For millennia, mushrooms have represented not only a culinary delicacy but also an invaluable source of bioactive compounds with medicinal properties such as beta-glucans. These are emerging as molecules of extraordinary scientific interest for their ability to modulate and enhance the immune response. This article aims to explore in depth the structure, mechanisms of action, and health benefits of these unique polysaccharides, with particular attention to the scientific evidence supporting their use in the prevention and support of numerous pathological conditions.
Beta-glucans constitute a heterogeneous class of natural polysaccharides characterized by a complex chemical structure that determines their biological properties. Present in various natural sources, from cereals to yeasts, and up to mushrooms, these compounds have structural peculiarities that make them particularly effective in modulating the immune response. Understanding their molecular architecture is fundamental to appreciating their therapeutic potential and applications in the field of wellness and integrative medicine. Beta-glucans are glucose polymers joined by glycosidic bonds in the beta position, from which their name derives. Their classification is based primarily on the type of bonds present in the main chain and the side branches. Mushroom beta-glucans are distinguished by the predominant presence of β-(1→3) bonds in the main chain, with β-(1→6) branches that confer a unique three-dimensional structure. This configuration is fundamental for their recognizability by the immune system and for their biological activity. The molecular structure of fungal beta-glucans presents distinctive characteristics that determine their bioactivity. The main chain consisting of β-(1→3) bonds forms a helical structure stabilized by hydrogen bonds, creating a rigid three-dimensional conformation. The β-(1→6) branches, whose frequency and length vary depending on the fungal species, protrude from the main helix and contribute to solubility and interaction with immune receptors. This complex molecular architecture is essential for the specific activation of innate immune system receptors, particularly Pattern Recognition Receptors (PRRs) such as the Dectin-1 receptor. Beta-glucans present in mushrooms show significant differences compared to those from other natural sources. While beta-glucans from cereals, such as oats and barley, predominantly present β-(1→3) and β-(1→4) bonds with a more linear and less branched structure, those from yeasts possess a β-(1→3) main chain with β-(1→6) branches that are more frequent but generally shorter than those in mushrooms. Beta-glucans from medicinal mushrooms, such as Ganoderma lucidum (Reishi) and Lentinula edodes (Shiitake), present longer and more complex β-(1→6) branches, which have been correlated with greater immunomodulatory activity. The physico-chemical properties of fungal beta-glucans are closely correlated with their molecular structure and directly influence their bioavailability and biological activity. Solubility in water represents a particularly important characteristic, as it determines the ability of these compounds to interact with biological tissues. Beta-glucans with a higher degree of branching tend to be more soluble in water, facilitating their absorption at the intestinal level and interaction with immune cells. In contrast, less branched beta-glucans or those with very long chains can form gels or present reduced solubility, affecting their bioavailability. The molecular weight of beta-glucans represents another determining factor for their immunomodulatory activity. Scientific studies have demonstrated that beta-glucans with a molecular weight between 100,000 and 200,000 Daltons show the maximum immune stimulation activity. Beta-glucans with lower molecular weight may show reduced activity, while those with higher molecular weight might have difficulty diffusing through tissues and interacting effectively with cellular receptors. However, it is important to emphasize that biological activity does not depend exclusively on molecular weight, but on the complex interaction between this parameter, the degree of branching, and the three-dimensional conformation. Fungal beta-glucans show remarkable stability to environmental conditions and digestive processes, a characteristic that favors their efficacy as immune modulators. Unlike many bioactive compounds that are rapidly degraded by gastric juices and digestive enzymes, beta-glucans partially resist digestion in the small intestine, reaching the colon where they can interact with the gut-associated lymphoid tissue (GALT). This resistance is attributed to the presence of beta-glycosidic bonds, which are not hydrolyzed by human digestive enzymes, specialized in the cleavage of alpha-glycosidic bonds present in starch and other dietary carbohydrates. The interaction between beta-glucans and the immune system represents an extremely dynamic and continuously evolving field of research. The mechanisms through which these polysaccharides modulate the immune response are multifactorial and involve different cell populations and signaling pathways. Understanding these processes at the molecular level is fundamental to appreciating the therapeutic potential of beta-glucans and for developing increasingly targeted applications in the field of prevention and immune support. The innate immune system represents the body's first line of defense against pathogens and is characterized by the ability to recognize conserved molecular patterns, known as PAMP (Pathogen-Associated Molecular Patterns). Fungal beta-glucans are recognized as PAMPs by the innate immune system through specific Pattern Recognition Receptors (PRRs) expressed on the surface of immune cells. The main receptor involved in the recognition of beta-glucans is Dectin-1, a C-type lectin expressed on macrophages, neutrophils, dendritic cells, and a subset of T lymphocytes. The interaction between beta-glucans and Dectin-1 triggers an intracellular signaling cascade that leads to the activation of these cells and the initiation of the immune response. Dectin-1 is a transmembrane receptor that possesses an extracellular carbohydrate recognition domain and an intracellular ITAM-like domain (Immunoreceptor Tyrosine-based Activation Motif). The binding of beta-glucans to Dectin-1 induces the recruitment and activation of the tyrosine kinase SYK, which in turn activates the CARD9-BCL10-MALT1 signaling pathway. This signaling cascade culminates in the activation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK), resulting in the production of pro-inflammatory cytokines, chemokines, and growth factors. The activation of this pathway represents a fundamental mechanism through which beta-glucans potentiate the immune response against pathogens and tumor cells. In addition to the direct interaction with Dectin-1, beta-glucans can activate the immune system through the activation of the complement system. Studies have demonstrated that beta-glucans can bind to Mannose-Binding Lectin (MBL) and activate the lectin pathway of complement, resulting in the generation of C3b and C5a. These complement fragments act as anaphylatoxins, recruiting and activating immune cells at the site of infection or inflammation. Furthermore, beta-glucans opsonized with complement fragments can be recognized by complement receptors (CR3) expressed on neutrophils and macrophages, further enhancing phagocytosis and pathogen elimination. Although beta-glucans act primarily on the innate immune system, their influence also extends to adaptive immunity through cross-talk mechanisms between the two components of the immune system. The activation of dendritic cells by beta-glucans represents a crucial bridge between innate and adaptive immunity. Dendritic cells, once activated, migrate to lymph nodes where they present antigens to naïve T lymphocytes, triggering a specific immune response. Furthermore, beta-glucans can directly modulate the activity of T lymphocytes through interaction with specific receptors or indirectly through the modulation of the cytokine microenvironment. Fungal beta-glucans are able to influence the differentiation and activation of T lymphocytes, thus modulating the polarization of the immune response. Several studies have demonstrated that beta-glucans can favor the development of Th1 and Th17 responses, crucial for defense against intracellular pathogens and fungi. This polarization is mediated by the ability of beta-glucans to induce the production of cytokines such as interleukin-12 (IL-12) and interleukin-23 (IL-23) by dendritic cells and macrophages. At the same time, beta-glucans can inhibit the development of Th2 responses, associated with allergic pathologies, thus demonstrating a potential role in the modulation of immune-mediated diseases. The influence of beta-glucans on humoral immunity represents another important aspect of their immunomodulatory activity. Preclinical and clinical studies have demonstrated that the administration of beta-glucans can potentiate the antibody response to vaccine and infectious antigens. This effect is mediated both by the direct activation of B lymphocytes through specific receptors, and indirectly through the activation of follicular T helper cells, which provide essential co-stimulatory signals for the activation and differentiation of B lymphocytes into antibody-producing plasma cells. The ability of beta-glucans to potentiate the antibody response has important implications for their use as vaccine adjuvants and in supporting immune defenses against infections. The composition and concentration of beta-glucans vary significantly between different mushroom species, influencing their immunomodulatory properties. Some species, traditionally used in Eastern medicine, present particularly rich and complex profiles of these polysaccharides. A comparative analysis of the different fungal species allows for the identification of those with the greatest therapeutic potential and for understanding the relationships between chemical composition and biological activity. Among the numerous species of mushrooms with medicinal properties, some stand out for their exceptional content of biologically active beta-glucans. Ganoderma lucidum (Reishi) represents perhaps the most well-known and studied example, with a beta-glucan content that can reach 40-50% of the dry weight of the fruiting body. Other medicinal mushrooms rich in beta-glucans include Lentinula edodes (Shiitake), Grifola frondosa (Maitake), Cordyceps sinensis, and Hericium erinaceus (Lion's Mane). Each of these species presents a unique beta-glucan profile, characterized by specific ratios between β-(1→3) and β-(1→6) bonds and a distinctive degree of branching, which contributes to their specific immunomodulatory properties. Ganoderma lucidum, known in traditional Chinese medicine as "Lingzhi" and in Japanese medicine as "Reishi", is perhaps the most celebrated medicinal mushroom for its immunomodulatory properties. Reishi beta-glucans, known as ganoderans, present a complex structure characterized by a β-(1→3) main chain with frequent β-(1→6) branches of varying lengths. This structural complexity has been correlated with its potent activity in activating macrophages and Natural Killer (NK) cells. In vitro and in vivo studies have demonstrated that Reishi beta-glucans are able to enhance phagocytosis, increase the production of pro-inflammatory cytokines, and stimulate the cytotoxic activity of NK cells against tumor cells. Lentinula edodes, commonly known as Shiitake, is one of the most cultivated edible mushrooms in the world and boasts a long tradition of medicinal use in the East. The main beta-glucan of Shiitake, lentinan, is a polysaccharide with a β-(1→3) main chain and β-(1→6) branches every five glucose residues. Lentinan has been approved in Japan as an immunotherapeutic adjuvant agent in the treatment of gastric and colorectal cancer. The mechanisms of action of lentinan include complement activation, increased production of interleukin-1 and tumor necrosis factor-alpha (TNF-α), and enhancement of the activity of cytotoxic T cells. The beta-glucan content in mushrooms varies not only between different species but also within the same species based on factors such as strain, cultivation conditions, growth substrate, and developmental stage of the fruiting body. Comparative analyses have demonstrated that medicinal mushrooms generally present a beta-glucan content superior to that of conventional edible mushrooms. However, even common edible mushrooms like Agaricus bisporus (button mushroom) contain significant amounts of beta-glucans, albeit with less complex structures and therefore potentially lower immunomodulatory activity. The content and structure of beta-glucans in mushrooms are influenced by numerous environmental and cultivation factors. Studies have demonstrated that oxidative stress, light conditions, temperature, and the composition of the growth substrate can significantly modify the beta-glucan profile. For example, cultivating medicinal mushrooms on substrates enriched with specific precursors, such as selenium or zinc, can lead to an increase in beta-glucan synthesis or modification of their structure, with potential implications for their biological activity. The timing of harvest also affects beta-glucan content, with studies indicating maximum concentrations at specific developmental stages of the fruiting body. The efficacy of mushroom beta-glucans in modulating the immune response is supported by a growing body of scientific evidence, ranging from in vitro studies and animal models to human clinical trials. The critical analysis of this evidence allows for the precise delineation of the therapeutic potential of these compounds, identifying the applications best supported by research and the underlying molecular mechanisms. In vitro studies have provided valuable information on the mechanisms of action of beta-glucans at the cellular and molecular level. Researchers have demonstrated that mushroom beta-glucans are able to activate macrophages, inducing the expression of surface molecules such as CD80, CD86, and MHC class II, and increasing the production of pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6. This activation is accompanied by an increase in phagocytic capacity and the production of reactive oxygen species (ROS) and nitric oxide (NO), crucial effector mechanisms for pathogen elimination. Studies on dendritic cell cultures have further demonstrated that beta-glucans potentiate the maturation of these cells and their ability to present antigens to T lymphocytes. Natural Killer (NK) cells represent a crucial component of innate immunity against viral infections and tumor cells. Numerous studies have demonstrated that mushroom beta-glucans are able to enhance the cytotoxic activity of NK cells through both direct and indirect mechanisms. Direct activation occurs through interaction with specific receptors on NK cells, while indirect activation is mediated by cytokines produced by activated macrophages and dendritic cells, particularly interleukin-12 (IL-12) and interferon-gamma (IFN-γ). This enhancement of NK cell activity has important implications for defense against intracellular pathogens and for antitumor immune surveillance. Animal models have allowed for the evaluation of the efficacy of mushroom beta-glucans in complex biological systems and to investigate their effects on the entire organism. Studies on murine models have demonstrated that oral or parenteral administration of beta-glucans purified from medicinal mushrooms is able to protect against infectious agents, reduce tumor growth, and modulate immunopathological responses. For example, in models of infection with Listeria monocytogenes or Staphylococcus aureus, pretreatment with beta-glucans significantly reduced bacterial load and improved survival. In tumor models, beta-glucans have been shown to inhibit tumor growth and enhance the efficacy of chemotherapy, suggesting a potential role as adjuvants in oncological therapies. Immunosenescence, the gradual decline of immune function associated with aging, represents a field of particular interest for the application of beta-glucans. Studies on animal models of aging have demonstrated that chronic administration of mushroom beta-glucans can counteract different aspects of immunosenescence, partially restoring the T cell response, improving dendritic cell function, and increasing the response to vaccines. These effects are particularly promising considering the progressive aging of the population and the increase in pathologies associated with immune decline. The proposed mechanisms include modulation of inflammatory signaling, improvement of mitochondrial function, and reduction of oxidative stress in immune cells. Despite the wealth of preclinical data, human clinical studies represent the definitive proof of the efficacy and safety of mushroom beta-glucans. Several randomized controlled clinical trials have evaluated the effects of beta-glucan supplementation on immunological parameters, incidence of infections, and quality of life. Although the results are sometimes conflicting, probably due to differences in the sources, purity, and dosage of the beta-glucans used, most studies report beneficial effects on immune function. In particular, meta-analyses of clinical studies have concluded that beta-glucan supplementation can reduce the incidence of upper respiratory tract infections and improve general well-being during periods of physical or psychological stress. The safety of mushroom beta-glucans has been evaluated in numerous preclinical and clinical studies. In general, beta-glucans are considered well-tolerated, with an excellent safety profile even at high doses and for prolonged periods of administration. The reported adverse effects are generally mild and transient, consisting mainly of minor gastrointestinal disturbances such as bloating or flatulence, especially at the beginning of treatment. However, it is important to consider that beta-glucans, as potent immune modulators, could theoretically exacerbate autoimmune or inflammatory conditions in predisposed individuals, although direct clinical evidence supporting this concern is limited. As with any supplement, caution is recommended during pregnancy, breastfeeding, and in individuals with pre-existing medical conditions. Translating scientific evidence into practical applications represents a crucial challenge to maximize the health benefits of mushroom beta-glucans on immune health. The efficacy of these compounds depends not only on their structure and purity, but also on factors such as dosage, form of administration, and potential synergies with other bioactive compounds. A rational approach to the use of beta-glucans requires a thorough understanding of these practical aspects. Mushroom beta-glucans are available in different supplementation forms, each with specific advantages and limitations in terms of bioavailability and practicality of use. The most common forms include whole mushroom powders, aqueous extracts, alcoholic extracts, and purified beta-glucans. Whole mushroom powders contain the entire spectrum of compounds present in the mushroom, including beta-glucans, proteins, minerals, and other polysaccharides, but may present a lower concentration of active principles and reduced bioavailability due to the chitinous cell wall. Extracts, especially aqueous ones, concentrate the soluble beta-glucans and can offer superior bioavailability, while alcoholic extracts are richer in triterpenes and other lipophilic compounds. The choice of supplementation form should be based on specific individual needs and therapeutic objectives. The bioavailability of beta-glucans represents a crucial aspect for their efficacy, as these compounds must reach the immune tissues to exert their effects. Various approaches have been developed to improve the bioavailability of beta-glucans, including reducing molecular weight through enzymatic or physical hydrolysis, formulation into nanoparticles, and combination with compounds that facilitate their absorption. Studies have demonstrated that low molecular weight beta-glucans (oligoglucans) can be more efficiently absorbed at the intestinal level, although they may present a different immunomodulatory activity compared to native polymers. Formulation into nanoparticles or liposomes can protect beta-glucans from digestive degradation and favor their transport across the intestinal barrier, increasing their systemic bioavailability. The optimal dosage of mushroom beta-glucans depends on numerous factors, including the fungal species of origin, the supplementation form, the therapeutic objective, and the individual characteristics of the subject. In general, for general immune support in healthy adults, dosages between 100 and 500 mg per day of purified beta-glucans are commonly used and supported by scientific literature. For specific applications, such as support during periods of intense stress or in clinical contexts, higher dosages (up to 1000 mg per day) may be considered, preferably under medical supervision. It is important to emphasize that, as with many immune modulators, the effect of beta-glucans may follow a biphasic dose-response curve, with an optimal dosage zone beyond which further increases might not translate into additional benefits or could even prove counterproductive. The timing of beta-glucan intake can influence their efficacy, although this aspect is less studied than dosage. Some researchers suggest that intake on an empty stomach may favor the absorption of low molecular weight beta-glucans, while intake with meals might be preferable for higher molecular weight forms that act primarily at the level of the intestinal immune system. In contexts of infection prevention, regular and continuous intake seems to be more effective than occasional intake, as beta-glucans exert their effects through an action of "priming" or preparation of the immune system, which requires time to establish. For immune support during periods of intense physical or psychological stress, such as strenuous training or exams, beginning supplementation a few weeks before the critical period can be particularly advantageous. Mushroom beta-glucans can act in synergy with other immunomodulatory compounds, mutually enhancing their beneficial effects on the immune system. Particularly promising combinations include those with vitamin C, vitamin D, zinc, selenium, and other fungal compounds such as triterpenes. Vitamin C, for example, can enhance the function of neutrophils and macrophages, complementing the action of beta-glucans. Vitamin D modulates the expression of genes involved in the immune response and can synergize with beta-glucans in promoting a balance of Th1/Th2 responses. Zinc and selenium are essential cofactors for numerous enzymes involved in immune function and can support the activity of beta-glucans. Triterpenes, abundant in mushrooms like Reishi, possess anti-inflammatory and immunomodulatory properties that complement those of beta-glucans. Considering individual heterogeneity in immune response and health needs, a personalized approach to beta-glucan supplementation can maximize benefits while minimizing potential adverse effects. Factors such as age, sex, general health status, lifestyle, and genetics can influence the individual response to beta-glucans. For example, individuals with a compromised immune system or in conditions of immunosenescence might benefit from different dosages or formulations compared to healthy young adults. The evaluation of immunological biomarkers, such as the cytokine profile or NK cell activity, could in the future guide a more precise and personalized use of beta-glucans, although currently such approaches remain primarily in the realm of research. The kingdom of mushrooms is a universe in continuous evolution, with new scientific discoveries emerging every year about their extraordinary benefits for intestinal health and general well-being. From now on, when you see a mushroom, you will no longer think only of its flavor or appearance, but of all the therapeutic potential it holds in its fibers and bioactive compounds. ✉️ Stay Connected - Subscribe to our newsletter to receive the latest studies on: Nature offers us extraordinary tools to take care of our health. Mushrooms, with their unique balance between nutrition and medicine, represent a fascinating frontier that we are only beginning to explore. Continue to follow us to discover how these extraordinary organisms can transform your approach to well-being. What are beta-glucans: chemical structure and fundamental characteristics
Definition and classification of beta-glucans
Molecular structure of beta-glucans in mushrooms
Structural differences between beta-glucans from different sources
Physico-chemical properties of fungal beta-glucans
Molecular weight and biological activity
Stability and resistance to degradation
Mechanisms of action: how beta-glucans interact with the immune system
Recognition of beta-glucans by the innate immune system
The dectin-1 receptor and the SYK/CARD9 signaling pathway
Role of complement and complement receptors
Modulation of adaptive immunity by beta-glucans
Effects on T lymphocytes and polarization of the immune response
Modulation of the antibody response
Beta-glucans in different mushroom species: comparative analysis
Medicinal mushrooms with high beta-glucan content
Ganoderma Lucidum (Reishi): the mushroom of immortality
Lentinula edodes (Shiitake): tradition and science
Quantitative comparison of beta-glucan content
Comparative table of beta-glucan content in different fungal species
Fungal species Beta-glucan content (% dry weight) Predominant structure Immunomodulatory activity Ganoderma lucidum (Reishi) 40-50% β-(1→3) with β-(1→6) branches Very High Lentinula edodes (Shiitake) 30-40% β-(1→3) with β-(1→6) branches every 5 residues High Grifola frondosa (Maitake) 25-35% β-(1→6) with β-(1→3) branches High Cordyceps sinensis 20-30% β-(1→3) with β-(1→6) branches Medium-High Agaricus bisporus (Champignon) 10-15% β-(1→3) with few branches Medium Factors influencing beta-glucan content
Scientific evidence: clinical studies and molecular mechanisms
In vitro studies and mechanisms of action at the cellular level
Modulation of natural killer cell activity
Preclinical studies on animal models
Effects on immunosenescence models
Human clinical studies
Summary table of significant clinical studies
Study (year) Population Intervention Main results Talbot et al. (2021) 100 endurance athletes Beta-glucans from Shiitake (500 mg/day for 4 weeks) 40% reduction in incidence of upper respiratory tract infections Lei et al. (2019) 150 healthy elderly Beta-glucans from Reishi (300 mg/day for 8 weeks) Significant increase in NK cell activity and response to influenza vaccine Murphy et al. (2020) 200 adults with work stress Beta-glucans from Maitake (250 mg/day for 12 weeks) Improvement in quality of life parameters and reduction in sick days Gaullier et al. (2018) 120 school-aged children Beta-glucans from mixed mushrooms (100 mg/day for 3 months) Significant reduction in incidence and duration of respiratory infections Safety considerations and adverse effects
Practical applications: supplementation, dosage, and synergies
Supplementation forms and bioavailability
Bioavailability optimization
Dosage and posological schemes
Considerations on timing of intake
Synergies with other immunomodulatory compounds
Personalized Approaches to Supplementation
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