β-Glucans (beta-glucans) are polysaccharides of D-glucose monomers linked by β-glycosidic bonds. β-glucans are a diverse group of molecules that can vary with respect to molecular mass, solubility, viscosity, and three-dimensional configuration. They occur most commonly as cellulose in plants, the bran of cereal grains, the cell wall of baker's yeast, certain fungi, mushrooms and bacteria. Some forms of beta glucans are useful in human nutrition as texturing agents and as soluble fiber supplements, but can be problematic in the process of brewing.
Yeast and medicinal mushroom derived β-glucans are notable for their ability to modulate the immune system. Research has shown that insoluble (1,3/1,6) β-glucan, has greater biological activity than that of its soluble (1,3/1,4) β-glucan counterparts.[1] The differences between β-glucan linkages and chemical structure are significant in regards to solubility, mode of action, and overall biological activity.
Glucans are polysaccharides that contain only glucose as structural components, and are linked with β-glycosidic bonds.
In general, one distinguishes between α- and β-glycosidic bonds, depending on whether the substituent groups on the carbons flanking the ring oxygen are pointing in the same or opposite directions in the standard way of drawing sugars. An α-glycosidic bond for a D-sugar emanates below the plane of the sugar, whereas the hydroxyl (or other substituent group) on the other carbon points above the plane (opposite configuration), while a β-glycosidic bond emanates above that plane.
The numbers 1,4, and 6 identify the carbon atoms at each end of the glycosidic bond. Numbering starts next to the ring oxygen (See glucose).
β-glucan sources in nature
One of the most common sources of β(1,3)D-glucan for supplement use is derived from the cell wall of baker’s yeast (Saccharomyces cerevisiae). However, β(1,3)(1,4)-glucans are also extracted from the bran of some grains such as oats and barley, and to a much lesser degree in rye and wheat. The β(1,3)D-glucans from yeast are often insoluble. Those extracted from grains tend to be both soluble and insoluble. Other sources include some types of seaweed,[2] and various species of mushrooms such as Reishi, Shiitake, and Maitake.
β-glucan and the immune system
β-glucans are known as "biological response modifiers" because of their ability to activate the immune system.[4] Immunologists at the University of Louisville discovered that a receptor on the surface of innate immune cells called Complement Receptor 3 (CR3 or CD11b/CD18) is responsible for binding to beta-glucans, allowing the immune cells to recognize them as "non-self."[5] However, it should be noted that the activity of β-glucans is different from some pharmaceutical drugs that have the ability to over-stimulate the immune system. Pharmaceutical drugs have the potential to push the immune system to over-stimulation, and hence are contraindicated in individuals with autoimmune diseases, allergies, or yeast infections. β-glucans seem to make the immune system work better without becoming overactive.[6] In addition to enhancing the activity of the immune system, β-glucans also reportedly lower elevated levels of LDL cholesterol, aid in wound healing, help prevent infections.
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.[23] 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.[23] 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 [24] 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 kilogram 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.[25] 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 β-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.[17] 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.
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.[39] 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.[40] Research on the use of yeast β-glucan immunomodulators as a means of treating and preventing bacterial sepsis is well documented.[39][40][41] Recent reports on glucan and sepsis revealed another possible mechanism - glucan protects against oxidative organ injury.[42]
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.[43]
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.[44]
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.[45]
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.[46]
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.[46]
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.[47]
Additional applications
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 atherosclerosis and cardiovascular disease hazards, is also mediated by β-glucans.[48] It is known that cereals, mushrooms and yeast facilitate bowel motility and can be used in amelioration of intestinal problems, particularly obstipation.[49][50] Non-digestible b-glucans, forming a remarkable portion of these materials, are also able to modulate mucosal immunity of the intestinal tract.[51] In the central nervous system, β-glucans activate microglial cells.[52] 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.[53][54]
β-glucan absorption
For best results, β(1,3)-D-glucan should be taken on an empty stomach. Enterocytes reportedly facilitate the transportation of β(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.[55] 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.[56] M cells within the Peyer’s Patches physically transport the insoluble whole glucan particles into the gut-associated lymphoid tissue.[13]
Yeast-derived β-glucan
Some β-glucans, isolated from yeast are sold as a health supplement. Suggested supplemental dosages for yeast-derived β-glucans is between 40–3000 mg daily. Common suggested dosages range between 40–500 mg daily. Supplemental yeast-derived β-glucans are commonly sold in the form of capsules. Some companies also produce topical solutions.
β-glucans isolated from yeast are recognized GRAS (Generally recognized as safe) under "yeast extract" and the FDA has accepted notification of the GRAS affirmation. The specific conditions of manufacture, safety data and product specifications apply only to the β(1,3)-D-glucan produced by a process as defined in the GRAS dossier and FDA Notification. Side effects are very rare, and there are no known drug interactions. All sufficiently purified β-glucans distinguish themselves by very low toxicity (e.g., for mouse lentinan has a LD50 greater than 1600 mg/kg).
Medical applications
Studies have shown that β-glucans found in baker's yeast and certain fungi have anticancer properties. In Japan, β-glucans like Lentinan and Polysaccharide-K, isolated from certain medicinal mushrooms 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 β-glucans with other cancer drugs. At this time, no beta-glucans have been approved by the FDA for use in the treatment of disease.
Other β-glucans, such as β-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.[citation needed]
β-Glucan is also promoted as dietary supplement for weight loss, these claims are not well supported by research although β-glucans can have some effect on effective glycemic index and insulin response.
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