Beta-Glucan as a Soluble Dietary Fiber Source The efficacy and function of yeast β - glucan

Keywords: β-glucan, cereals, fungus, microbes, bioavailability, biofunctionalities, industrial applications

Table 1.

Different sources of β-glucan and their molecular characterization.

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Table 2.

Genes involved in the synthesis of β-Glucan in cereals.

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4.1. Advances in Extraction Procedure

The achievement of high-purity β-glucan is a critical concern for both laboratory and commercial applications. This focus is particularly on factors such as purity, molecular integrity, and yield. The extraction method used plays a significant role in determining the molecular weight and structural characteristics of β-glucan. Discrepancies in the estimated molecular weight of β-glucan can result from variations in extraction and purification procedures, aggregation phenomena, and depolymerization events that occur during the extraction process. Consequently, extraction methods should aim to maintain the integrity of the β-glucan molecules while maximizing both yield and purity to effectively assess the structural properties of the isolated β-glucans. Since β-glucan's discovery, numerous extraction techniques have been developed and optimized to enhance yield. Common wet extraction methods include aqueous, alkaline, acidic, and enzymatic techniques. Among these, hot water extraction is the most widely utilized. However, wet extraction methods have their drawbacks, including lengthy extraction times, high operational costs, and environmental concerns. These methods use water, acidified water, or alkali to solubilize β-glucan by hydrolyzing whole grains such as barley or oats. After solubilization, centrifugation and ethanol precipitation are employed to separate the β-glucan from the slurry. The use of ethanol may inhibit native enzymes, which can lead to the removal of nonpolar molecules and the dissociation of proteins and sugars. Following the initial rough extraction, further refinement is performed to eliminate contaminants like starch, protein, and fat. Various extraction and purification techniques for β-glucan are illustrated in Figure 3. Alternatively, dry separation techniques such as pearling and air classification are commonly employed to avoid using solvents. However, these dry techniques typically result in lower β-glucan recovery rates (less than 30%) compared to wet methods, which can achieve a recovery range of 20 to 70%.

Figure 3.

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Extraction and purification of β-Glucan, along with the factors influencing their extraction and purification. Abbreviations: EtOH: ethanol, HClO₄: perchloric acid, Vol.: volume, NaOH: sodium hydroxide, HCl: hydrochloric acid, C₂H₃NaO₂: sodium acetate, dd H₂O: double distilled water, Ppt.: precipitates, Sup.: supernatant.

A commercially viable and environmentally friendly extraction process for β-glucan would address the challenges currently faced in its extraction. Recently, two innovative techniques—superheated water extraction and rapid solvent extraction—have been developed. These methods are not only commercially viable but also environmentally friendly, and they offer improved yields of β-glucan.

Choosing the appropriate extraction technique depends on several factors, including the source of raw materials, the desired purity levels, and cost considerations (see Supplementary Table S2). Different cereals have varying β-glucan content and extraction efficiency, with barley and oats being the top sources, followed by wheat, rye, and corn.

Particle size is a crucial factor, as smaller particle dimensions increase surface area and enhance extraction efficiency. The choice of extraction solvent is also important; water, ethanol, and acetone are commonly used, depending on the type of β-glucan and the purity goals.

Moreover, adjusting the pH of the extraction solution has a significant effect on β-glucan solubility, with alkaline solutions proving more effective than acidic ones. Temperature is another critical factor, as it affects the extraction rate. However, it must be carefully controlled to avoid degrading β-glucan.

The enzymatic content in the extraction solution should be inactivated using heat treatment or enzyme inhibitors. Extraction time influences β-glucan yield significantly—longer extraction times generally result in higher yields, although they also increase the risk of damaging the β-glucan.

It is important to note that solubilized β-glucan is vulnerable to molecular fragmentation caused by shear forces during mixing and centrifugation, as well as enzymatic degradation from intrinsic β-glucanases present in the solution. This enzymatic breakdown and shear-induced fragmentation can lead to reduced molecular weight and viscosity of the β-glucan, compromising its potential cholesterol-lowering and blood sugar-lowering effects.

In the following sections, we will discuss some commonly used techniques for extracting β-glucan in detail.

4.2. Advances in Purification Procedure

Recent advancements in β-glucan purification have significantly elevated the field, leading to innovations that have transformed its separation and refinement processes. These breakthroughs have increased the purity of β-glucan, making it suitable for a broader range of applications. Researchers have utilized cutting-edge techniques to enhance the efficiency and precision of β-glucan purification, effectively addressing challenges related to impurities and yield. One common method for purifying β-glucan involves using a suitable solvent to induce precipitation, with ethanol being the most widely used due to its compatibility with water. The precipitation process occurs in two sequential steps: first, β-glucan is dissolved in the solvent, and then β-glucan molecules aggregate and precipitate due to the solvent's nonpolar nature. To isolate the precipitate from the solution, centrifugation or filtration is employed. The choice of solvent is influenced by the solubility of β-glucan; when water fails, ethanol or acetone can be used as alternatives. Despite this, water generally remains the ideal solvent for β-glucan precipitation. The concentration of β-glucan in the solution directly affects the effectiveness of the precipitation process, as higher concentrations increase the likelihood of successful precipitation. This method is notably fast and cost-effective, efficiently removing various impurities from β-glucan solutions, although time constraints and the potential risk of β-glucan degradation may limit its application. Dialysis is another purification technique that separates molecules based on size. In β-glucan purification, dialysis involves passing the solution through a semipermeable membrane that allows small molecules and water to pass while blocking β-glucan. Cellulose acetate membranes are commonly used for this purpose, as they are impermeable to β-glucan while allowing the passage of water and small molecules. Dialysis is a gentle method for removing contaminants from the β-glucan solution, often followed by ethanol and ammonium sulfate precipitation. Additionally, dialysis can extract glucose, peptides, and amino acids from β-glucan, thus increasing the final product's purity. While dialysis is time-consuming and may not be ideal for large-scale production, it produces a product with superior purity and viscosity compared to alternative methods. Nonetheless, this approach requires additional time and specialized equipment. Ultrafiltration has emerged as a time-saving purification method that uses semipermeable membranes with pore sizes ranging from 250 to 500 nm. This method employs strong shear forces, resulting in reduced viscosity and molecular weight of β-glucan. Among the various techniques explored, a combination of alcohol extraction and ammonium sulfate precipitation has been particularly effective, achieving a remarkable 91.38% purity, despite a moderate yield. Chromatography has also become a well-regarded method for β-glucan purification, providing meticulous separation of its constituents. Gel filtration chromatography is a popular choice, involving columns filled with porous gel matrices of varying sizes. β-glucan molecules adhere to these matrices based on their size, allowing for the sequential elution of smaller and larger molecules. Although this technique is highly effective at enhancing β-glucan purity, it poses challenges in terms of time and cost. Furthermore, chromatography is a more complex approach that requires suspending the β-glucan solution in a solid matrix column; the specific binding of solution components to the matrix facilitates separation through solvent elution. Various chromatographic methods, such as gel filtration, ion exchange, and affinity chromatography, can be tailored to the unique characteristics of β-glucan and the desired purity levels. In summary, recent innovations in β-glucan purification have greatly improved its purity and versatility across various industries. Techniques such as precipitation, dialysis, ultrafiltration, and chromatography effectively address challenges related to impurities and yield. While precipitation is speedily cost-effective, dialysis offers superior purity, ultrafiltration reduces viscosity, and chromatography ensures precise separation. However, all these methods require time and resources, which must be taken into consideration.

7.1. Mechanism of Hypoglycemic Effect

Diabetes is a chronic condition characterized by elevated blood sugar levels and is known to be a precursor to various cardiovascular diseases, including hypertension, coronary artery disease, peripheral vascular disease, and atherosclerosis. The World Health Organization (WHO) reports a concerning increase in the global prevalence of type II diabetes. The causes of diabetes are multifaceted, involving factors such as dysfunctional beta (β) cells, insulin resistance, abnormal mitochondrial activity, and cell death (apoptosis).

β-glucan has emerged as a crucial agent in improving insulin activity and lowering postprandial blood glucose levels. Researchers have been investigating the health benefits of β-glucans derived primarily from cereals like barley and oats. These compounds have gained attention for their ability to lower blood sugar and cholesterol levels while modulating insulin responses. Barley, in particular, is notable for its low glycemic index compared to other cereals, making it a valuable dietary choice. For instance, adding just 4 grams of barley-derived β-glucan to chapattis reduced their glycemic index from 54 to 30. The mechanism behind this effect involves β-glucan acting as dietary fiber (DF), which delays gastric emptying and slows the release of glucose, ultimately leading to lower blood glucose levels. Oat-derived β-glucan has similarly demonstrated the capacity to lower blood sugar and insulin levels. It has also been observed that oat β-glucan can hinder enzyme activity, resulting in decreased starch digestion and lower postprandial glucose levels. Its gel-forming properties in the small intestine delay the interaction of digestive enzymes with nutrients, reducing the absorption of glucose and temporarily lowering peak postprandial blood glucose concentrations.

In addition to its glycemic control properties, β-glucan has been linked to the reduction of menaquinol, a form of vitamin K2 associated with type 2 diabetes. Studies have shown that incorporating natural oat products rich in β-glucans into the diets of individuals with diabetes can improve glucose levels, especially when consumed in higher daily doses.

As a dietary fiber, β-glucan avoids digestion in the small intestine and is fermented in the large intestine, producing short-chain fatty acids (SCFAs). These SCFAs help maintain gut pH and regulate the secretion of gut hormones, playing a significant role in signaling satiety. Research has demonstrated the anti-diabetic potential of β-glucans, showing reductions in cholesterol, triglycerides, and glucose levels in obese rats. Oat β-glucans have been found to decrease the activity of key intestinal disaccharidases, thereby lowering glycemic responses in a dose-dependent manner in both in vivo and in vitro studies, especially when these sugars are mixed with high-viscosity β-glucan gel. The viscosity of this gel is inversely correlated with spikes in post-meal blood glucose. Studies involving mice suggest that the effects of endogenous β-glucanases on hyperglycemia and LDL cholesterol management remain unaffected by the incomplete hydrolysis of barley β-glucans. Additionally, the expression of the enzyme α-glycosidase is inhibited, and the expression of glucose transporters SGLT1 and GLUT2 is reduced. These factors help regulate carbohydrate absorption and elevate GLP-1 levels.

A meta-analysis encompassing 17 trials with 68 distinct protocols and 212 individuals found that the consumption of barley β-glucan significantly reduced postprandial glycemic reactions, indicating a scientifically meaningful reduction in blood sugar levels.

Overall, β-glucans from cereals like barley and oats show great promise in managing blood sugar and cholesterol levels and improving insulin responses through various mechanisms. This makes them a topic of considerable scientific interest and potential clinical relevance. Future research could explore personalized β-glucan interventions, clarify specific molecular pathways, and develop innovative β-glucan-enriched food products to optimize glycemic control, cholesterol management, and metabolic health for individuals with diverse dietary and genetic profiles.

7.2. Mechanism of the Cholesterol Lowering Effect

Dyslipidemia, a chronic condition characterized by elevated lipid and cholesterol levels in the bloodstream, poses a significant risk for the development of life-threatening diseases such as myocardial infarction, ischemic and hemorrhagic stroke, and atherosclerotic vascular disease. It is imperative to investigate potential treatments to mitigate the rising mortality associated with dyslipidemia. The American Heart Association reported that 11.7% of individuals aged 20 or older, totaling 28.5 million people, have blood total cholesterol levels exceeding 240 mg/dL [54]. β-glucan emerges as a promising therapeutic agent, acting through multiple mechanisms to combat dyslipidemia. These mechanisms include reducing blood cholesterol levels, slowing bowel transit time, preventing constipation, increasing SCFA production, enhancing the growth of beneficial gut microbes, and reducing the risk of colorectal cancer.

One pivotal action of β-glucan is its ability to bind with bile acids, facilitating their excretion. This, in turn, reduces plasma cholesterol and bile acid levels. An increased elimination of bile acids promotes cholesterol metabolism in the liver, lowering lipid absorption and decreasing plasma cholesterol levels. Moreover, the fermentation of β-glucan in the large intestine produces acetate and butyrate, which inhibit cholesterol biosynthesis. β-glucan also participates in the degradation of LDL cholesterol. Recent research demonstrates that a daily intake of 3 g of β-glucan effectively lowers LDL cholesterol without significantly affecting high-density lipoproteins [55]. Furthermore, the high viscosity of β-glucan substantially impacts the absorption of cholesterol, fats, and other biomolecules in the gastrointestinal tract by increasing its viscosity. Incorporating fiber, particularly β-glucan-rich sources, into the diet offers a dual benefit: lowering serum cholesterol and reducing the intake of total fat, saturated fat, and dietary cholesterol [56].

The FDA has granted approval for the relationship between reduced blood cholesterol levels and increased DF absorption, specifically concerning psyllium and oat fiber. Notably, oat β-glucan supplementation has demonstrated a remarkable reduction in total cholesterol and LDL cholesterol by approximately 10% and 15% in a clinical trial involving slightly hypercholesterolemic individuals [57]. Further insights from studies involving oat-based diets in both rodents and humans suggest a link between increased acetate and butyrate levels and reduced cholesterol biosynthesis. Similarly, a comprehensive meta-analysis of 14 clinical studies reports a significant reduction in LDL cholesterol using barley β-glucan [58]. To delve into the mechanistic details, Ref. [59] explored hypercholesterolemic hamsters and observed that β-glucan from hull-less barley modulated the expression of key enzymes such as cholesterol 7-α hydroxylase (CYP7A1) and 3-hydroxy-3-methyl glutaryl-coenzyme A (HMG-CoA) reductase. This led to increased elimination of fecal lipids, resulting in decreased LDL cholesterol levels in the bloodstream. In vitro studies emphasize the significant impact of highland barley’s soluble DF in slowing cholesterol uptake, demonstrating a dose-dependent effect [60]. Human research, as exemplified by [61], indicates that the consumption of HB sprouts can enhance lipid metabolism and reduce the risk of cardiovascular disease, particularly in individuals with marginal cholesterol levels. In murine studies, the prolonged administration of highland barley β-glucan resulted in decreased serum total cholesterol, non-HDL cholesterol, LDL cholesterol, Lee’s index, and increased levels of SCFA. Similarly, mice subjected to higher doses of whole highland barley β-glucan exhibited reduced liver organ indices, abdominal fat, and liver lipid levels [62].

Notably, the molar mass of barley β-glucan plays a crucial role, with lower molar mass showing a 13% decrease in LDL cholesterol at a dosage of 5 g/day, while higher molar mass displays a 15% reduction [63]. An interesting dosage-dependent effect was observed in beverages fortified with β-glucan; the 5 g dose effectively lowered LDL and total cholesterol, whereas the 10 g dose did not [64], highlighting the significance of higher molar masses due to the solubility of solutions. A study was conducted with 29 hypercholesterolemia (early stage) children aged 6-14 years. This experiment assessed the performance of a packaged cereal containing β-glucan, including a minimal saturated fat and cholesterol intake, for lowering LDL cholesterol levels in children. In the initial four weeks, the children were kept on a diet of 3 g/d of β-glucan, and for the next four weeks, the children were provided with a substitute. In participants who were at least 80% in accordance (n = 18), total and soluble DF levels rose extensively (26.7%, p~0.01 and 30.8%, p~0.02, respectively), while LDL sank to an average of 5.3% (p~0.03). Individuals with a BMI under the median (25.7 kg/m²) had the greatest decrease in LDL levels(9.2%, p< 0.001) [65]. The β-glucan effects on the lipid profile, glycemia, and intestinal health (BELT) study looked into how 3 g of oat β-glucan per day affected plasma lipids, glucose levels in the fasting state, and intestinal sanity. The study took place in an 8 week, double-blind, placebo-controlled, cross-over randomized clinical experiment that enrolled 83 Italian adults who followed a Mediterranean diet and had mild hypercholesterolemia and narrow cardiovascular disease prospects. The BELT research shows an intermediate effectiveness of 3 g/day β-glucan supplementation in lowering LDL, total cholesterol, and non-HDL levels in moderate hypercholesterolemic patients despite being a Mediterranean culture [66].

Barley β-glucans of Mw, 290 kDa and 1350 kDa, at two distinct dosages, 3 and 5 g, were the subject of a pair of studies that examined the consequences of their use. When β-glucans were added to ready-to-eat cereal and fruit juice in the first research, both high and low MW were effective at lowering LDL and total cholesterol after six weeks of use in comparison to the control products without β-glucans. The second trial offered participants a breakfast of β-glucan-infused crepes, tortillas, oatmeal, or chips for five weeks. A substantial decrease in circulating total cholesterol was seen only with high β-glucan products, instead of the control goods made with wheat and rice. They concluded that the cholesterol-lowering benefits of β-glucans are determined by their physicochemical features (i.e., Mw) rather than their daily consumption [67]. Ref. [68] conducted a study where β-glucans were incorporated in a variety of dietary products, resulting in a noticeable reduction of LDL and TC. Another study that looked at administering 5 or 10 g of β-glucans to a beverage to supplement the typical diet for eight weeks found that β-glucans from oats instead of barley drastically dropped total cholesterol concentrations [64].

Research exploring the beneficial effects of β-glucans from various sources in dyslipidemia management is in its nascent stages, often involving small-scale clinical trials. The transition to large-scale trials for validation is essential. While the potential of β-glucans in dyslipidemia management is promising, significant questions persist. Detailed investigation into the influence of β-glucan properties, optimal dosage levels, and interactions with other dietary components is imperative. This knowledge will enable more precise and efficacious interventions for cholesterol management, ultimately reducing the risk of cardiovascular disease.

7.3. Mechanism of Immunomodulatory Effect of β-Glucan

The immune system is our body’s defense mechanism against invading pathogens and diseases. It comprises two primary components: the innate immune system and the adaptive immune system. The innate immune system acts rapidly and non-specifically against pathogens and includes cells like monocytes (macrophages), mast cells, dendritic cells, and complement proteins. These cells respond swiftly through mechanisms like phagocytosis, opsonization, and the release of cytokines, aiding in the differentiation of lymphocytes. On the other hand, the adaptive immune system, involving B and T lymphocytes and Natural Killer (NK) cells, provides a highly specific and long-lasting immune memory. B cells contribute to humoral immunity by producing antigen-specific antibodies, while T cells induce cytotoxic responses by secreting cytokines and chemokines.

A critical component in the realm of immunomodulation is β-glucan, a polysaccharide found in various sources, including cereals, fungi, and bacterial cells. This remarkable compound can serve as an adjuvant, generating immune signals. Its immunomodulatory effects are due to its recognition as a pathogen-associated molecular pattern (PAMP) by cell surface receptors known as pattern recognition receptors (PRRs). The innate immune system is the first line of defense, where β-glucan primarily exerts its influence. One key PRR that interacts with β-glucan is Dectin-1, which is expressed on myeloid cells like neutrophils, macrophages, and dendritic cells. Dectin-1 possesses an extracellular C-type lectin-like carbohydrate-recognizing domain (CRD), a transmembrane domain, and a cytosolic intracellular immune receptor tyrosine-based activation motif (ITAM). It has been demonstrated that Dectin-1 specifically recognizes a particular structural configuration of glucans, particularly β-glucans, with a minimum of seven glucan monomers in the backbone and one side chain branch. This recognition triggers downstream signaling that results in immune responses such as phagocytosis, respiratory burst, microbial cell destruction, and the secretion of cytokines [69].

Another receptor that interacts with β-glucan is Complement Receptor 3 (CR3), found on neutrophils, NK cells, and monocytes. CR3 plays a crucial role in the phagocytosis and opsonization of tumor cells through the binding of inactivated complement protein (iC3b). To activate CR3, β-glucan must bind to both β-1,3 glucan and iC3b. This interaction recruits NK cells and other phagocytic cells to the site of inflammation, stimulating phagocytosis and degranulation of opsonized complexes with iC3b, ultimately leading to the death of tumor cells. Toll-like receptors (TLRs) are another group of PRRs that recognize and bind to pathogen-associated molecular patterns (PAMPs). TLRs play a crucial role in activating both the innate and adaptive immune systems. Lactosylceramide, a glycosphingolipid found on the plasma membrane of immune cells, binds to β-glucan, triggering an immune response by inducing respiratory burst and secreting cytokines. β-glucan influences innate immunity and shapes the balance between T Helper (Th) 1 and Th2 cells. Maintaining this balance is essential, as an imbalance can lead to allergies and autoimmune diseases. β-glucan plays a role in shifting this equilibrium towards Th1 cells, reducing the risk of allergic diseases by altering the Th1/Th2 balance [70]. A study examined the impact of brewers’ yeast (1,3)-(1,6)- β-D-glucan ingestion on the frequency of common cold events in normal individuals. The current investigation showed that yeast β-D-glucan preparation improved the body’s ability to resist attacking bacterial and viral infections [71]. Grifola β–glucan can stimulate the growth of NK cells and lymphocytes in immunocompromised mice treated with cyclophosphamide (CTX). Grifola β–glucan may help safeguard mice from reduced immunity and bone marrow degradation resulting from cyclophosphamide by increasing the activity of kinases and transcription factors like p-Jak2/Jak2, p-Stat3/Stat3, and Socs3) in the Jak2/Stat3/Socs signaling cascade [72]. Another research sought to examine the influenced-by-time implications of oat beta-glucans affecting colon apoptosis and autophagy in the CD (Crohn’s disease) rat. Daily consumption of (high-molar-mass oat β-glucans) βGl and (high-molar-mass oat β-glucans) βGh dramatically decreased colitis through the time-varying alteration of autophagy and apoptosis, with βGl having a larger impact in apoptosis and βGh over autophagy. The pathway followed could be explained by the responsiveness of receptors like Dectin-1 and TLRs [73]. Taken together, β-glucan’s immunomodulatory effects are multifaceted and intricate, impacting various immune system components. Through interactions with PRRs, such as Dectin-1, CR3, and TLRs, β-glucan initiates a cascade of signaling events that activate immune cells and the secretion of various cytokines and chemokines. This intricate network of interactions and signaling pathways ultimately leads to enhanced immune responses, making β-glucan a promising agent for immune modulation and disease prevention. Future research should focus on optimizing the use of β-glucan as an immunomodulatory agent, exploring its potential in treating autoimmune diseases, and uncovering its interactions with other immune components. Additionally, more studies are needed to understand the specific mechanisms involved in β-glucan’s immunomodulation.

7.4. As a Potential Anticancer Molecule

Cancer, a highly intricate and multifaceted group of diseases characterized by uncontrolled cellular proliferation, poses formidable challenges in the realm of treatment. It stands as the second leading cause of mortality worldwide, responsible for approximately one in every six deaths [74]. Annually, there are nearly 19.3 million reported new cancer cases, resulting in approximately 10 million global fatalities [75]. The current gold-standard therapies, including surgery, chemotherapy, and radiotherapy, are associated with considerable side effects and yield a less-than-ideal prognosis.

β-glucan exerts potent anticarcinogenic effects by stimulating the host’s immune system, thereby thwarting oncogenesis and inhibiting tumor metastasis. Its anticancer impact stems from a multi-faceted approach involving direct tumor inhibition, immune system enhancement, and inherent anticancer properties. Various factors influence its antitumor efficacy, including the source, molecular structure, branching pattern, and chemical modifications of β-glucan. The remarkable repetitive structure of β-glucans enables them to bind to specific receptors on the membranes of immune cells, eliciting a robust anti-tumor response. This binding activates innate immunity, leading to accelerated antigen presentation, increased production of reactive oxygen species (ROS), enhanced phagocytosis, and the secretion of critical cytokines [76]. The secreted cytokines play a pivotal role in activating both B cells and T cells, thereby initiating adaptive immunity through humoral and cell-mediated immune responses, respectively.

To maximize the effectiveness of β-glucan’s anticarcinogenic properties, precise delivery throughout the body and the immune system is essential, underscoring the importance of understanding β-glucan trafficking [77]. Predominantly, oral administration serves as the primary mode of β-glucan delivery, although intraperitoneal (IP) and intravenous (IV) administration are also employed, albeit less frequently [77]. Following oral administration, β-glucans enter the proximal small intestine, where they are phagocytosed by intestinal epithelial cells or pinocytic microfold cells (M-cells). Subsequently, β-glucan is transported from the intestinal lumen to immune cells in Peyer’s patches. Upon encountering β-glucan, gastrointestinal macrophages migrate to the lymphatic system via the bloodstream [78]. In lymph nodes, β-glucan activates dendritic cells, which capture and imprison damaged tumor cells in the tumor microenvironment. This process leads to the differentiation and activation of antigen-specific CD4+ and CD8+ T-cells. Degraded fragments of β-glucan further activate neutrophils by binding with CR3 and modulating hematopoietic myeloid progenitors in the bone marrow. These events collectively trigger CD3-dependent cellular cytotoxicity (CR3-DCC) in proximity to opsonized iC3b-coated carcinogenic cells [79]. Orally administered β-glucan not only accelerates respiratory bursts and the rate of phagocytosis but also enhances the secretion of crucial cytokines, including interleukin-1 (IL-1), IL-6, and TNF-α within macrophages. Additionally, it regulates the acute phase of humoral immunity and augments the activity of lysozyme and ceruloplasmin in animal models [80]. These multifaceted mechanisms underpin the promising potential of β-glucan in combating cancer and stimulating immune responses.

The tumor microenvironment (TME) is an intricate network of elements, including blood vessels, extracellular matrix, malignant cells, and non-malignant immune cells. β-glucan, derived from fungi, possesses the remarkable ability to modulate the TME by regulating both innate and adaptive immune signals. This modulation begins with the activation of the host’s innate immunity through the binding of β-glucan to PRRs, triggering the differentiation, activation, and deployment of specific acquired adaptive immune cells, crucial for the host’s defense mechanism [81]. Macrophages, particularly those within the TME, significantly influence cancer prognosis. Notably, β-glucan’s interaction with Dectin-1 on tumor-associated macrophages (TAMs) accelerates the transition of M1 macrophages, enhancing antigen presentation and Th1 cytokine secretion [82]. Furthermore, β-glucan extracts and ganoderic acid from G. lucidum exhibit direct cytotoxic properties by activating M1 macrophages and subsequently destroying HepG2 cells [83]. The progression of the tumor is also influenced by Myeloid-derived suppressor cells (MDSCs), a distinct class of immune cells. Yeast-derived whole β-glucan particles (WGP) lead to a reduction in polymorphonuclear-MDSCs (PMN-MDSCs) through enhanced respiratory burst and apoptosis. β-glucan also impacts B lymphocyte differentiation and activation, promoting the development of humoral immune responses via the secretion of cytokines such as IL-6, IL-8, and TNF-α, mediated by the activation of NF-κB and AP-1 [84]. However, tumor cells can limit dendritic cell antigen presentation by secreting IL-10 and vascular endothelial growth factor (VEGF), evading the immune response [85]. Astragalus polysaccharide (APS) enhances dendritic cell activation by upregulating MHC-II, CD-80, and CD86 on dendritic cell surfaces, promoting synergistic interactions between T cells and dendritic cells [86]. Moreover, the TME orchestrates a process to stimulate angiogenesis to enhance oxygen and nutrient supply and eliminate metabolic waste, countering the hypoxic and acidic microenvironment. Furthermore, sulfated derivatives of glucan from Phellinus ribs (PRP-S1 and PRP-S2) inhibit tumor angiogenesis by reducing VEGF expression [87]. In an experiment, 20 participants who had terminal malignant tumors were administered a β-(1,3)/(1,6) D-glucan formulation and evaluated for tolerance and impact on hematopoiesis during chemotherapy. The findings suggest that β-glucan may improve hematopoiesis in cancer victims undergoing chemotherapy [88]. When paired with chemotherapy, Grifola β–glucan reduced the dimensions of breast, lung, and liver tumors in more than sixty percent of the subjects in contrast to chemotherapy isolated [89]. Research conducted revealed that oat β-D-glucan can hinder HTB-140 melanoma cells by escalating the stimulation of caspase-3/7 along with the surge of phosphatidylserine towards the extracellular face of the plasma membrane, which suggests the ordination of mitochondrial apoptosis [90]. A low-MW oat β-glucan showed firm activity of caspase-12 against A431 and Me45 cancer cell lines, leading to apoptosis and thereby showing its potential anticancerous activity [91].

In summary, β-glucan holds immense promise in the fight against cancer by stimulating the immune system, inhibiting tumor growth, and modulating the TME. However, there remain gaps in our understanding of the optimal delivery methods and the precise mechanisms underlying β-glucan’s multifaceted actions within the TME. Future research should focus on refining the delivery strategies, elucidating the specific immune pathways involved, and exploring potential combination therapies to maximize β-glucan’s anticancer potential.

7.5. Apoptosis

Apoptosis, a vital process in multicellular organism development, is a regulated form of cell death. It primarily eliminates damaged cells with irreversible DNA damage, contributing to the organism’s overall health. Key apoptotic hallmarks include chromatin condensation, cell shrinkage, membrane blebbing, and the loss of contact inhibition. Two primary pathways, the extrinsic and intrinsic pathways, orchestrate apoptosis. The extrinsic pathway relies on external signals, like TNF family death receptors (e.g., FasL/FasR), which activate caspase-8 and caspase-3, ultimately causing cell death [92]. In contrast, the intrinsic pathway involves factors such as the Bcl-2 protein family, with anti-apoptotic (e.g., Bcl-2) and pro-apoptotic (e.g., BAX) members. Dysregulation of these proteins can lead to cancer.

Various studies have elucidated the potent mechanisms by which different β-glucan isoforms or crude extracts can stimulate apoptosis, offering promising avenues for anti-cancer interventions. Notably, β-glucans sourced from bacterial origins have demonstrated their ability to induce apoptosis in SNU-C4 cells, as confirmed by TUNEL assay validation. This pro-apoptotic effect is underpinned by the upregulation of caspase-3, Bax, and the downregulation of Bcl-2. Furthermore, these β-glucans induce dose-dependent changes in cell morphology, the formation of apoptotic bodies, and chromatin condensation [93]. Hot water extracts from Chaga mushrooms have been shown to elevate apoptosis in HT-29 colon cancer cells. This effect is attributed to the modulation of key apoptotic regulators, including increased Bax and caspase-3 levels, coupled with a reduction in Bcl-2 expression [94]. In another line of investigation, β-glucans derived from Agaricus blazei Murill have exhibited a multifaceted mechanism of apoptosis induction. This includes the acceleration of cytochrome-C release, enhanced p38 MAPK activity, Bax translocation to mitochondria, and the activation of caspase-9. These molecular events culminate in apoptosis induction and contribute to reduced metastasis in a mouse tumor model [95]. Studies with extracts from Inonotus obliquus have unveiled their inhibitory effect on B16-F10 melanoma cells and human hepatoma HepG2 cells. This inhibition is associated with G0/G1 cell cycle arrest, apoptosis induction, and a reduction in key regulatory proteins like p53, p27, pRB, cyclin, and CDK [96]. Notably, extracts from Ganoderma lucidum have exhibited the ability to enhance apoptosis in ovarian cancer cells. This effect is achieved through the modulation of Akt, p53, and caspase-3 activation [97]. Breast cancer cells expressing estrogen receptors have been effectively hindered from proliferation through the treatment with β-1,3 glucan from Lentinus edodes (LNT). This anti-proliferative effect is corroborated using Western blotting, which revealed elevated p53 levels, phosphorylated ERK1/2, PARP-1, caspase-3, and reduced levels of p65, NF-kB, TERT, and MDM2 in tumor cells [98]. Furthermore, oat β-glucan has demonstrated its potential to induce apoptosis in human skin melanoma HTB-140 cells in a concentration-dependent manner. This action is marked by enhanced caspase 3/7 activation and phosphatidylserine accumulation on the cell surface, both of which drive apoptosis [90]. Lastly, extracellular β-glucans isolated from botryosphaeran and lasiodiplodan have been shown to induce oxidative stress in MCF-7 cells. The underlying mechanism of β-glucan-regulated apoptosis is supported by RT-PCR results, indicating the increased mRNA expression of forkhead transcription factor (FOXO-3a), p27, p53, AMP-activated protein kinase (AMPK), and a concomitant decrease in p70S6K [99].

The highlighted studies shed light on the multifaceted mechanisms by which various β-glucan isoforms and extracts induce apoptosis, holding significant promise for potential anti-cancer interventions. These mechanisms involve the modulation of key apoptotic regulators, the upregulation of pro-apoptotic factors like caspase-3 and Bax, and the downregulation of anti-apoptotic elements such as Bcl-2, as illustrated in Figure 5. The intrinsic and extrinsic pathways of apoptosis are influenced, and various cancer cell types are targeted, offering diverse strategies for combatting cancer. However, there are notable gaps and future perspectives in this area of research. While the mechanisms of action are becoming clearer, further studies are needed to unravel the specific signaling pathways and molecular interactions that underlie the effects of β-glucans on apoptosis. Additionally, more comprehensive in vivo studies are necessary to validate the potential clinical applications of these findings. The development of standardized β-glucan formulations and dosage regimens is also critical in translating this research into practical cancer therapies. Moreover, investigating the interplay between β-glucans and existing cancer treatments and exploring their potential synergy or antagonism is an important avenue for future research. Lastly, the safety profiles and long-term effects of β-glucans in human trials warrant careful examination. Overall, continued research in this field promises to expand our understanding of apoptosis regulation and improve cancer treatment strategies.

Figure 5.

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Immunomodulatory and proapoptotic effects of β-Glucan. β-glucan binds to the receptors such as dectin-1, CR-3, and TLRs present in immune cells like macrophages, dendritic cells, neutrophils, and natural killer cells to induce the production of cytokines and co-stimulatory molecules, including IL-12, IL-6, IL-1, TNF-α, B7.1, and B7.1 which results in the activation of Th and Tc cells. TH cells and Tc cells, along with natural killer cells, release perforin and granzyme, resulting in the apoptosis of cells. Also, β-glucan in the tumor cells binds to the FAS receptor, promotes Bax/Bak, and inhibits Bcl2, leading to the activation of caspases and, consequently, apoptosis of tumor cells. Abbreviations: TLRs: Toll-like receptors, CR3: complement receptor 3, IL: interleukin, TNF-α: tumor necrosis factor-α, TH: T helper cells, TC: T cytotoxic cells, Bcl2: B-cell lymphoma, Bax: Bcl associated X-protein, Bak: Bcl-2 antagonistic/killer, CytC: Cytochrome C, FAS: TNF Family death receptor, FADD: FAS associated protein and death domain.

7.6. β-Glucan in Gut Microbiota

The gut microbiota, often referred to as the “second brain” of the body, plays a pivotal role in maintaining overall human health. One of the critical functions of gut microbiota is the utilization of β-glucan, a DF, as a substrate. This fiber is essential for promoting healthy biological functions. Any disruption in the composition of gut microbes can lead to increased intestinal permeability, causing colonic inflammation that may contribute to the development of colon cancer. The human gut is home to an astounding population of over 100 trillion microbial organisms, collectively encoding a far greater number of genes than the human system itself. These microorganisms are indispensable for sustaining a healthy gut environment, actively participating in processes such as angiogenesis, modulation of signaling cascades, vitamin K biosynthesis, and the regulation of metabolic pathways [100].

The introduction of indigestible polysaccharides from various sources into the diet can enhance health by fostering the growth of beneficial microbial communities [101]. Once they escape digestion, these DFs reach the large intestine, where they undergo fermentation, producing SCFA, including acetate, propionate, and butyrate. Furthermore, the fermentation process yields compounds like indole, tryptophan derivatives, and secondary bile acids, all of which contribute to the advantageous effects observed [102]. In the processing of β-(1,3)-glucans, gut microbiota employs enzymes from the glycoside hydrolase family, such as β-(1,3) glucosidase (EC 3.2.1.58) and β-(1,3) glucanases (EC 3.2.1.6 and EC 3.2.1.39). β-(1,3)-glucanases break down internal glucosidic linkages, resulting in oligopolymers, while β-(1,3)-glucosidases act on the linkage at the non-reducing ends, releasing free glucose monomers [103]). The presence of carbohydrate-binding domains on a fraction of endo-acting β-(1,3)-glucanases enhances their binding capacity to water-insoluble compounds. To break down β-(1,6)-linked branched chains, another crucial enzyme, β-(1,6)-glucanase (EC 3.2.1.75), belonging to the GH30 family, is essential. The proliferation of epithelial cells may alter gut permeability and lead to inflammation, significantly affecting overall human health. Lactobacilli and Bifidobacteria species are particularly beneficial for gut health, and β-glucans from sources like oats and barley have been found to promote the growth of these species. [104] studied the effects of orally administered β-glucan on rabbit gut health and body growth, revealing improvements in body weight, total feed consumption, and antioxidant enzyme activity, indicating a modulation of anti-inflammatory responses and improved gut health. Furthermore, research involving the continuous administration of β-glucans from cereals to rats demonstrated an increase in the numbers of Lactobacillus and Bifidobacterium after 3, 6, and 7 weeks [105]. A clinical investigation evaluated the prebiotic ability of barley β-glucan in vivo using a randomized, double-blind, placebo-controlled design. Fifty-two healthy participants aged 39–70 had been allocated to have a cake with 0.75 g of barley β-glucan or a placebo every day for 30 days. The study found that taking a daily cake with barley β-glucan was tolerated effectively and had strong bifidogenic characteristics in healthy seniors [106].

The exploration of gut microbiota and its interaction with dietary β-glucan opens up several compelling avenues for future research. Understanding the specific enzymes and metabolic pathways that govern β-glucan processing by gut microbes is a fundamental research gap. This knowledge could optimize the dietary delivery of β-glucan for therapeutic purposes. Furthermore, investigating how gut microbiota composition can prevent colonic inflammation and related diseases, such as colon cancer, is a promising area. Identifying the key microorganisms and their functions in maintaining gut health is crucial for targeted interventions. The potential for DF to modulate the gut microbiota is an exciting research prospect, offering insights into how different fibers influence microbial communities and their metabolites, including SCFAs. Long-term studies on the effects of β-glucan supplementation in populations with metabolic syndrome are necessary to determine sustained benefits and potential side effects. The complex relationship between gut microbiota, β-glucan, and human health presents numerous research opportunities. Investigating microbial interactions, their impact on diseases, and long-term dietary interventions can enhance our understanding of gut health and personalized nutrition strategies.

8.1. Food and Beverage Industries

β-glucan, a multifunctional polysaccharide, is an essential ingredient in the food and beverage industry due to its remarkable thickening and gelation properties, as well as its ability to enhance solution solubility. This versatile compound improves the flavor, texture, and appearance of culinary delights such as ice creams, gravies, and salad dressings. Additionally, it acts as a calorie-reducing fat substitute, helping to meet the growing demand for healthier food options.

However, despite its promising applications, β-glucan presents significant technical challenges related to its flow behavior and gelling characteristics. These challenges can lead to limited yield, precipitation issues during beer storage, and delayed filtration in various industrial applications. To address these concerns, there is increasing interest in technologically advanced β-glucan texture enhancers, which have the potential to revolutionize its incorporation into different food matrices. Recent research highlights the effectiveness of hull-less barley β-glucan as a thickener and dietary fiber source in beverages and liquid products, supported by comprehensive rheological evaluations. Nonetheless, the high viscosity of β-glucans and their complex handling characteristics have restricted their widespread use. Therefore, it is crucial to understand the intricate relationship between β-glucan concentration and the properties it imparts to finished products.

β-glucan serves as a proficient thickening agent, fat substitute, emulsifier, and stabilizer for foams and emulsions. When combined with other hydrocolloids, it becomes a valuable source of soluble fiber in meat emulsions. Furthermore, β-glucan shows potential as a prebiotic in high-folate products. Recent research has examined the metabolic effects of functional bread enriched with β-glucans and resistant starch, assessing glycemic and insulin levels, as well as responses related to hunger and sensory attributes. Incorporating dates and Agaricus bisporus mushrooms into bread recipes enhances protein, iron content, nutritional quality, texture, sensory acceptance, and shelf life.

In the dairy sector, adding high molecular weight oat β-glucan to milk results in products with reduced calories and cholesterol. The phase behavior, rheological characteristics, and microstructure of these dairy products influence their flow behavior, particularly at higher concentrations. Yogurts enriched with pectin and β-glucan demonstrate enhanced proteolysis, reduced release of large peptides, and a higher proportion of free amino acids compared to counterparts made with starch or without β-glucan. The β-glucan content in food products, whether extracted from commercial sources or laboratories, varies significantly, with food matrix properties affecting the ideal concentration. For example, noodles may contain up to 10% β-glucan, soups about 2%, and meat emulsions range from 0.3% to 3%. Milk and dairy products typically contain around 2.5%, while bread can incorporate between 5.5% and 20%.

A study investigated the effects of hydroxypropyl methylcellulose, yeast β-glucan, and whey protein isolate in gluten-free bread made from rice starch-based formulas. Sensory evaluations revealed that yeast β-glucan-enhanced rice starch bread was well-received. Although the optimal β-glucan levels for different food groups remain unclear, research has established that electrostatic interactions between proteins and β-glucan occur during aggregation. Additionally, while β-glucans improve dough production due to their hydrocolloid nature, they can also affect the structural qualities of baked goods, leading to increased hardness, gumminess, and decreased cohesion and elasticity. Despite sensory differences, consumers generally prefer bread made with wheat flour over hulled barley whole grain flour. Nonetheless, these findings provide valuable insights for formulating functional bakery products.

Recent studies have primarily focused on β-glucan as an encapsulating agent for substances like fish oil and probiotics. As we progress into the twenty-first century, consumer demand for natural ingredients over synthetic ones is driving food processors to seek out dietary fibers and β-glucans as promising candidates in the growing nutraceutical market. β-glucan, derived from barley and oats, has been incorporated into two different soups. As predicted, freezing significantly impacted the molecular weight and sensory attributes of these soups, profoundly influencing their quality. Meanwhile, researchers successfully developed a barley extract beverage reminiscent of tea, with extraction temperatures ranging from 150 °C to 280 °C. The extracted materials were analyzed for their physical and chemical properties.

8.2. Cosmetic Industries

β-glucan has found widespread application in the cosmetics and personal care product industry. Scientific studies have highlighted its numerous benefits in skincare. Derived from sources such as mushrooms, cereals, and microorganisms, β-glucan exhibits soothing, moisturizing, and anti-irritant properties. Its skin-regenerating capabilities are well-documented, making it a valuable addition to cosmetic formulations. Notably, β-glucan is recognized for its ability to hydrate the skin and mucosa, revitalizing them to an optimal condition. Researchers have also harnessed β-glucan’s exceptional moisture retention properties for innovative applications.

The efficacy of natural β-glucan from various sources has been studied in relation to improving overall skin health. It extends its significance beyond skincare, being utilized to address a range of concerns, including skin aging, vaccine production, eye ulcer treatment, and dermatological procedures. Its presence in cosmetic products—such as sunscreens, creams, and powders—is supported by its roles in stimulating collagen production, reducing fine wrinkles, and alleviating conditions like eczema. Additionally, β-glucan shows promise for wound healing and has the potential to mitigate oxidative tissue damage, making it a candidate for wound dressing applications. The combination of β-glucan with chitosan opens up new possibilities for therapeutic wound dressings. Research also indicates that β-glucan may help reverse skin aging and minimize wrinkles, showcasing its versatility and appeal in the cosmetic industry.

From its potential as an eye drop derived from mushrooms to its ability to strengthen the immune system and scavenge free radicals, the applications of β-glucan are extensive. Studies have shown that β-glucan derived from baker's yeast may also have promising prospects in cosmetics and therapeutic products. Evidence suggests that CM-glucan stimulates keratinocyte growth, enhances skin resilience against damage from detergents, and accelerates the regeneration of the stratum corneum. Oat β-glucan, such as “Avenacare,” is a preferred ingredient in personal care and cosmetic products due to its calming, hydrating, and anti-irritant properties.

Despite the extensive research highlighting the diverse applications and benefits of β-glucan in the cosmetics and personal care industry, several research gaps and opportunities for future exploration remain. One key area for investigation is optimizing β-glucan’s extraction methods from various natural sources. Improved techniques for maximizing yield and purity could enhance its utility in cosmetic formulations. Although evidence supports its effectiveness in skin regeneration, further studies are needed to clarify the underlying mechanisms and determine the precise dosages required for optimal results. The role of β-glucan in addressing specific skin conditions, such as eczema and skin aging, could be a central focus for future research, including clinical trials to establish its practical efficacy.

Moreover, understanding the synergistic effects of β-glucan when combined with other skincare ingredients could lead to the development of more impactful formulations. Research on the long-term effects of β-glucan in skincare products and its interaction with various skin types and conditions is essential. While the potential use of β-glucan in wound dressings is promising, further studies could explore the development of innovative wound care products that effectively leverage its properties. Investigating the application of β-glucan in hair care products and its benefits for scalp health is another exciting avenue worth exploring.

Rigorous safety and toxicity assessments are necessary to establish a comprehensive scientific basis for incorporating β-glucan into cosmetics and personal care products. This includes examining any potential side effects or sensitivities across different populations. By addressing these research gaps, we can unlock the full potential of β-glucan in enhancing skincare and personal care products.

8.3. Medical Industries

The significance of β-glucans in the medical industry is immense. Clinical trials dating back to the 1980s introduced the concept of using fungal β-glucans as adjuvant therapies for cancer, paving the way for new treatment approaches. In the ever-evolving landscape of medical research, β-glucans have emerged as a beacon of hope in the ongoing battle against cancer. These remarkable compounds, derived from sources such as lentinan, D-fraction, and schizophyllan, have garnered considerable attention for their potential to revolutionize cancer therapy. As one of the leading causes of death worldwide, cancer remains a challenge for conventional treatment methods, including radiation therapy, chemotherapy, and surgical resection. However, β-glucans offer a transformative alternative. These natural agents have demonstrated potent anticancer effects against various types of cancer, including gastrointestinal, breast, and lung cancers. They work by inducing cytotoxicity in cancer cells, inhibiting proliferation, and promoting apoptosis through complex molecular pathways. The profound potential of β-glucans in medical science provides a promising glimpse into a future where cancer treatment is more effective, safer, and less likely to entail the horrors of metastasis and recurrence. Ongoing research heralds the dawn of a new era in cancer therapy, emphasizing the vital role of β-glucans as a catalyst for innovation within the medical field. Moreover, the impact of β-glucans extends beyond direct cancer treatment. Their immunomodulatory properties initiate a cascade of immune responses, including the secretion of pro-inflammatory and anti-inflammatory cytokines and the activation of natural killer (NK) cells, T cells, and macrophages, all of which actively engage with tumor cells. Recent studies have explored the immunological mechanisms of various β-glucans, highlighting their ability to enhance phagocytosis and IL-2 release, as well as to inhibit cancer growth. Additionally, these compounds have shown promise in mitigating the effects of experimental infections. Recent research has identified β-glucans as having significant potential for use in the treatment of COVID-19, caused by the SARS-CoV-2 virus. β-glucans have been reported to boost immunity and alleviate COVID-19 symptoms when taken as preventive oral supplements. They can stimulate several immune pathways, including antibody production, and promote an immunomodulatory effect, improving the cellular responses involved in the infectious process and reducing the inflammatory cytokines associated with COVID-19. Specifically, β-glucans from Lentinula edodes (lentinan) have been studied for their ability to reduce lung damage caused by pneumonia associated with SARS-CoV-2 due to their cytoprotective effects. Although there has been limited research on autoimmune disorders, an extract from Agaricus blazei was tested in inflammatory bowel disease with modest results regarding inflammatory cytokines and clinical symptoms. Furthermore, β-glucans expedite wound healing by enhancing macrophage infiltration, promoting tissue granulation, collagen synthesis, and skin re-epithelialization. A clinical trial found that using soluble yeast β-1,3-glucan allowed 59% of all ulcers to heal by week 12, compared to just 37% in the control group. It is hypothesized that the gel-forming properties of β-glucans play a major role in their ability to regulate bile acid and cholesterol metabolism. By reducing the intestinal absorption of dietary cholesterol and blocking bile acid reabsorption, β-glucans also increase the requirement for bile acids to be synthesized from cholesterol catabolism, resulting in lower blood cholesterol levels. Recently, the regulation of cholesterol homeostasis has been linked to the effect of β-glucans on gut microbiota modulation, particularly on bacterial species that influence bile acid metabolism and the generation of short-chain fatty acids. Consumption of oats or oat-derived β-glucans has been associated with reduced LDL cholesterol levels in several randomized controlled studies and subsequent meta-analyses. The multifaceted potential of β-glucans in the medical industry presents a fertile ground for future research. While significant progress has been made in understanding their role in cancer therapy, several research gaps remain. There is a need for further clinical trials and mechanistic studies to determine the optimal dosage, administration methods, and long-term effects of β-glucans in cancer treatment. Additionally, exploring their synergistic potential in combination with conventional therapies could enhance their clinical utility. Furthermore, the immunomodulatory properties of β-glucans, particularly in the context of infectious diseases, warrant further investigation.

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