By Yousry Naguib, Ph.D.

In the past three decades, various beta glucans have been isolated from mushrooms (club fungi), yeast (sac fungi), oats and barley. Beta glucans are becoming popular supplements for their promising pharmacological activities such as immuno-modulatory, anti-tumor, and cholesterol lowering properties. Beta-glucans belong to a group of biopolymers known as polysaccharides, made up of many smaller sugar molecules, with different types of glycosidic linkages such as 1,3- and 1,6-beta-glucans.

Immuno-modulatory Activity

Edible mushrooms are considered a good source of beta-glucans. Studies showed such mushrooms as Lentinus (shiitake), Pleurotus (oyster), Auricularia (mu-er), Flammulina (enoki-take), Tremella (yin-er), and Grifola (maitake) have immuno-modulatory, lipid-lowering, anti-tumor, and other therapeutic benefits without any significant toxicity.

In Japan , the Health and Welfare Ministry -- equivalent to the United States FDA -- has approved three beta-glucans extracted from mushrooms as anti-cancer drugs. These beta-glucans are Lentinan, derived from Shiitake (Lentinus edodes);  Schizophyllan (SPG, Sonifilan), derived from Suehirotake (Scbizophyllum commune); and PSK (Krestin), derived from Kawaratake (Coriolus versicolor).  Lentinan and schizophyllan are pure beta-glucans, whereas PSK is a protein-bound beta-glucan. [1] Beta-glucans from mushrooms are identified as biological response modifiers (BRMs) that stimulate the immune system.  BRMs have been defined as those agents that modify the host's biological response by a stimulation of the immune system, which may result in various therapeutic effects.

How Beta-Glucan Works In The Immune System

Beta-glucan works by stimulating the immune system response to keep immune cells in a heightened state of vigilance against invaders (bacteria, viruses, foreign substances). Beta-glucan activates B-lymphocytes, and interacts with macrophages through beta-glucan receptors on macrophages, thereby inducing release of cytokines. Cytokines are proteins produced by the immune system, lymphocytes and monocytes (which include macrophages), to regulate cellular processes such as proliferation and differentiation. Cytokines include interleukins, interferons, natural killer cells (NK cells), and tumor necrosis factor-alpha (TNF-alpha). NK cells are responsible for destroying cancer cells and other potentially harmful cells. Macrophages (from the Greek macro, large; and phagein, to eat) are large white blood cells capable of trapping and engulfing foreign substances. Lymphocytes are special types of white cells, such as T cells. T-cells have the ability to stimulate other cellular components of the immune system to kill or neutralize invading bacteria and viruses, and have the ability to fight cancer.

What Do Studies Show?

A small clinical trial on nine patients with malignant melanoma, carcinoma of the lung and carcinoma of the breast showed that injection of glucan into the tumor resulted in shrinking the tumor. This effect indicates the efficacy of the glucan as a potent macrophage activator. [2]

The immuno-modulating activity of beta-glucan to stimulate or to inhibit TNF-alpha activity has been demonstrated in a test tube experiment. Incubation of rat macrophages with a low concentration (500 microgram/ml) of fungal beta-glucan resulted in stimulation of TNF-alpha release, while incubation with high concentration of beta-glucan (greater than 500 micrograms/ml) resulted in suppression of TNF-alpha activity.

These results indicate that the level of TNF-alpha can be modulated using different amounts of beta-glucan. [3] This TNF-alpha modulation was further illustrated in another test tube experiment, where high concentration of beta-glucan was shown to inhibit the secretion of TNF-alpha induced by bacterial lipopolysaccharide. The study suggested that treatment of animals with beta-glucan prior to bacterial challenge could reduce TNF­alpha release and, therefore, may prevent death. [4]

The immune-enhancing activity of a branched beta-glucan Grifolan from Grifola frondosa (GRN) was demonstrated in an animal study. Administration of GRN to mice was found to activate the liver Kupffer cells by increasing the expression of beta­glucan receptors on Kupffer cells, to produce cytokines and nitric oxide. [5] Kupffer cells have anti-tumor activity, and their aug­mentation has been proposed to prevent tumor growth in the liv­er. GRN was also shown to stimulate the production of cy­tokines from mice macrophages in vitro. [6]

The ability of another fungal beta-glucan, SSG, extracted from Sclerotinia sclerotiorum to potentiate the immune system, was demonstrated in an animal study where oral administration of SSG to mice resulted in enhancing the activities of both nat­ural killer (NK) cells in spleen and the lysosomal enzyme of peri­toneal macrophages. SSG was also shown to protect mice against microbial pneumonia infection [7].

Branched beta-glucans were demonstrated to modulate toxin-induced cytokine production during septic shock (a serious complication of severe burns and abdominal wounds, frequently fatal), resulting in a reduced mortality rate. Researchers found that stimulation of leukocytes (lymphocytes and monocytes) iso­lated from beta-glucan-treated mice with lipopolysaccharide or staphylococcal toxins, suppressed production of the proinflammatory cytokines TNF-alpha and interleukin-2 and interleukin-6, compared to those in cells isolated from untreated mice. [8]

The ability of fungal beta-glucan to induce nitric oxide synthesis (an important molecule for the anti-microbial and anti-tumor effects of macrophages) depends on the source, and structure of beta-glucan. Researchers in Japan reported that highly branched soluble beta-glucans Grifolan from maitake administered intravenously to mice enhanced nitric oxide synthesis of peritoneal macrophages. Other highly branched beta-glucan SSG, and a particulate beta-glucan Zymosan, also showed similar activity. [9]

A Japanese study showed that lentinan, derived from shiitake, has the ability to enhance immunity and to prolong the survival time of some cancer patients. [10] Pleuran a highly branched beta-glucan from Pleurotus ostreatus (oyster mushroom, also called Hiratake in Japan ), was reported to have anti-tumor activity similar to other branched beta-glucans, lentinan, schizo­phyllan and scleroglucan. [10a]

Research found that the molecular weight of 1,3 beta-glu cans is an important factor for the production of cytokines from macrophages, in vitro. The action of beta-glucan Grifolan (from Grifola frondosa, GRN) on TNF-alpha release correlated with the molecular weight of GRN, with the highest molecular fraction exhibiting the strongest activity. [11]

The dosage of beta-glucan also plays an essential role in its immuno-modulatory activity. Overdose of schizophyllan (Sonifian) failed to act as a biological response modifier with radiation therapy for cancer treatment. This overdose effect of sonifilan was attributed to modulation of the cytokine synthesis and reduction of TNF-alpha production. [12]

A multi-center, prospective, randomized, double-blind, placebo-controlled trial of 1249 patients demonstrated that peri­operative administration of PGG-glucan (Betafectin) derived from yeast cell walls reduced serious postoperative infections or death by 39 percent after high-risk gastrointestinal operations. [13]

In one study, the beta-glucan Zymosan isolated from the baker's yeast Saccharomyces cerevisiae was recognized as an antigen and as a non-specific immune stimulant in mice immunized with Zymosan. [14]

In addition to the above studies on the immuno-modulatory activities of fungal beta-glucans, beta-glucans from oats were also found to potentiate the immune system. Intraperitoneal (i.p.) administration of oat beta-glucan in mice resulted in accu­mulation of leukocytes (white blood cells), predominantly macrophages, in the peritoneal cavity. Survival of mice challenged with Staphylococcus aureus was enhanced by a single dose of 500 micrograms of oat beta-glucan three days prior to bacterial challenge. [15] These results demonstrate that oat beta-glucans also stimulate the immune functions.

Administration of oat beta-glucan by intragastric or subcutaneous routes to mice enhanced their resistance to E. vermiformis infection, further demonstrating its immune stimulating activity. [16]

Several studies have indicated that consumption of oat bran lowers blood cholesterol, and this effect has been attributed specifically to oat bran's soluble fiber, beta-glucan.

In 1997, the FDA allowed a health claim to be made for foods containing oat bran to be marketed as a cholesterol-reducing supplement at a dosage of three grams beta-glucan. However, a recent double-blind, placebo-controlled randomized trial in­volving 62 healthy men and women found that consumption of 20 grams of oat bran concentrate (providing three grams beta­glucan) daily for eight weeks did not significantly reduce total cholesterol or LDL-cholesterol. The study concluded that three grams of beta-glucan per day is a low dosage to lower plasma cholesterol levels. [17]

In a controlled double-blind study, 66 men were randomly assigned to either oat milk (0.5 percent beta-glucan) or rice milk (control) for five weeks (0.75 liter/day). At the end of the study, the intake of oat milk significantly reduced serum total choles­terol (6 percent) and LDL-cholesterol (6 percent) levels, indicat­ing that oat milk deprived of insoluble fiber has cholesterol-low­ering properties. [18]

In a Canadian study, 20 hypercholesterolemic adults were randomly given either oat gum diet con­taining 2.9 grams beta-glucan, or a placebo (maltodextrin) twice daily for four weeks. There were no significant changes in blood cholesterol in the placebo group, while the total cholesterol and LDL-cholesterol levels decreased 9 percent relative to the initial value in the oat group. [ 19]

In a dose-controlled study involving 156 adults, supplementation with oat bran resulted in higher reduction in LDL-cholesterol levels than that with oatmeal. This effect was ascribed to higher beta-glucan content in oat bran than in oatmeal. [20] The dose-response of oat beta-glucan was also demonstrated in a study on 23 mildly hypercholesterolemic subjects, who were fed oat extract containing a low (1 percent) or high (10 percent by weight) beta-glucan. Both diets reduced total and LDL-cholesterol levels significantly. The high beta-glucan dosage is more effective than the low beta-glucan dosage in reducing total cholesterol levels. [21]

Beta-glucan derived from barley was also found to lower cholesterol in humans. Twenty-one mildly hypercholesterolemic men were randomly provided with either barley as a source of beta-glucan, or wheat (which contains largely cellulose insoluble fibers) for four weeks. Only the barley group showed a significant fall in plasma total cholesterol and in LDL-cholesterol. 122]

A study at the University of Massachusetts on 15 obese and hypercholesterolemic men found that supplementation with 15 grams of beta-glucan fiber derived from yeast daily for eight weeks significantly reduced total cholesterol (by 6 percent) and LDL-cholesterol (by 8 percent). [23]

Other Therapeutic Qualities

An insoluble fiber (cellulose) and four soluble fibers (guar gum, carboxymethyl cellulose, and oat beta-glucan) were fed to rats for 10 days. Guar gum and oat beta­glucan reduced the food intake, whereas cellulose increased it. Soluble fibers signifi­cantly decreased insulinemia 45 minutes after the meal. [24]

When nine healthy subjects consumed 14.5 grams oat gum (80 percent beta-glucan) with 50 grams glucose, their plasma glucose and insulin were lower than those who consumed only glucose. These results establish that beta-glucan in oat gum has the ability to lower postprandial plasma glucose and insulin levels in humans. [25]

The effect of oat beta-glucan in cereals on plasma glucose and insulin responses was evaluated in a dose-dependent study on eight non-insulin-dependent diabetes mellitus (NIDDM) sufferers. Subjects ate cereals containing oat bran enriched with varying amounts of beta-glucan -- 4, 6, and 8.4 grams. Their plasma glucose levels were 33 per­cent, 58 percent, and 62 percent, respectively, lower than that of those who ate a conti­nental breakfast. The beta-glucan group had postprandial insulin 50 percent lower than that of the continental group. The results indicated an inverse relationship between the plasma glucose level and the intake of beta-glucan, and showed that incorporating beta­glucan into a diet could lower postprandial plasma glucose and insulin level in NIDDM subjects. [26]

A highly purified bioactive beta-glucan from Maitake mushroom (Grifron DCR) was shown, in a dose-response test tube study, to induce apoptosis (programmed cell death) in human prostatic cells, suggesting the potential use of this bioactive beta-glucan as an alternative therapeutic modality for prostate cancer. [27]

Safety & Summary

Beta-glucan isolated from the common baker's yeast Saccharomyces cerevisiae is typically used in a highly purified form, to minimize allergic reaction to yeast-sensitive individuals. No known side effects associated with beta-glucans in humans have been reported.

Though most of fungal beta-glucan research studies have been done on animals, the results seem promising for these beta-glucans' potential as immuno-modulators. Oat and barley beta-glucans, on the other hand, were shown in human studies to lower blood cholesterol levels, in particular the bad LDL-cholesterol, and to lower the glycemic index of the food (the ability of a food to raise blood sugar).

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