ+ T cells in IELs; ↑ IFN-γ mRNA expression in IELs and spleen

        [28]

        Sclerotinia sclerotiorum

        SSG

        6-8-week specific pathogen-free ♂ CDF1 mice (3/group)

        40 or 80 mg/kg days 1-10

        2 weeks

        Healthy animals

        10 mg dose ↑ acid phosphatase activity of peritoneal Mø (day 14)

        [30]

           

        40, 80 or 160 mg/kg days 2-6

        35 days

        Implanted SC Metha A fibrosarcoma cells day 1

        80 mg dose ↓ tumor weight

         
          

        6-8-week specific pathogen-free ♂ CDF1 mice (10/group)

        40, 80 or 160 mg/kg days 2-11

         

        Injected ID IMC carcinoma cells day 1

          
          

        6-8-week specific-pathogen free ♂ mice of BDF1 and C57BL/6 mice (7/group)

        0.5, 1, 2, or 4 mg days 1-10

        2-3 weeks

        Injected IV Lewis lung carcinoma (3LL) cells

        2 mg ↓ # of 3LL surface lung nodules at 2 weeks

        [83]

        Sclerotium rofsii

        Glucan phosphate

        ♂ ICR/HSD mice (3/group)

        1 mg

        1 day

        Healthy animals

        ↑ systemic IL-6; ↑ Mø expression of Dectin-1 in GALT cells; ↑ TLR2 expression in dendritic cells from Peyer's patches

        [29]

        Trametes (Coriolus) versicolor

        PSP

        6-8-week ♂ BALB/c mice (10/group)

        35 μg days 5-29 in drinking water

        29 days

        Implanted SC Sarcoma-180 cells day 1

        ↓ tumor growth & vascular density

        [94]

        Table 2

        Immunomodulatory Non-Glucan Extracts: Oral Animal Studies

        Extract

        Source

        Animal

        Oral dose/day

        Duration

        Treatment

        Significant effects

        Reference

        Fucoidans

        Cladosiphon okamuranus Tokida

        8-week ♀ BALB/c mice, 10/group

        0.05% w/w of diet

        56 days

        DSS-induced UC

        ↓ disease activity index and myeloperoxidase activity; ↓ # of B220-positive colonic B cells; ↓ colonic MLN IFN-γ and IL-6 and ↑ IL-10 and TGF-β; ↓ colonic IgG; ↓ colonic epithelial cell IL-6, TNF-α, and TLR4 mRNA expression

        [49]

         

        Undaria pinnatifida

        5-week ♀ BALB/c mice (10-12/group)

        5 mg, days 1-14 or 7-14

        2 weeks

        Injected HSV into cornea day 7

        ↓ facial herpetic lesions; ↑ survival, particularly in pre-treated animals

        [45]

           

        10 mg

        1 week

        Administered

        5-fluorouracil

        ↑ plasma NK cell activity

         
             

        Injected SC HSV

        ↑ cytotoxic splenic T lymphocyte activity

         
           

        0.1 or 0.5 mg

        3 weeks

        Injected IP HSV

        Both doses ↑ serum neutralizing Ab titers, weeks 2 and 3

         
          

        6-week ♂ ddY mice (5/group)

        50, 100, 200 400 or

        500 mg/kg

        days 1-28

        3 weeks

        Injected with Ehrlich carcinoma in back day 14

        200-500 mg/kg ↓ tumor growth

        [116]

          

        6-week ♂ BALB/c mice (8/group)

        40 mg/kg alternating days

        7-19

        19 days

        Injected IP Meth A fibrosarcoma day 1

        ↓ tumor growth

         

        Furanose (COLD-FX®)

        Panax quinquefolium

        Weanling ♂ SD rats (10/group)

        450 or

        900 mg/kg in food

        1 week

        Healthy animals

        Both doses ↑ spleen Il-2 and IFN-γ production following ConA or LPS stimulation; ↓ proportion of total MLN and Peyer's patch CD3+ cells & activated T cells; high dose ↑ spleen cell IL-1β production following 48 h ConA stimulation.

        [33]

        Galacto-mannan (partially hydrolyzed guar gum)

        Cyamopsis tetragonolobus

        10-week ♀ BALB/c mice,

        11-15/group

        5% of diet

        3 weeks

        DSS-induced UC at beginning of

        week 3

        ↓ disease activity index scores, ↓ colonic mucosal myeloperoxidase activity & lipid peroxidation; ↓ colonic TNF-α protein levels & mRNA expression up regulated by DSS exposure

        [50]

        Galacto-mannans

        (guar gum)

         

        8-month- SD rats, 5/group

        5% of diet

        3 weeks

        Older animals

        ↓ serum IgG; ↑ MLN lymphocyte IgA, IgM and IgG production

        [36]

        Glucomannan (KS-2)

        Lentinula edodes

        DD1 mice (10-20/group)

        140 mg/kg days

        2-13

        50 days

        Injected IP Ehrlich ascites tumor cells day 1

        ↑ survival

        [84]

           

        0.1, 1, 10, or 100 mg/kg dose days 2-13

        100 days

        Injected Sarcoma-180 tumor cells

        day 1

        1, 10, and 100 mg/kg doses ↑ survival

         

        Heteroglycan (ATOM)

        A. subrufescens

        Mice (10/group): 1) 5-week ♂ Swiss/NIH; 6 week- ♀ DS mice; 3) 8-week ♀ BALB/c nude; 4) 5-week C3H/HcN

        100 or

        300 mg/kg

        days 2-11

        8 weeks

        Implanted SC 1) Sarcoma-180, 2) Shionogi carcinoma 42, 3) Meth A fibrosarcoma, or 4) Ehrlich ascites carcinoma cells

        Both doses ↓ Sarcoma-180 tumor size at 4 weeks & ↑ survival; 300 mg/kg ↑ peritoneal macrophage and C3-positive cells; 300 mg/kg ↓ Shionogi and Meth A tumor sizes at 4 weeks. Both doses ↑ survival of Ehrlich ascites mice

        [93]

        Heteroglycan (LBP3p)

        Lycium barbarum

        ♂ Kunming mice (10/group)

        5, 10 or

        20 mg/kg

        10 days

        Injected SC Sarcoma-180 cells

        5 & 10 mg/kg ↑ thymus index; all doses ↓ weight, ↓ lipid peroxidation in serum, liver and spleen & ↑ spleen lymphocyte proliferation, cytotoxic T cell activity, IL-2 mRNA

        [91]

        Heteroglycan (PNPS-1)

        Pholiota nameko

        SD rats (5/group)

        100, 200 or 400 mg/kg days 1-8

        8 days

        Implanted SC cotton pellets in scapular region

        day 1

        ↓ granuloma growth positively correlated with dose: 11%, 18% and 44%, respectively

        [55]

        Heteroglycan (PG101)

        Lentinus lepideus

        8-10-week ♀ BALB/c mice (3/group)

        10 mg

        24 days

        6 Gy gamma irradiation

        ↑ colony forming cells, granulocyte CFUs/Mø, erythroid burst-forming units, and myeloid progenitor cells in bone marrow; induced proliferation of granulocyte progenitor cells in bone marrow; ↑ serum levels of GM-CSF, IL-6, IL-1β

        [92]

        Mixed poly-saccharides (Ambrotose® or Advanced Ambrotose® powders)

        Aloe barbadensis, Larix spp, and other plant poly-saccharides

        ♂ SD rats (10/group)

        37.7 or 377 mg/kg Ambrotose® powder or 57.4 or 574 mg/kg Advanced Ambrotose® powder

        2 weeks

        5% DSS in drinking water beginning day 6

        574 mg/kg Advanced Ambrotose powder ↓ DAI scores; 377 mg/kg Ambrotose complex & both doses Advanced Ambrotose powder ↑ colon length and ↓ blood monocyte count

        [52]

        Pectin

        Pyrus pyrifolia

        6-8-week ♂ BALB/c mice (11/group)

        100 μg

        days 1-7

        22 days

        Injected IP OVA day 7, provoked with OVA aerosol day 21

        bronchial fluid:↓ IFN-γ & ↑ IL-5; splenic cells: ↑ IFN-γ, ↓ IL-5; normalized pulmonary histopathological changes; ↓ serum IgE

        [54]

        Pectins (bupleurum 2IIc)

        Bupleurum falcatum

        6-8-week ♀ specific-pathogen-free C3H/HeJ mice

        250 mg/kg

        1 week

        Healthy animals

        ↑ spleen cell proliferation

        [35]

        Pectins (highly methoxylated)

        Malus spp.

        8-month- SD rats (5/group)

        5% of diet vs. cellulose control

        3 weeks

        Older animals

        ↑ MLN lymphocyte IgA & IgG

        [36]

        Pectins

        Citrus spp.

        5-week ♀ F344 rats (30/group)

        15% of diet

        34 weeks

        Injected SC AOM once a week, weeks 4-14

        ↓ colon tumor incidence

        [86]

         

        Malus spp.

        5-week ♀ BALB/c mice (6/group)

        5% of diet

        2 weeks

        Healthy animals

        ↑ fecal IgA and MLN CD4+/CD8+ T lymphocyte ratio & IL-2 & IFN-γ secretion by ConA-stimulated MLN lymphocytes

        [51]

          

        5-week ♀ BALB/c mice (6/group)

        5% of diet days 5-19 vs. cellulose control

        19 days

        DSS-induced UC days 1-5

        Significantly increased MLN lymphocytes IgA, and significantly decreased IgE; significantly decreased ConA-stimulated IL-4 and IL-10

         
          

        4-week ♂ Donryu rats (20-21/group)

        20% of diet

        32 weeks

        Injected SC AOM once a week,

        weeks 2-12

        ↓ colon tumor incidence

        [85]

          

        4-week ♂ Donryu rats (19-20/group)

        10 or 20% of diet

        32 weeks

        Injected SC AOM once a week,

        weeks 2-12

        Both doses ↓ colon tumor incidence; 20% ↓ tumor occupied area & ↓ portal blood and distal colon PGE2

        [90]

        Pectins (modified)

        Citrus spp.

        2-4-month BALB/c mice (9-10/group)

        0.8 or 1.6 mg/ml drinking water,

        days 8-20

        20 days

        Injected SC with 2 × 2 mm section of human colon-25 tumor on day 1

        Both doses ↓ tumor size

        [87]

          

        NCR nu/nu mice (10/group)

        1% (w/v) drinking water

        16 weeks

        Orthotopically injected human breast carcinoma cells (MDA-MB-435) into mammary fat pad on day 7

        ↓ tumor growth rate & volume at 7 weeks, lung metastases at 15 weeks, # of blood vessels/tumor at 33 days post-injection

        [89]

          

        NCR nu/nu mice (10/group)

        1% (w/v) drinking water

        7 weeks

        Injected human colon carcinoma cells (LSLiL6) into cecum on day 7

        ↓ tumor weights and metastases to the lymph nodes and liver

         
          

        SD rats (7-8/group)

        0.01%, 0.1% or 1.0% wt/vol of drinking water, days 4-30

        1 month

        Injected SC MAT-LyLu rat prostate cancer cells

        0.1% and 1.0% ↓ lung metastases; 1.0% ↓ lymph node disease incidence

        [88]

        Table 3

        Immunomodulatory Polysaccharide-Rich Plant Powders: Oral Animal Studies

        Source

        Animal

        Oral dose/day

        Duration

        Treatment

        Significant effects

        Reference

        Agaricus (A. blazei) subrufescens (fruit bodies)

        6-week ♂ C57BL/6, C3H/HeJ and BALB/c mice (3/group)

        16, 32 or 64 mg

        2 weeks

        Healthy animals

        32 and 64 mg ↑ liver mononuclear cell cytotoxicity

        [25]

        Grifola frondosa

        6-week ♀ ICR mice (10-15/group)

        5% of diet

        36 weeks

        Oral N-butyl-N'-butanolnitrosamine daily for first 8 weeks

        ↓ #s of animals with bladder tumors; ↓ tumor weight; ↑ peritoneal Mø chemotactic activity, splenic lymphocyte blastogenic response & cytotoxic activity

        [70]

        Laminaria angustata

        Weanling SD rats (58/group)

        5% of diet

        26 weeks

        IG DMBA, beginning of week 5

        ↑ time to tumor development and ↓ # of adenocarcinomas in adenocarcinoma-bearing animals

        [77]

        Lentinula (Lentinus) edodes

        6-week ♀ ICR mice (10-17/group)

        5% of diet

        36 weeks

        Oral BBN daily for first 8 weeks

        ↓ # of animals with bladder tumors; ↓ tumor weight; ↑ Mø chemotactic activity, splenic lymphocyte blastogenic response, cytotoxic activity

        [70]

         

        7-8 -week ♂ Swiss mice (10/group)

        1%, 5% or 10% of diet of 4 different lineages days 1-15

        16 days

        Injected IP N-ethyl-N-nitrosourea day 15

        All 3 doses of one lineage and the 5% dose of two other lineages ↓ #s of micronucleated bone marrow polychromatic erythrocytes

        [79]

        Lentinula edodes (fruit bodies)

        5-week ♀ ICR mice

        (14/group × 2)

        10%, 20% or 30% of diet

        25 days

        Injected IP Sarcoma-180 ascites

        All 3 doses ↓ Sarcoma-180 tumor weight

        [78]

         

        Mice: 1) CDF1; 2) C3H; 3) BALB/c; 4,5) C57BL/6N (9/group × 3)

        20% of diet

        25 days

        Injected SC 1) IMC carcinoma, 2) MM-46 carcinoma, 3) Meth-A fibrosarcoma, 4) B-16 melanoma, or 5) Lewis lung carcinoma cells

        ↓ growth of MM-46, B-16, Lewis lung, and IMC tumors; ↑ lifespan in Lewis lung and MM-46 animals

         
         

        ICR mice (14/group × 2)

        20% of diet days 1-7, days 7-31 or days 14-31

        31 days

        Injected IP Sarcoma-180 ascites

        ↓ tumor weight & growth when fed days 7-31 or 14-31

         
         

        Mice: 1) CDF1; 2) C3 H (5/group × 4)

        20% of diet

        7-12 days

        Injected SC: 1) IMC carcinoma or 2) MM-46 carcinoma cells

        ↑ spreading rate of activated Mø ↑ phagocytic activity

         

        Phellinus linteus

        4-week ♂ ICR mice (10/group)

        2 mg

        1 month

        Healthy animals

        ↓ serum & splenocyte IgE production; ↑ proportion of splenic CD4+ T cells & splenocyte IFN-γ production

        [31]

        Pleurotus ostreatus

        6-week ♀ ICR mice

        (10-20/group)

        5% of diet

        36 weeks

        Oral BBN daily for first 8 weeks

        ↓ #s of animals with bladder tumors; ↓ tumor weight; ↑ plasma Mø chemotactic activity, splenic lymphocyte blastogenic response, cytotoxic activity

        [70]

        Table 4

        Immunomodulatory Polysaccharide Products: Oral Human Studies

        Extract

        Source

        Study design

        Population

        N (experimental/control)

        Dose/day

        Dura-tion

        Significant effects

        Reference

        Arabino-galactans

        Larix occidentalis

        Randomized, double-blind, placebo-controlled

        Healthy adults

        8/15

        4 g

        6 weeks

        ↑ % CD8+ lymphocytes & blood lymphocyte proliferation

        [18]

        Arabino-galactans (ResistAid™)

          

        Healthy adults given pneumococcal vaccinations day 30

        21/24

        4.5 g

        72 days

        ↑ plasma IgG subtypes

        [19]

        Fucoidans

        Undaria pinnatifida sporophylls

        Randomized, single-blind, placebo-controlled

        Healthy adults

        25 (75% fucoidan, 6 (10% fucoidan)/6

        3 g

        12 days

        75% fucoidan: ↓ #s blood leukocytes, lymphocytes' ↑ plasma stromal derived factor-1, IFN-γ, CD34+ cells; ↑ % CXCR4-expressing CD34+ cells

        [21]

        Furanose extract (Cold-FX®)

        Panax quinque-folium

        Randomized, double-blind, placebo-controlled

        Healthy older adults given influenza immunization at the end of week 4

        22/21

        400 mg

        4 months

        During weeks 9-16, ↓ incidence of acute respiratory illness, symptom duration

        [20]

        Glucans

        Agaricus subru-fescens

        Randomized, double-blind, placebo-controlled

        Cervical, ovarian or endometrial cancer patients receiving 3 chemotherapy cycles

        39/61

        5.4 g (estimated)

        6 weeks

        ↑ NK cell activity, ↓ chemotherapy side effects

        [64]

        Glucans

        (β-1,3;1,6)

        Not identified

        Placebo-controlled

        Recurrent aphthous stomatitis patients

        31/42

        20 mg

        20 days

        ↑ PBL lymphocyte proliferation,↓ Ulcer Severity Scores

        [48]

        Glucans

        (β-1,3;1-6)

        S. cerevisiae

        Randomized, double-blind, placebo-controlled

        Adults with seasonal allergic rhinitis

        12/12

        20 mg

        12 weeks

        30 minutes after nasal allergen provocation test, nasal lavage fluid: ↓ IL-4, IL-5, % eosinophils, ↑ IL-12

        [47]

        Glucans (PSK)

        Trametes versicolor

        Randomized, controlled

        Patients with curatively resected colorectal cancer receiving chemotherapy

        221/227

        200 mg

        3-5 years

        ↑ disease-free survival and overall survival

        [56]

          

        Controlled

        Post-surgical colon cancer patients receiving chemotherapy

        123/121

        3 g for 4 weeks, alternating with 10 4-week courses of chemo-therapy

        7 years

        ↑ survival from cancer deaths; no difference in disease-free or overall survival

        [57]

           

        Post-surgical colorectal cancer patients receiving chemotherapy

        137/68

        3 g daily

        2 years

        ↑survival in stage III patients; ↓ recurrence in stage II & III patients

        [58]

           

        Post-surgical gastric cancer patients receiving chemotherapy

        124/129

        3 g for 4 weeks, alternating with 10 4-week courses of chemo-therapy

        5-7 years

        ↑ 5-year disease-free survival rate, overall 5-year survival

        [59]

           

        Pre-surgical gastric or colorectal cancer patients

        16 daily; 17 every other day/13

        3 g daily or on alternate days before surgery

        <14 days or 14-36 days

        ≥14 day treatment: ↑ peripheral blood NK cell activity, PBL cytotoxicity, proportion of PBL helper cells; ↓ proportion of PBL inducer cells; <14 day treatment: ↑ PBL response to PSK and Con A, proportion of regional node lymphocyte suppressor cells

        [62]

          

        Randomized, double-blind, placebo-controlled

        Post-surgical stage III-IV colorectal cancer patients

        56/55

        3 g for 2 months, 2 g for 22 months, 1 g thereafter

        8-10 years

        ↑ remission & survival rates

        [61]

          

        Controlled

        Post-surgical stage III gastric cancer patients receiving chemotherapy

        32/21

        3 g

        1 year

        ↑ survival time

        [60]

        Glucans (PSP)

        Trametes versicolor

        Randomized, double-blind, placebo-controlled

        Conventionally-treated stage III-IV non-small cell lung cancer patients

        34/34

        3.06 g

        1 month

        ↑ blood IgG & IgM, total leukocyte and neutrophil counts, % body fat; ↓ patient withdrawal due to disease progression

        [63]

        Table 5

        Immunomodulatory Polysaccharide Products: Composition and Structure

        Source

        Category

        Features

        MW

        Monosaccharide composition

        Reference

        Agaricus subrufescens (A. blazei)

        Extract

        β-1,6-D-glucan

        10,000

        NA

        [66]

        Agaricus subrufescens (fruit body)

        Extract

        α-1,6- and α-1,4 glucans with β-1,6-glucopyranosyl backbone (629.2 mcg/mg polysaccharides, 43.5 mcg/mg protein)

        170,000

        glucose

        [24]

          

        α-1,4 glucans & β-1,6 glucans with β-1,3 side branches; α-1,6 glucans; β-1,6; 1-3 glucans, β-1,4 glucans; β-1,3 glucans; β-1,6; α-1,3 glucans; riboglucans, galactoglucomannans, β-1,2; β-1,3 glucomannans

        NA

        glucose, mannose, galactose, ribose

        [25, 117, 118]

        Agaricus subrufescens (mycelia)

        Extract (ATOM)

        β-1,6-D-glucan, protein complex, 5% protein

        100,000-1,000,000

        glucose, mannose, galactose, ribose

        [93]

        Aloe barbadensis (leaf gel)

        Whole tissue

        Dry weight: 10% polysaccharides; acemannan, aloemannan, aloeride, pectic acid, galactans, arabinans, glucomannans

        average 2,000,000

        mannose, glucose, galactose, arabinose, xylose, rhamnose

        [119, 120]

         

        Extract (aloemannan)

        neutral partially acetylated glucomannan, mainly β-1,4-mannans

        >200,000

        mannose, glucose

        [121]

         

        Extract (aloeride)

        NA

        4,000,000-7,000,000

        37% glucose, 23.9% galactose, 19.5% mannose, 10.3% arabinose

        [122]

         

        Extract (acemannan)

        β-1,4 acetylated mannan

        80,000

        mannose

        [123]

        Aloe barbadensis, (leaf gel), Larix sp. (bark), Anogeissus latifolia (bark), Astragalus gummifer (stem), Oryza sativa (seed), glucosamine

        Extracts (Ambrotose® powder)

        β-1,4 acetylated mannan, arabinogalactans, polysaccharide gums, rice starch, 5.4% protein

        57.3% ≥ 950,000; 26.4% < 950,000 and ≥80,000; 16.3% ≤ 10,000

        mannose, galactose, arabinose, glucose, galacturonic acid, rhamnose, xylose, fructose, fucose, glucosamine, galacturonic acid

        (unpublished data, Mannatech Incorporated)

        Aloe barbadensis (leaf gel), Larix sp. (bark), Undaria pinnatifida (frond), Anogeissus latifolia (bark), Astragalus gummifer (stem), Oryza sativa (seed), glucosamine

        Extracts (Advanced Ambrotose® powder)

        β-1,4 acetylated mannan, arabinogalactans, polysaccharide gums, fucoidans, rice starch, 6% protein, 1% fatty acids

        13% = 1,686,667; 46% = 960,000 30% <950,000 and ≥70,000; 11% ≤ 10,000

          

        Avena spp. (seed endosperm)

        Extract

        β-1,3;1,4 particulate (1-3 μ) glucans

        1,100,000

        glucose

        [43]

        Avena spp. (seed)

        Extract

        β-1,4,1,3 particulate glucans (linear chains of β-D-glycopyranosyl units; 70% β 1-4 linked)

        2,000,000

        NA

        [41, 124]

        Buplerum falcatum (root)

        Extract (bupleuran 2IIc)

        6 linked galactosyl chains with terminal glucuronic acid substituted to β-galactosyl chains

        NA

        galactose, glucuronic acid, rhamnose

        [35]

        Citrus spp. (fruit)

        Extract

        α-1,4-linked partially esterified D-anhydrogalacturonic acid units interrupted periodically with 1,2-rhamnose

        70,000-100,000

        galactose, galacturonic acid, arabinose, glucose, xylose, rhamnose

        [125]

        Cladosiphon okamuranus (frond)

        Extract

        α-1,3-fucopyranose sulfate

        56,000

        fucose:glucuronic acid (6.1:1.0)

        [126]

        Cordyceps sinensis (mycelia)

        Extract

        β-1,3-D-glucan with 1,6-branched chains

        NA

        NA

        [127]

        Cyamopsis tetragonolobus (seed)

        Extract (guar gum)

        Main chain of β-1,4-mannopyranosyl units with α-galactopyranosyl units

        220,000

        mannose, galactose

        [36, 128]

         

        Extract (partially-hydrolyzed guar gum)

        NA

        20,000

        mannose, galactose

        [50]

        Flammulina velutipes

        Extract

        NA

        NA

        glucose, mannose, galactose

        [117]

        Flammulina velutipes (fruit body)

        Extract

        β-1,3 glucan

        NA

        glucose

        [129]

        Ganoderma lucidum

        Whole tissue

        Linear β-1,3-glucans with varying degrees of

        D-glucopyranosyl branching, β-glucan/protein complexes, heteropolysaccharides

        400,000-1,000,000

        glucose, galactose, mannose, xylose, uronic acid

        [130]

         

        Extract

        NA

        7,000-9,000

        NA

        [67]

        Ganoderma lucidum (fruit body)

        Extract

        NA

        7,000-9,000

        NA

         
          

        β-linked heteroglycan peptide

        513,000

        fructose, galactose, glucose, rhamnose, xylose (3.167:

        0.556:6.89:0.549:3.61)

        [15]

        Ganoderma tsugae

        Extract

        55.6% carbohydrates (12.5% polysaccharides); 12% triterpenes, 1.7% sodium, 0.28% protein, 0% lipid

        NA

        NA

        [53]

        Ginkgo biloba (seed)

        Extract

        89.7% polysaccharides

        NA

        glucose, fructose, galactose, rhamnose

        [131]

        Grifola frondosa

        Whole tissue

        β-1,3; 1, 6-glucans, α-glucans, mannoxyloglucans, xyloglucans, mannogalactofucans

        NA

        glucose, fucose, xylose, mannose, galactose

        [117]

        Grifola frondosa (fruit body)

        Extract

        (D fraction)

        β-1,6-glucan with β-1,3 branches, 30% protein

        NA

        glucose

        [132]

         

        Extract

        (X fraction)

        β-1,6-D-glucan with α-1,4 branches, 35% protein

        550,000-558,000

        glucose

         

        Hordeum spp. (seed)

        Extract

        β-1,3;1,4-and β-1,3;1,6-D-glucans

        45,000-404,000

        glucose

        [75]

          

        Primarily linear β-1,3;1,4- glucans

        NA

        glucose

        [124]

        Laminaria spp.

        (frond)

        Extract (laminarin)

        β-1,3;1-6 glucan

        7,700

        glucose

        [29]

          

        β-1,3 glucan with some β-1,6 branches and a small amount of protein

        4,500-5,500

        glucose

        [44]

         

        Extract

        Fucoidan

        NA

        NA

        [133]

        Larix occidentalis (bark)

        Extract

        β-1,3;1,6-D-galactans with arabinofuranosyl and arabinopyranosyl side chains

        19,000-40,000

        galactose:arabinose (6:1), uronic acid

        [128, 134]

        Lentinula edodes

        Extract (SME)

        β-1,3-glucans (4-5%), α-1,4-glucan (8-10%), protein (11-14%)

        NA

        glucose

        [80]

         

        Extract

        β-glucan

        1,000

        glucose

        [27]

         

        Whole tissue

        Linear β-1,3-glucans, β-1,4;1,6-glucans, heterogalactan

        NA

        glucose, galactose, mannose, fucose, xylose

        [135]

         

        Extract (lentinan)

        β-1,3-glucan with 2 β-1,6 glucopyranoside branchings for every 5 β-1,3-glucopyranoside linear linkages

        500,000

        glucose

        [136]

        Lentinula edodes (fruit body)

        Lentinula edodes

        Extract (lentinan)

        Neutral β-1,3-D glucan with two β-1,6 glucoside branches for every five β-1,3 units

        400,000-800,000

        glucose

        [137]

         

        Extract

        (KS-2)

        Peptide units and mannan connected by α-glycosidic bonds

        60,000-90,000

        mannose, glucose

         

        Lentinula edodes (mycelia or fruit body)

        Extract

        Triple helical β-1,3-D glucan with β-1,6 glucoside branches

        1,000,000

        glucose

        [3]

        Lentinula edodes (mycelia)

        Extract

        (LEM)

        44% sugars, 24.6% protein

        ~1,000,000

        xylose, arabinose, glucose, galactose, mannose, fructose

        [3]

         

        Extract (PG101)

        72.4% polysaccharides, 26.2% protein, 1.4% hexosamine

        NA

        55.6% glucose, 25.9% galactose, 18.5% mannose

        [138]

        Lycium barbarum

        Whole tissue

        α-1,4;1,6-D-glucans, lentinan, β-1,3;1,6 heteroglucans, heterogalactans, heteromannans, xyloglucans

        NA

        glucose, galactose, mannose, xylose

        [139]

        Lycium barbarum (fruit body)

        Extract

        (LBP3p)

        88.36% sugars, 7.63% protein

        157,000

        galactose, glucose, rhamnose, arabinose, mannose, xylose (molar ratio of 1:2.12:1.25:1.10:1.95:1.76)

        [91]

        Panax quinquefolium (root)

        Extract

        Poly-furanosyl-pyranosyl saccharides

        NA

        arabinose, galactose, rhamnose, galacturonic acid, glucuronic acid

        [33]

          

        NA

        NA

        glucose, mannose, xylose

        [140]

         

        Extract

        (Cold-fX®)

        90% poly-furanosyl-pyranosyl-saccharides

        NA

        furanose

        [20]

        Phellinus linteus (fruit body)

        Extract

        α- and β-linked 1,3 acidic proteoglycan with 1,6 branches

        150,000

        glucose, mannose, arabinose, xylose

        [141]

        Phellinus linteus (mycelia)

        Extract

        83.2% polysaccharide (4.4% β-glucan), 6.4% protein, 0.1% fat

        NA

        glucose

        [142]

        Pholiota nameko (fruit body)

        Extract (PNPS-1)

        NA

        114,000

        mannose, glucose, galactose, arabinose, xylose (molar ratio of 1:8.4:13.6:29.6:6.2)

        [55]

        Pleurotus ostreatus (mycelia)

        Extract

        β-1,3;1,6-D-glucans

        316,260

        glucose

        [143]

        Saccharomyces cerevisiae

        Extract (WGP)

        Particulate β-1,3;1,6-D-glucan

        NA

        glucose

        [144]

         

        Extract

        β-glucans with β-1,6 branches with a β-1,3 regions

        NA

        glucose

        [124]

         

        Extract

        (SBG)

        soluble β-1,3-D-glucan with β-1,3 side chains attached with β-1,6 linkages

        20,000

        glucose

        [145]

        Sclerotinia sclerotiorum (mycelia)

        Extract

        (SSG)

        β-1,3-D-glucan, <1% protein (>98% polysaccharide)

        NA

        glucose

        [83]

        Sclerotium rofsii

        Extract (scleroglucan)

        β-1,3;1,6 glucan

        1,000,000

        glucose

        [29]

        Trametes versicolor (fruit body)

        Extract

        (PSP)

        α-1,4, β-1,3 glucans, 10% peptides

        100,000

        glucose, arabinose, mannose, rhamnose

        [146]

        Trametes versicolor (mycelia)

        Extract

        (PSK)

        β-1,4;1,3;1,6-D-glucans, protein

        94,000

        glucose (74.6%), mannose (15.5%), xylose (4.8%), galactose (2.7%), fucose (2.4%)

        [137, 147]

        Undaria pinnatifida (sporophyll)

        Extract

        Galactofucan sulfate

        9,000

        fucose:galactose 1.0:1.1

        [148]

          

        Galactofucan sulfate

        63,000

        fucose:galactose:gluc-uronic acid (1.0:1.0:0.04)

        [149]

          

        β-1,3-galactofucan sulphate

        38,000

        fucose, galactose

        [150]

        Unidentified source

        Extract (modified citrus pectin)

        NA

        10,000

        galactose, rhamnose, uronic acid

        [125]

         

        Extract (highly methoxylated pectin)

        NA

        200,000

        NA

        [36]

        Table 6

        Safety of Immunomodulatory Polysaccharide Products Following Oral Intake

        Category

        Source

        Test group

        Test

        Design

        Results

        Equivalent human dose*

        Reference

        Arabino-galactans

        Argemone mexicana (arabinogalactan protein)

        Pregnant rats

        Develop-mental toxicity

        250, 500, or 1,00 mg/kg, gestational days 5-19

        No developmental toxicity: NOAEL = 1 g/kg

        68 g

        [151]

          

        ♀ and ♂ rats

        Fertility

        250, 500, or 1,00 mg/kg, 1 month

        No effects on reproduction: NOAEL = 1 g/kg

          

        Fucoidans

        Undaria pinnatifida

        Rats

        Subchronic toxicity

        1.35 g/kg, 1 month

        No evidence of toxicity

        91.8 g

        [152]

        Galacto-mannans

        Cyamopsis tetragonolobus

        Adolescent and adult ♂ rats

        Subchronic and chronic toxicity

        8% of diet, 6-67 weeks

        No evidence of toxicity

        8% of diet

        [153]

          

        Rats

        Acute toxicity

        One 7.06 g/kg dose: observed 2 weeks

        LD50 = 7.06 g/kg

        480 g

        [96]

           

        Subchronic and chronic toxicity

        1, 2, 4, 7.5 or 15% of diet, 3 months

        All doses ↓ ♀ BW; 7.5-15% ↓ ♂ BW; 15% ↓ bone marrow cellularity; ↓ kidney and liver weights

        1-15% of diet

         
          

        19 adults with hypercholesterol-emia

         

        18 g/day, 1 year

        Short-term gastric bloating/loose stools, in 8 subjects, resolved in 7-10 days; 2 withdrew because of diarrhea. No toxicity for 13 subjects completing study

        18 g

        [154]

          

        16 Type II diabetics

         

        26.4-39.6 g/day, 6 months

        No effects on hematologic, hepatic, or renal function

        39.9 g

        [155]

          

        18 Type II diabetics

         

        30 g/day, 4 months

         

        30 g

         
         

        Cyamopsis tetragonolobus (partially hydrolyzed guar gum)

        Mice & rats

        Acute toxicity

        One 6 g/kg dose; observed

        2 weeks

        LD50 > 6 g/kg

        >408 g

        [156]

          

        Rats

        Subchronic toxicity

        0.2, 1.0 or 5% of diet, 13 weeks

        No evidence of toxicity

        5% of diet

         
            

        0.5 or 2.5 g/kg, 1 month

        NOAEL > 2.5 g/kg

        >170 g

        [157]

          

        S. typhimurium

        Mutagenicity

        Ames test

        Not mutagenic

        NA

         

        Glucans

        Agaricus subrufescens (aqueous extract)

        Rats

        Subchronic toxicity

        0.63, 1.25, 2.5 or 5% of diet, 3 months

        NOAEL = 5% of diet

        5% of diet

        [158]

          

        3 women with advanced cancers

        Case reports

        Specific identity of products, doses, and durations of intake unknown

        Severe hepatotoxicity; two patients died

        NA

        [97]

         

        Agaricus subrufescens (freeze dried powder)

        24 normal adults and 24 adults with liver problems

        Subchronic toxicity

        3 g, 4 months

        No evidence of toxicity

        3 g

        [159]

         

        Ganoderma lucidum

        (supplement)

        Elderly woman

        Case report

        1 year G. lucidum (and another unidentified product, initiated one month previous)

        Elevated liver enzymes and liver tissue damage

        NA

        [98]

         

        Grifola frondosa (powder)

        Rats

        Acute toxicity

        One 2 g/kg dose

        No evidence of toxicity

        136 g

        [160]

         

        Lentinula edodes (powder)

        10 adults

        Safety

        4 g/day for 10 weeks; repeated

        3-6 months later

        50% of subjects experienced blood eosinophilia, ↑ eosinophil granule proteins in serum and stool, ↑GI symptoms

        4 g

        [99]

         

        Lentinula edodes

        (SME)

        Nude mice

        Safety

        10% of diet days 1-18, 33-50

        No adverse events

        10% of diet

        [80]

          

        61 men with prostate cancer

         

        0.1 g/kg, 6 months

        No adverse events

        6.8 g

         
         

        Lentinus lepideus (PG101)

        Female mice

        Subchronic toxicity

        0.5 g/kg, 24 days

        No evidence of toxicity

        34 g

        [92]

         

        Phellinus linteus

        (crude extract)

        Rats

        Acute toxicity

        One 5 g/kg dose; observed

        2 weeks

        LD50 > 5 g/kg

        349 g

        [161]

         

        Pleurotus ostreatus (aqueous extract)

        Mice

        Acute toxicity

        One 3 g/kg dose; observed

        1 day

        LD50 > 3 g/kg

        >204.g

        [100]

           

        Subacute toxicity

        319 mg/kg, 1 month

        Hemorrhages in intestine, liver, lung, kidney; inflammation and microabscesses in liver

        21.7 g

         
         

        Saccharomyces cerevisiae (particulate glucan [WGP])

        Rats

        Acute toxicity

        One 2 g/kg, observed 2 weeks

        LD50 > 2 g/kg

        >136 g

        [144]

           

        Subchronic toxicity

        2, 33.3 or 100 mg/kg, 3 months

        NOAEL = 100 mg/kg

        6.80 g

         

        Heteroglycans

        Trametes versicolor

        (PSP)

        Rats

        Subchronic toxicity

        1.5, 3.0 or 6.0 mg/kg, 2 months

        No evidence of toxicity

        408 mg

        [162]

          

        Rats & monkeys

        Subchronic and chronic toxicity

        100-200X equivalent human dose, 6 months

        No evidence of toxicity

        NA

         
         

        Trametes versicolor

        (PSK)

        Humans with colon cancer

        Safety

        3 g/day, up to 7 years

        No significant adverse events

        3 g

        [57]

          

        Humans with colorectal cancer

         

        3 g/day, 2 years

         

        3 g

        [58]

        Mannans

        Aloe vera gel

        Dogs

        Acute toxicity

        Fed one 32 g/kg; observed 2 weeks

        LD50 > 32 g/kg

        >2,176 g

        Bill Pine, personal communi-cation

          

        Rats

         

        One 21.5 g/kg; observed 2 weeks

        LD50 > 10 g/kg

        >680 g

         

        *150 lb adult

        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

        Category

        Product

        Metabol-ized by human gut bacteria?

        Study type

        Fate

        (method: tissues detected)

        References

        Arabinogalactans

        Larix spp.

        yes

        in vitro

        NA

        [163169]

        Fucoidans

        Undaria pinnatifida

        no

        in vitro

        Ab: human plasma

        [108, 170]

        Galactomannans

        Cyamopsis tetragonolobus (partially hydrolyzed guar gum)

        yes

        in vivo

        NA

        [171]

         

        Cyamopsis tetragonolobus (guar gum)

        yes

        in vitro

        NA

        [167]

        Glucans

        Hordeum vulgare

        NA

        in vivo

        Fluorescein-labeled: mouse Mø in the spleen, bone marrow, lymph nodes

        [73]

         

        Laminaria digitata (laminarin)

        yes

        in vitro

        NA

        [29, 170, 172]

         

        Sclerotium rofsii (scleroglucan) glucan phosphate, Laminaria spp. (laminarin)

        NA

        in vivo

        Alexa Fluor 488-labeled: mouse intestinal epithelial cells, plasma, GALT

        [29]

         

        Saccharomyces cervisiae (particulate)

        NA

        in vivo

        Fluorescein-labeled: mouse macrophage in the spleen, bone marrow, lymph nodes

        [73]

         

        Trametes versicolor

        (PSK)

        NA

        in vivo

        14C-labeled: rat and rabbit serum; mouse GI tract, bone marrow, salivary glands, liver, brain, spleen, pancreas

        [173]

        Mannans

        Aloe barbadensis (aloemannan)

        yes

        in vitro

        FITC-labeled: mouse, GI tract

        [121, 174]

         

        Aloe barbadensis

        (gel powder)

        yes

        in vitro

        NA

        [163]

         

        Aloe barbadensis (acemannan)

        NA

        in vivo

        14C-labeled: dog systemic, particularly liver, bone marrow, gut, kidney, thymus, spleen

        (Carrington Laboratories, personal communication)

        Mixed polysaccharide products

        Ambrotose complex®, Advanced Ambrotose® powder

        yes

        in vitro

        NA

        [163, 175]

        Pectins

        NA

        yes

        in vitro

        NA

        [165167, 176]

         

        Buplerum falcatum (bupleuran 2IIc)

        NA

        in vivo

        Ab bound: mouse Peyer's patch, liver

        [109]

        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

        List of 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

        H202

        hydrogen peroxide

        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

        Declarations

        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.

        Authors’ Affiliations

        (1)
        Mannatech™, Incorporated

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        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.

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