Beta-glucan

β-Glucans (or beta-glucans) are polysaccharides occurring in the bran of cereal grains, the cell wall of baker's yeast, certain types of fungi, and many kinds of mushrooms. The cereal based beta glucans occur most abundantly in barley and oats and to a much lesser degree in rye and wheat. They are useful in human nutrition as texturing agents and as soluble fiber supplements, but problematic in brewing as excessive levels make the wort too viscous. An insoluble (1,3/1,6) beta glucan derived from baker's yeast has a different molecular structure than that of its soluble (1,3/1,4) counterparts and has a greater biological activity due to its structural "branching". Yeast derived beta glucans are notable for their immunomodulatory function. The differences between soluble and insoluble beta glucans are significant in regards to application, mode of action, and overall biological activity.

Overview
Glucans are polysaccharides that only contain glucose as structural components. Beta 1, 3-D glucans are chains of D-glucose molecules, with the six-sided D-glucose rings connected at the 1 and 3 positions. Smaller side chains branch off the 1,3 polysaccharide “backbone.” The most active form of Beta 1, 3-D glucans are apparently those that contain 1,6 side-chains branching off from the longer beta-1,3 glucan backbone. These are referred to as beta-1,3/1,6 glucan. Some researchers have suggested that it is the frequency, location, and length of the side-chains rather than the backbone of beta glucans that determine their immune system activity. Another variable is the fact that some of these compounds exist as single strand chains, while the backbones of other beta-1,3 glucans exist as double or triple stranded helix chains. In some cases, proteins linked to the beta-1,3 glucan backbone may also be involved in providing therapeutic activity. Although these compounds have exciting potential for enhancement of the immune system, it must be emphasized that this research is in its infancy, and there are differing opinions on which molecular weight, shape, structure, and source of beta-1, 3 glucans provide the greatest therapeutic benefit.

One of the most common sources of Beta 1, 3-D glucan is derived from the cell wall of baker’s yeast (Saccharomyces cerevisiae). However, beta-1,3 glucans are also extracted from the bran of some grains such as oats and barley. The Beta 1, 3-D glucans from yeast are often insoluble whereas those extracted from grains tend to be soluble. Other sources include some types of seaweed [1], and various species of mushrooms such as Reishi, Shiitake, and Maitake.[2]

Beta 1, 3-D glucans are being referred to as biological response modifiers because of their ability to activate the immune system.[3] However, it should be noted that the activity of Beta 1, 3-D glucan is different from agents that stimulate the immune system. Agents that stimulate the immune system can push the system to over-stimulation, and hence are contraindicated in individuals with autoimmune diseases, allergies, or yeast infections. Beta 1, 3-D glucans seem to make the immune system work better without becoming overactive. They accomplish this by activating phagocytes, which are immune system cells whose function is to trap and destroy foreign substances in our bodies such as bacteria, viruses, fungi, and parasites.[4] In addition to enhancing the activity of phagocytes, beta-1,3 glucans also reportedly lower elevated levels of LDL cholesterol, aid in wound healing, help prevent infections, enhance NK cell function, and help in the prevention and treatment of cancer.

Clinical Applications (conclusions of investigators)
· Cancer: β-Glucan has been used as an immunoadjuvant therapy for cancer since 1980, primarily in Japan. Numerous studies report that beta-1, 3 glucan has anti-tumor and anti-cancer activity.[5] [6] In one study, intralesional administration of beta-1,3 glucans resulted in rapid tumor shrinkage.[7] In another study with mice, beta 1,3 glucan in conjunction with interferon gamma inhibited both the establishment of tumors and liver metastasis.[8] In some studies, beta-1,3 glucans enhanced the effects of chemotherapy. In studies on bladder cancer with mice, administration of cyclophosphamide, in conjunction with beta-1,3 glucans derived from yeast resulted in reduced mortality.[9] In human patients with advanced gastric or colorectal cancer, the administration of beta-1,3 glucans derived from shiitake mushrooms, in conjunction with chemotherapy resulted in prolonged survival times compared to a control group receiving identical chemotherapy.[10]

Preclinical studies have shown that a soluble yeast β-glucan product, Imprime PGG, when used in combination with certain monoclonal antibodies or cancer vaccines, offers significant improvements in long-term survival versus monoclonal antibodies alone.[11] This benefit, however, does not result from Betafectin enhancing the specific killing action of the antibody. The anti-tumor activity is caused by a unique killing mechanism that involves neutrophils that are primed with Betafectin and which are not normally involved in the fight against cancer.[11][12] Recent research by Hong et al, demonstrates that this mechanism of action is effective against a broad range of cancers when used in combination with specific monoclonal antibodies that activate or cause complement to be bound to the tumor.[13] The complement enables these primed neutrophils to find and bind to the tumor, which facilitates killing. Innate immune cells are the body’s first line of defense and circulate throughout the body engaging in an immune response against “foreign” challenges (bacteria, fungus, parasites). Typically, neutrophils are not involved in the destruction of cancerous tissue because these immune cells view cancer as "self" rather than foreign or "non-self." Current cancer immunotherapies involve monoclonal antibodies and vaccines, which stimulate the acquired immune response, but do nothing to change the innate immune system's view of cancer as "self." As a result the monoclonal antibodies alone do not engage or initiate the potential killing ability of the innate immune system, which is our primary mechanism of defense against bacteria and yeast (fungal) infections.

Dr. Gordon Ross and Dr. Vaclav Vetvicka, respected immunologists and cancer researchers at the University of Louisville, discovered that a receptor on the surface of these innate immune cells called Complement Receptor 3 ( CR3 or CD11b/CD18) was responsible for binding to fungi or yeast, allowing the immune cells to recognize them as "non-self."[11] This receptor is a dual occupancy receptor in that it has two binding sites. The first site is responsible for binding to a type of complement, a soluble blood protein, known as C3 (or iC3b). C3 becomes attached to pathogens that specific antibodies have targeted and opsonized. The second site of this receptor binds to a carbohydrate on yeast or fungal cells that allows the innate immune cell to recognize yeast and fungi as being "non-self ”.[12][14] Both of these receptor sites must be simultaneously occupied to trigger the innate immune cell to destroy the yeast or fungi. Two obstacles prevent neutrophils from using this mechanism of action against cancer. First, the body usually does not generate enough natural antibodies to bind to the tumor, and this prevents the activation and attachment of (or “fixing”) complement to the surface of the cancer cell. Therefore, neutrophils don’t bind to cancer via the first receptor site of CR3. The second obstacle is that even when the natural antibody response is supplemented with monoclonal antibodies that fix complement and binding occurs at the first site, tumors do not contain a foreign carbohydrate serving as “second signal” on their surface that allows neutrophils to recognize the cancer as "non-self “.[12][15]

Dr. Ross discovered that a bio-processed fragment of Imprime PGG specifically binds to the second CR3 receptor site on neutrophils. When neutrophils bind to tumors, the Betafectin allows them to “see” cancer as if it were a yeast or fungal pathogen and provide the “second signal” to trigger killing. In summary, Betafectin engages neutrophils in the fight against cancer, dramatically and synergistically enhancing the effectiveness of complement activating monoclonal antibodies and vaccines through a different killing mechanism.

Multinational research has successfully demonstrated that the oral form of yeast Beta 1,3-D glucan has similar protective effects as the injected version, including defense against infectious diseases and cancer.[16][17][18][19][20] Recently, orally-delivered glucan was found to significantly increase proliferation and activation of monocytes in peripheral blood of patients with advanced breast cancer.[21]

The technology has wide applicability for cancer therapy. Each form of cancerous tumor cell has specific antigens on the cell surface, some of which are common to other types of cancer. (Example: Mucin 1 is present on about 70% of all types of cancer cells) Different immunotherapies target different antigens for binding monoclonal antibodies to tumor cells. This has resulted in the development of hundreds of monoclonal antibodies, many targeting a different specific antigen on cancer cells. In research studies, Betafectin has improved the effectiveness of all complement-activating monoclonal antibodies tested including breast, liver and lung cancer (company data). The magnitude of success varies based on the specific monoclonal antibody used and the type of cancer.

·       Prevention of infection: To date there have been numerous studies and clinical trials conducted with the soluble yeast β-glucan and the whole glucan particulate. These studies have ranged from the impact of β-glucan on post-surgical nosocomial infections to the role of yeast β-glucans in treating anthrax infections.

Post-surgical infections are a serious challenge following major surgery with estimates of 25-27% infection rates post-surgery.[22] Alpha-Beta Technologies conducted a series of human clinical trials in the 1990’s to evaluate the impact of β-glucan therapy for controlling infections in high-risk surgical patients.[22] In the initial trial 34 patients were randomly (double-blind, placebo-controlled) assigned to treatment or placebo groups. Patients that received the PGG-glucan had significantly fewer infectious complications than the placebo group (1.4 infections per infected patient for PGG-glucan group vs. 3.4 infections per infected patient for the placebo group). Additional data from the clinical trial revealed that there was decreased use of intravenous antibiotics and shorter stays in the intensive care unit for the patients receiving PGG-glucan vs. patients receiving the placebo.

A subsequent human clinical trial [23] further studied the impact of β-glucan for reducing the incidence of infection with high-risk surgical patients. The authors found a similar result with a dose-response trend (higher dose provided greater reduction in infectious occurrences than low doses). In the human clinical trial 67 patients were randomized and received either a placebo or a dose of 0.1, 0.5, 1.0 or 2.0 mg PGG-Glucan per KG of body weight. Serious infections occurred in four patients that received the placebo, three patients that received the low dose (0.1 mg/KG) of PGG-Glucan and only one infection was observed at the highest dose of 2.0 mg/KG of PGG-Glucan.

The results of a phase III human clinical trial showed that PGG-Glucan therapy reduced serious post-operative infections by 39% after high-risk noncolorectal operations.[24] This study was conducted in patients that were already as high-risk because of the type of surgery and were more susceptible to infections and other complications.

At this point in the development of an injectable form of b-glucan (Betafectin PGG-glucan) most scientists already concluded that yeast-derived b-glucan promoted phagocytosis and subsequent killing of pathogenic bacteria. A phase III clinical trial was proposed and conducted at thirty-nine medical centers in the U.S. involving 1,249 subjects stratified according to colorectal or non-colorectal surgical patients. The PGG-glucan was given once pre-operatively and three times post-operative at 0, 0.5 or 1.0 mg/kg body weight. The measured outcome was serious infection or death of the subjects within 30 days post-surgery. The results of the phase III human clinical trial showed that injectable PGG-Glucan therapy reduced serious post-operative infections by 39% after high-risk noncolorectal operations.[25]

There have been studies with humans and animal models that further support the efficacy of β-glucan in combating various infectious diseases. One human study demonstrated that consumption of oral whole glucan particles increased the ability of immune cells to consume a bacterial challenge (phagocytosis). The total number of phagocytic cells and the efficiency of phagocytosis in healthy human study participants increased while consuming a commercial particulate yeast β-glucan. This study demonstrated the potential for yeast β-glucan to increase the reaction rate of the immune system to infectious challenges. The study concluded that oral consumption of whole glucan particles represented a good enhancer of natural immunity.

Anthrax is a disease that cannot be tested in human studies for obvious reasons. In a study conducted by the Canadian Department of Defense, Dr. Kournikakis showed that orally administered yeast β-glucan given with or without antibiotics protected mice against anthrax infection.[16] A dose of antibiotics along with oral whole glucan particles (2 mg/KG body weight or 20 mg/KG body weight) for eight days prior to infection with Bacillus anthracis protected mice against anthrax infection over the 10-day post-exposure test period. Mice treated with antibiotic alone did not survive.

A second experiment was conducted to investigate the effect of yeast β-glucan orally consumed after exposure of mice to B. anthracis. The results were similar to the previous experiment with an 80-90% survival rate for mice treated with β-glucan, but only 30% for the control group after 10-days of exposure. The hopeful inference is that similar results would be observed with humans.

Since there are many commercial products on the market called “glucan”, there is much confusion among consumers as to which type(s) may be the most effective. One of the most comprehensive published studies to date showed Glucan #300, a highly purified yeast glucan, to be “the biologically most relevant immunomodulator” out of a wide ranging group.[26]

·       Radiation exposure: β-glucan is a well-known biological response modifier (BRM) isolated from the yeast cell wall polysaccharides and is made up entirely of glucose β(1,3)-linked together in linear chains with variable frequency of β(1,6)-linked side chains.[27] Specific hematopoietic activity was first demonstrated with β-glucan in the mid-1980s in an analogous manner as granulocyte monocyte–colony stimulating factor (GM-CSF).[28]Research was carried out initially with particulate β-glucan and later with soluble β-glucans, all of which were administered intravenously to mice.[29][30][31]Mice exposed to 500-900 cGy (500-900 mrads) of gamma radiation exhibited a significantly enhanced recovery of blood leukocyte, platelet and red blood cell counts when given i.v. β-glucan.[32] Other reports showed that β-glucan could reverse the myelo-suppression produced with chemotherapeutic drugs such as fluorouracil,[24] carboplatinum or cyclophosphamide.[33] Moreover, the anti-infective activity of β-glucan combined with its hematopoiesis-stimulating activity resulted in enhanced survival of mice receiving a lethal dose of 900-1200 cGy of radiation.[22] In vitro studies showed that β-glucan could enhance granulocyte and megakaryocyte colony formation by hematopoietic stem progenitor cells when used in combination with GM-CSF and interleukin-3 (IL-3), respectively.[34]

Original studies delivered glucan almost entirely by injection. Later, numerous studies tried to evaluate the possibility that glucan can be delivered orally without compromising its biological activities,[12][35][36][37]opening the oral route of administration as a more pleasant alternative. A study by Allendorf et al.[38] clearly demonstrated that oral Beta glucan had hematopoietic effects analogous to Beta glucan administered by i.v. methods, work of Vetvicka’s group showed the mechanisms of the glucan transfer through the gastrointestinal tract.[36] Allendorf et al. demonstrated that orally administered whole glucan particulate functions to accelerate hematopoiesis following irradiation in an analogous manner as i.v. administered β-glucan. Experiments by Cramer et al.[39] or Vetvicka [36] clearly demonstrated that oral β-glucan stimulates hematopoiesis in radiation-treated mice. Currently, there is renewed interest in the potential usefulness of β-glucan as a radioprotective drug for chemotherapy, radiation therapy and nuclear emergencies, particularly because glucan can be used not only as a treatment, but also as a prophylactic.

·       Septic shock: One of the mechanisms of the immune-enhancing ability of yeast β-glucan is its ability to prime leukocytes to more easily locate and kill non-self cells including bacteria. Early research by Onderdonk et al.[40] investigated the ability of yeast b-glucan to reduce septic infections using in vivo models. Onderdonk et al. found that mice challenged with E. coli or S. aureus bacteria were protected against septic infections when they were injected with PGG-glucan 4–6 hours prior to infection. Additional research further supports that yeast β-glucan reduces septic shock by killing bacteria present in blood. Work by Kernodle et al. demonstrated that preventative dosing of yeast β-glucan prior to infection with S. aureus prevented sepsis in a guinea pig model. [41] Research on the use of yeast β-glucan immunomodulators as a means of treating and preventing bacterial sepsis is well documented.[40][41][42] Recent reports on glucan and sepsis revealed another possible mechanism - glucan protects against oxidative organ injury.[43]

·       Surgery:  There have been numerous studies and clinical trials conducted with the soluble yeast β-glucan particle and the whole glucan particle. Immunomodulators that enhance macrophage function have been shown to be beneficial in human, as well as, animal models. One such study that looked at this correlation examined wound tensile strength and collagen biosynthesis. Positive effects were observed.[44]

In a prospective, randomized, double-blind study, 38 trauma patients received an I.V. of a soluble yeast derived glucan for 7 days or placebo. The total mortality rate was significantly less in the glucan group (0% vs. 29%). There was also a decrease in septic morbidity (9.5% vs. 49%). Further such trials to evaluate Biological Response Modifiers (BRM’s) in trauma patients are indicated.[45]

Yeast derived beta glucan significantly enhanced phagocytic activity in control and operated mice. In an experimental C. albicans model, mice had induced sepsis along with a midline laparotomy. The non-operated mice on glucan had a 100% survival vs. 73% in the surgical group. Detrimental effects of surgery on survival of C. albicans infection manifested in a 47% survival in the non-surgical vs a 20% survival in the surgery-infected group.[46]

The nonspecific immunostimulation of yeast derived glucan appears to have significant potential as a treatment strategy against post-operative infections. In a post splenectomy mouse model, glucan increased survival vs. controls via 75% as opposed to 27%, Severe sepsis enhances risks in both adult and pediatric patients. These works suggest another option beyond prophylactic antibiotics and bacterial vaccines that often have limited success against morbidity and mortality.[47]

·       Wound healing: Macrophage activity is known to play a key role in wound healing from surgery or trauma. In both animal and human studies, therapy with Beta glucan has provided improvements such as fewer infections, reduced mortality, and stronger tensile strength of scar tissue.

·       Allergic rhinitis: This disease is caused by an IgE-mediated allergic inflammation of the nasal mucosa. Orally-administered yeast-glucan decreased levels of IL-4 and IL-5 cytokines responsible for the clinical manifestation of this disease, while increased the levels of IL-12. Based on these studies, glucan may have a role as an adjunct to standard treatment in patients with allergic diseases.[48]

·       Arthritis: Using paramagnetic resonance spectroscopy, yeast-derived glucan was found to cause decline in oxidative tissue damage during the progress of arthritic diseases, suggesting the role in treatment of arthritis.[49]

·       Additional functions: Influence of certain cereals (barley, oats) and edible mushrooms upon decrease of levels of serum cholesterol and liver low-density lipoproteins, leading to lowering of arteriosclerosis and heart disease hazards, is also mediated by b-glucan.[50] It is known that cereals, mushrooms and yeast facilitate bowel motility and can be used in amelioration of intestinal problems, particularly obstipation.[51][52] Non-digestible b-glucans, forming a remarkable portion of these materials, are also able to modulate mucosal immunity of the intestinal tract.[53] In the central nervous system, β-glucans activate microglial cells.[54] These cells act as scavengers of the brain cell debris and play a positive role in Alzheimer’s disease, AIDS, ischemia injury and multiple sclerosis.[55][56]

Functions in the Body
Beta-1,3 glucans improve the body’s immune system defense against foreign invaders by enhancing the ability of macrophages, neutrophils and natural killer cells to respond to and fight a wide range of challenges such as bacteria, viruses, fungi, and parasites.

Symptoms and Causes of Deficiency: Beta-1, 3 glucans do not occur naturally in humans, hence no deficiency condition exists.

Absorption: For best results, Beta 1, 3-D glucan should be taken on an empty stomach. Enterocytes reportedly facilitate the transportation of beta-1, 3 glucans and similar compounds across the intestinal cell wall into the lymph where they begin to interact with macrophages to activate immune function.[57] Radiolabeled studies have verified that both small and large fragments of beta glucans are found in the serum, which indicates they are absorbed from the intestinal tract.[58] M cells within the Peyer’s Patches physically transport the insoluble whole glucan particles into the GALT.[12]

Dietary Sources: Although beta-1 3 glucans occur in baker’s yeast, seaweed, grains such as oats and barley, and numerous mushrooms, they are not readily usable in their natural state. The indigestible cell walls of these substances must be processed in order to free up the beta-1, 3 glucans and make them available for useful purposes.

Yeast Derived Beta Glucan
Yeast Beta 1, 3-D Glucan

These are sometimes seen as synonyms:

β-Glucan | (1,3/1,6)-β-D-glucan | whole glucan particulate | 1,3/1,6 glucan | (1→3,1→6) glucan

Dosage Range: From 40 mg to 3000 mg daily.

Most Common Dosage: Variable, depending upon body weight and whether it is being used for maintenance or an acute condition. As a dietary supplement (maintenance use), the most common dose range has been reported as 40-500 mg per day. When the dosage is reported on a kilogram of body weight basis the dose range is 2-6 mg/kg. If the particulate glucan is being self-administered for an acute condition, a higher dose of 500-3000 mg/day is typically administered.

Active Forms: Immune-enhancing activity has been reported for Beta 1, 3-D glucan with 1,6 glucan side chains, which are derived from yeasts. Many varieties of mushrooms have also been reported that have a Beta-1,3/1,4 glucan linkage, similar to glucans from oats and barley.

Dosage Forms: As a dietary supplement the most common forms are capsules and tablets. Additional uses also include topical creams and injectables.

Toxicities, Cautions, and Contraindications: Beta 1, 3-D glucan has been recognized as GRAS and the FDA has accepted notification of the GRAS affirmation. The specific conditions of manufacture, safety data and product specifications apply only to the Beta 1, 3-D glucan produced by a process as defined in the GRAS dossier and FDA Notification. Although side effects are very rare, occasionally an allergic reaction is reported. All sufficiently purified polysaccharidic immunomodulators distinguish themselves by very low toxicity (e.g., for mouse lentinan has LD50 > 1600 mg/kg).

Potential Interactions:

Drug/Nutrient Interactions: None known

Nutrient/Nutrient Interactions: None known

Medical applications
Beta-glucans found in baker's yeast and certain fungi are thought to have anticancer properties. In Japan, mushroom-derived extracts rich in beta-glucans have been used for over 20 years in intravenous forms and are approved for use as adjuncts to chemotherapy. There are phase III trial in the U.S. using beta-glucans with other cancer drugs. No forms of beta-glucans have been approved by the FDA to treat cancer.

Other beta-glucans, such as beta-D-glucan, can play an important role in the diagnosis of toxic mycosis caused by fungi that contain such compounds, such as Candida and Aspergillus species.

Beta-glucan is also promoted as dietary supplement for weight loss. These claims are not well supported by research although beta-glucan (like other soluble fibers) has some effect on effective glycemic index and insulin response.

Beta-D-glucan
β-D-glucan (properly known as (1→3)β-D-glucan, but also incorrectly called 1,3-β-D-glucan or even just glucan) forms part of the cell wall of certain medically important fungi, especially Aspergillus species. An assay to detect the presence of (1→3)β-D-glucan in the blood has been produced by Fungitell and is marketed as a means of diagnosing invasive fungal infection in patients.

One of the limitations of the assay is the presence of fungal contaminants in amoxicillin-clavulanate and piperacillin-tazobactam which may result in false-positive results in those patients receiving these antibiotics.