Medical Applications of Beta-Glucan

By Betül Gürünlü

Beta-glucan is a polysaccharide and an important food supplement that strengthens the immune system. Beta-glucan can be obtained from many food sources such as mushrooms, yeast, or oats. Beta-glucan has a therapeutic use in the treatment of many diseases, thanks to its immune system strengthening effect. Its use helps curtail the need for administering high levels of antibiotics in case of serious infections. This book presents information about the medical applications of beta-glucan. Starting with an introduction to the basic biochemistry and classification of beta-glucan, the contents explain the readers about its use in treating a variety of medical conditions. These include cancer, allergies, COVID-19, respiratory tract infections, hypercholesterolemia, diabetes and many other other endocrinological, immunological and infectious diseases. This book is a comprehensive resource about the medical use of beta-glucan where any reader can find topical information and learn about recent studies on the therapeutic effects of beta-glucan on the treatment of different diseases.

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Jun 1, 2003
• ISBN: 9789815039238

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Introduction To β-glucans

Betül Gürünlü

Postdoctoral Researcher at Istanbul Technical University

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Correspondence: All the correspondence: [e-mail]

Introduction

Generally, β -glucan is a chemical name of a polymer of β -glucose. The therapeutic effect of β-glucans (beta-glucan) has long been known. Mushrooms are sacred food in ancient Egypt and used for prolonging life three thousand years ago. The medicinal usage of mushrooms that are a major source for β-glucans were mentioned in the texts in India dating back 500 years [1]. US Food and Drug Administration (FDA) recommends an intake of 3 g/day of β-glucan as cholesterol-reducing foodstuffs in 1997 [2]. American Diabetes Association (ADA) pointed that main aim should be kept the LDL-cholesterol (LDL-C) level less than 2.6 mmol/l (100 mg/dl) in individuals without overt cardiovascular disease (CVD). It also has a strong anti-oxidative property which helps in overcoming the problem of oxidative stress of the human body. β-glucan also reduces the chronic fatique syndrome and inhibits the cancer development.

β-glucan is a soluble fiber obtained from the cell walls of bacteria, algae, yeast, fungi, and plants. Also, to a lesser extent in rye and wheat. There are two main types of β-glucan: yeast and mushroom derived type that consisting of 1,3 and 1,6-glucan linkages and oats and barley derived type that including 1,3 and 1,4 linkages [3]. The biological activity of the yeast derived β-1,3/1,6-glucan is greater than the 1,3/1,4 counterparts.

Β-glucans have a long history as nonspecific biological modulators. β-1,3-glucan strenghtens the immune system and protect the body against the bacteria, viruses, fungi, and parasites by boosting the fighting ability of macrophages, neutrophils, and natural killer cells [4, 5].

Classification of β-glucans

β-Glucans are glucose polymers that naturally occur in yeasts, molds, algae, mushrooms, bacteria, oats and barleyas shown in Fig. (1) [6, 7]. The health benefits associated with consuming β-Glucans-rich foods include lowering blood glucose, insulin, and blood lipids, in particular serum total and low density lipoprotein (LDL) cholesterol. Some of these effects have been shown to depend on the capacity of β-Glucan to increase the viscosity (defined as a measure of re-

sistance to flow) of intestinal contents, which in turn depends on physicochemical characteristics of β-Glucan such as molecular weight (MW) and solubility. In microbial sources, they are a structural component and in grain sources, they are found in the endospermic and aleuronic walls [8-10].

Fig. (1))

Classification of sources of β-glucan.

The structural features of β-glucans are important determinants of their physical properties and functionality, including their physiological responses [11]. The molecular size and fine structural features of β-glucans play an important role on the solubility and chain conformation or shape, and hence on their rheological properties in solution. Structural differences, biological sources and molecular masses are presented in Table 1.

Table 1 Beta-glucan types and structural differences [15].

Structurally, β-glucans are comprised of glucose units linked together by several different types of beta-glycosidic linkages (Fig. 2). In the basic form, the molecule is a polymer of monosaccharide residues. β-glucans are composed of β-D-glucose monomer units, which are held together by glycosidic linkages at differing positions (1,3), (1,4) or (1,6). This structure can be either branched or unbranched [12]. The monosaccharide units interconnect at several points to form a wide variety of different branched and linear structures [13]. The β-glucans source will determine if the molecule has branched structures and to what extent.

Fig. (2))

Structure of cereal β-glucans (1,3 1,4) and non-cereal β-glucans (1,3 1,6).

The fine structure of β-glucans can vary in meaningful ways that modify its effects and mechanisms of action. A variance will occur between glycosidic linkages, molecular weight, branching, degree of polymerization, and solubility. β-glucans from different sources will have different effects or functions [14].

The MW, water retention properties, and solubility of β-glucan have a huge impact on its viscosity and flow behavior [16]. β-glucan is very hydrophilic due to the abundance of hydroxyl groups that participate in hydrogen bonding with water and give the molecule an ability to hold water in both soluble and insoluble forms [17, 18]. Solubility also depends on the MW that influencing by the chain length and degree of branching in the molecule. Two other phenomena that affect the molecular weight of β-glucan, namely self-association and aggregation, are dependent on certain physicochemical properties such as the conformation, the molar ratios of trimers and tetramers in the molecules, and the hydrodynamic radius [19].

β-glucans can be divided into two sub-groups, namely cereal and non-cereal (Fig. 3). Cereal or grain derived β-glucans usually have 1,3 1,4 glycosidic linkages without any 1,6 bonds or branching [20-22]. They are fibrous structures found in aleurone (proteins stored as granules in the cells of plant seeds), in the sub-aleurone layer and the cell wall of endospores [23]. Cereals include oat, barley, wheat and rice [23].

Fig. (3))

Sources and mechanisms of β-glucans dependent on structure. (a) cereal β-glucans; in the panel (b) non cereal β-glucans.

Regardless of source cereal β-glucans share similar structures, some differences include variation in 1,3 1,4 linkage ratio, molecular size, and some have large cellulose structures [24, 25]. β-glucan content also varies among cereal sources—there is higher glucan content in barley then oats, the least is found in rice and wheat [26].

Non-cereal β-glucans are fibrous structures found in yeast, fungi, bacteria, and algae [27]. β-glucans originating from yeast have linear (1,3) backbones with long chains of 1,6 branching [21, 28, 29]. Unlike grain β-glucans, fungal β-glucans differ between species concerning the degree of branching and distribution.

Fungi Based β-glucans

β-glucan, the most abundant fungal cell wall polysaccharide, has gained much attention from the scientific community in the last few decades for its fascinating but not yet fully understood immunobiology. Study of this molecule has been motivated by its importance as a pathogen-associated molecular pattern upon fungal infection as well as by its promising clinical utility as biological response modifier for the treatment of cancer and infectious diseases.

Fungal β-glucans, that represent the most abundant polysaccharides found in the cell wall of fungi, are mainly characterized by the presence of β(1,6)-linked branches coming off of the β(1,3) backbone as demonstrated in Fig. (4). β-glucans of mushrooms have short β(1,6)-linked branches whereas those of yeast have β(1,6)-side branches with additional β(1,3) regions [30]. Briefly, fungal β-glucans are made of straight β (1→3) glucan with short-branched chains connected through β (1→6) [31-33]. The structural diversity also depends on the fungal source [34].

Fig. (4))

General molecular structure of mushroom derived β-glucans.

A popular mushroom known as Agaricus blazeii is native to a small area of the mountains of Brazil near Sao Paulo. More recently, apparent lower incidences of cancers, viral and bacterial-induced illnesses, and increased life spans seen in people living in a small area of the mountains of Brazil near Sao Paulo were attributed by some to the ingestion of this popular local mushroom known as Agaricus blazeii [35]. There are at least 700 species of mushrooms like A. blazeii that are considered to possess medicinal properties [36, 37]. Their immune effect is attributed to the ability to bind to different receptors expressed on the cell surface of phagocytic and cytotoxic innate immune cells, including monocytes, macrophages, neutrophils, and natural killer cells. The characteristics of the immune responses generated depend on the cell types and receptors involved.

Lentinan, a (1,6)-branched (1,3)-β-glucan isolated from Japanese mushroom Lentinus edodes reduces Mycobacterium tuberculosis infection in mice and rats infected intraperitoneally and intranasally, respectively. Mouse peritoneal or rat alveolar macrophages show an increased acid phosphatase activity, free radicals production, and killing activity against M. tuberculosis [38, 39]. The antitumor activity of GRN, a (1,6)-branched (1,3)-β-glucan obtained from mycelia of Grifola frondosa, is reduced when macrophage function are impaired with carrageean, suggesting a key role of macrophages in the antitumor-mediated mechanism [40]. Peritoneal macrophages isolated from intraperitoneally lentinan-treated mice have a higher in vitro antitumor cytotoxic activity against murine or human target cells [41].

Oral administration of L. edodes and G. frondosa counteract the inhibition of the chemotactic activity of macrophages induced by the carcinogen BBN (N-butyl-N-butanolnitrosoamine) [42]. Blockage and inhibition in mice of dectin-1 expression on macrophages with mAbs, decrease the antitumor activity of SPG, a (1,6)-branched (1,3)-β-glucan from S. commune [43]. Moreover, intravenous administration in mice of β-glucan isolated from S. cerevisiae strain reduces the colon 26-M3.1 carcinoma cell growth and increases the survival time of the tumor-bearing mice. These effects are associated with a higher production of pro-inflammatory cytokines and tumoricidal activity of peritoneal macrophages as well as an increased NK cell cytotoxicity [44]. Orally administered β-glucan can enhance the tumoricidal activity of phagocytes toward iC3b-opsonized cancer cells.

Barley and Oats Based β-glucans

β-Glucans are soluble fiber found in many cereal grains; they are large linear polysaccharides of glucose monomers. Specifically, the mixed linkage (1→3, 1→4)-β-D-glucans are linear homopolymers of D-glucopyranosyl residues. Barley grain is an excellent source of soluble and insoluble DF and other bioactive constituents, such as vitamin E (including tocotrienols), B-complex vitamins, minerals, and phenolic compounds [45, 46]. Beta-glucans, the major fibre constituents of barley, have been implicated in lowering plasma cholesterol, improving lipid metabolism, and reducing glycaemic index [47-52]. Among these sources, barley typically has the highest beta-glucan content and oats the second highest [53]. Barley is considered to be the richest source of bGs that account for approximately 75% of the total cell wall polysaccharides in the endosperm cell walls; the rest consists of arabinoxylans, cellulose, glucomannans, and proteins. In barleys with low of content β-glucans, levels were relatively higher in the subaleurone region than the endosperm, whereas barleys with average to high content of β-glucans contained more β-glucans in the endosperm than the subaleurone.

The recent focus and renewed interest in barley as a human food are largely due to the health benefits attributed to bG. The bG content of barley can range from approximately 2% to 11%, which is generally higher than oats (2.2–7.8%) and wheat (0.4–1.4%). Barley grain is notable for a high content of β-glucans that ranges from 2.5% to 11.3%. The level of β-glucans in oats (2.2–7.8%), rye (1.2–2.0%), and wheat (0.4–1.4%) may also vary substantially, but it is generally lower than in barley [54]. The content of β-glucans in barley is influenced by both genetic and environmental factors and the interactions between the two [55]. The US Food and Drug Administration (FDA) has recently allowed whole grain barley and barley-containing products to carry a claim that they reduce the risk of coronary heart disease [56].

Mixed linkage (1 → 3,1 → 4)-β-d-glucans, commonly known as β-glucans, are linear homopolymers of d-glucopyranosyl (Glcp) residues linked mostly via two or three consecutive β-(1 → 4) linkages that are separated by a single β-(1 → 3) linkage. Less frequent are longer segments of consecutively β-(1 → 4) - linked Glcp with degree of polymerization (DP) 5–20 [54, 57, 58]. General molecular structure of barley derived β-glucans and hydrolysis products obtained upon digestion of β-glucans with lichenase were given in Fig. (5).

Fig. (5))

General molecular structure of barley derived β-glucans and hydrolysis products obtained upon digestion of β-glucans with lichenase.

The molecular features of β-glucans are usually construed from the analysis of the oligomers obtained by digestion of the polymers with a specific (1→3, 1→4)-β-D-glucanohydrolase that releases 3-O-β-D-cellobiosyl-D-glucose (trisaccharide unit, DP3) and 3-O- β-D-cellotriosyl-D-glucose (tetrasaccharide unit, DP4) accounting for 90–95% of the total oligosaccharides, and longer oligosaccharides (DP≥5) accounting for 5–10% of the total oligosaccharide chain segments. Differences in the proportions of tri- and tetrasaccharides, observed among different β glucans from various sources and reflected in the molar ratio of cellotriose to cellotetraose units (DP3/DP4), follow the order of wheat (3.0-4.5), barley (1.8-3.5), rye (1.9-3.0) and oats (1.5-2.3); this ratio is considered to be a main fingerprint of the structure of cereal β-glucans.

Yeast Based β-glucans

Yeast (e.g., curdlan, zymosan, pachyman, and scleroglucan) is a good source of β-glucans that are present in the cell walls as branch-on-branch molecules containing linear (1,3)-β-glucosyl chains joined through (1,6)-linkages [59]. Spray-dried yeast β-glucans are useful for food production, as food thickeners, replacers, dietary fibers, emulsifiers, and films [60]. Furthermore, yeast glucans have important properties as water-holding, fat-binding, and oil-binding characteristics, as well as gelling properties [61]. For these reasons, they can also be used in the production of sausages and meat products, mayonnaise, and other food products, such as dressings, frozen desserts, sauces, yogurts, and other fermented milks and soft doughs [62]. They are safe for oral application and have a GRAS (generally recognized as safe) status. Optimized yields of β-glucan extracted from baker’s yeast (Saccharomyces cerevisiae) gave only 5%–7% [63]. Β-glucans from yeasts (e.g., Saccharomyces cerevisiae) are mixtures of linear β (1→3) backbones with 30-residue straight chains and connected to these are long branches attached via β (1→6) linkages [33].

Beta Glucan Synthesis from Yeast

In Saccharomyces cerevisiae, two classes of alkali-insoluble β-glucans exist. (1→3)- β-Glucan, making up approximately 25% of the cell wall dry weight, has a degree of polymerization estimated as 1500 residues and is attached predominantly as 1→3 linkages and branched with occasional 1→6 linkages [64]. (1→6)-β-Glucan is a more complex, smaller, alkali-insoluble polymer with an average degree of polymerization of 140 residues and makes up approximately 7% of the cell wall dry weight [65]. It is composed of a 1→6-linked core, branched by occasional 1→3 linkages, with 1→6 side chains providing many terminal glucopyranosyl residues [66]. Despite the natural abundance of these polymers and the apparent simplicity of their structure as glucose homopolymers, little is known about the mechanism of β-glucan biosynthesis. In yeast both chitin and glycogen synthesis use more than one synthase gene, and the resulting functional redundancy has complicated a genetic analysis. Roemer and Bussey described an S. cerevisiae gene, KRE6, that encodes a predicted type II membrane protein involved in beta glucan synthesis in vivo and is required for full activity of beta-glucan synthase in vitro [64].

β-glucans and Cancer

Today, β-glucans are widely marketed as biologically active compounds that have the potential to improve health [67]. Of therapeutic importance, β-glucans have potentially important metabolic and gastro-intestinal effects, modulating the gut microbiome, altering lipid and glucose metabolism, reducing cholesterol, leading to their investigation as potential therapies for metabolic syndrome, obesity and diet regulation, gastrointestinal conditions such as irritable bowel, and to reduce cardiovascular and diabetes risk. β-glucans also appear to have immune-modulating effects, leading to their investigation as adjuvant agents for solid cancers and haematological malignancies, for immune-mediated conditions, such as allergic rhinitis and respiratory tract infections, and to enhance wound healing. Two glucan isolates were licensed as drugs in Japan as an immune-adjuvant therapy for cancer in 1980 [68, 69]. As an immunomodulating agent, β-glucan acts through the activation of innate immune cells such as macrophages, dendritic cells, granulocytes, and natural