Immunomodulatory Effects of Edible and Medicinal Mushrooms

This scientific article, published in the Journal of Fungi in 2020, explores the immunomodulatory effects of edible and medicinal mushrooms and their bioactive compounds. Different classes of molecules, such as polysaccharides, lectins, fungal immunomodulatory proteins (FIPs), and terpenes, are examined, highlighting their structures, functions, and mechanisms of action. The paper summarizes existing clinical studies and discusses the potential therapeutic applications of these compounds, while also highlighting the challenges and areas requiring further investigation for their broader use in medicine. Finally, the role of genomics in the study of medicinal mushrooms is discussed.

What are the main categories of bioactive compounds present in medicinal mushrooms and what immunomodulatory activities do they possess?

The main categories of bioactive compounds present in medicinal mushrooms that possess immunomodulatory activities are mainly four: polysaccharides, lectins, fungal immunomodulatory proteins (FIPs), and terpenes and terpenoids.

• Polysaccharides: Polysaccharides are among the most frequently reported mushroom-derived bioactive compounds with immunomodulatory activity. These polysaccharides are heterogeneous in sugar composition, backbone structure, degree of branching, conformation, molecular weight, and other physical properties, which influence their bioactivity and mechanism of action. They can be homoglycans or heteroglycans and combine with peptides to form peptidoglycans or polysaccharide-protein complexes. In general, polysaccharides with higher molecular weights exhibit greater bioactivity. Many medicinal mushroom polysaccharides have been shown to stimulate natural killer (NK) cells, macrophages, and dendritic cells, as well as induce the production of cytokines such as TNF, IFN-γ, and IL-1. Specific examples include lentinan from shiitake ( Lentinula edodes ) and schizophyllan from Schizophyllum commune , both β-1,3-D-glucans with β-1,6 branches, which have shown immunomodulatory and antitumor activities and have been approved for clinical use in Japan. Other polysaccharides with immunomodulatory effects are present in several species such as Agaricus blazei , Auricularia auricula-judae , Ganoderma lucidum , Grifola frondosa , Hericium erinaceus , and many others (see Table 24). Mechanisms of action may include activation of the TLR4-NFκB system in macrophages. 5 Structure, including the presence of triple helices in some β-D-glucans such as lentinan and schizophyllan, and chemical modifications such as sulfation, may influence the immunomodulatory activity of polysaccharides.

• Lectins: Lectins are proteins that recognize and interact with various carbohydrates/glycoproteins on the cell surface. Medicinal mushroom lectins have been shown to possess specific immunomodulatory, antiproliferative, and antitumor activities. They work by stimulating nitrite production, increasing the expression of TNF-α and interleukins, activating lymphocytes, and promoting the production of macrophage-activating factors. Several mushroom lectins, such as Agaricus bisporus lectin (ABL), Grifola frondosa lectin (GFL), and Schizophyllum commune lectin (SCL), have shown such effects (see Table 310). Some mushroom lectins have also shown antiviral, mitogenic, antimicrobial, and antioxidant activities.

• Fungal Immunomodulatory Proteins (FIPs): FIPs are a group of proteins with highly similar amino acid sequences that exist as dimers. FIPs stimulate antigen-presenting cells by binding to Toll-like receptors (TLRs) and releasing cytokines such as NO and IL-1211. They can also promote the proliferation and differentiation of T helper (Th0) cells into Th1 and Th2 cells, activate macrophages and B cells, and produce a variety of cellular factors through activation of p38/MAPK phosphorylation and increased production of NF-κB11. Examples of FIPs with immunomodulatory activity include FIP-fve from Flammulina velutipes and LZ-8 from Ganoderma lucidum (see Table 412).

• Terpenes and Terpenoids: Terpenes are hydrocarbons biosynthetically derived from isopentenyl pyrophosphate units, while terpenoids are terpenes with oxygen-containing functional groups. Terpenes and terpenoids from various medicinal mushrooms have shown immunoregulatory activities. For example, Ganoderma species are known for their high content of triterpenoids, which have shown strong immunomodulatory and anti-infective activities. Studies have indicated that terpenes and terpenoids modulate immune system functions by stimulating the expression of genes encoding proteins in the nuclear factor (NF)–κB pathway and mitogen-activated protein kinases. Several terpenoids isolated from Ganoderma lucidum and Ganoderma lingzhi , such as ganoderic acids, have demonstrated immunomodulatory, antitumor, and/or anti-infective activities. However, their mechanisms of action and structure-activity relationships are still poorly understood.

It is important to note that the distribution of these compounds varies among fungal species, and their immunomodulatory activities depend on their basic structures and chemical modifications of the fraction composition. Furthermore, different extractions of the same fungus may exhibit non-overlapping but complementary activities.

How are immunomodulators classified in clinical practice?

In clinical practice, immunomodulators are usually classified into three categories: immunosuppressants, immunostimulants, and immunoadjuvants.

• Immunosuppressants are used to suppress the immune response.

• Immunostimulants are used to stimulate or enhance the function of the immune system.

• Immunoadjuvants are substances that increase the immune response to an antigen, often used in combination with vaccines.

The market share of these immunomodulators has increased rapidly in recent years due to their broad medical applications for patients requiring immune system modulation. Immune system modulators are also commonly used as prophylactic medicine for a growing number of healthy people.1

Although most immunomodulators are synthetic or semi-synthetic compounds, there is growing interest in natural immunomodulators, such as those derived from medicinal mushrooms.

What mechanisms mediate the immunomodulatory effects of mushrooms?

The mechanisms mediating the immunomodulatory effects of mushrooms are diverse and depend on the specific categories of bioactive compounds present. The main ways in which mushrooms exert their immunomodulatory action involve both the innate and adaptive immune systems. In general, bioactive compounds in mushrooms can activate components of the innate immune system such as natural killer (NK) cells, neutrophils, and macrophages, and stimulate the expression and secretion of cytokines. These cytokines, in turn, activate adaptive immunity by promoting the proliferation and differentiation of B cells for antibody production and by stimulating the differentiation of T cells into T helper (Th) 1 and Th2 cells, which mediate cellular and humoral immunity, respectively.

Here are the main mechanisms associated with the different categories of bioactive compounds in mushrooms:

• Polysaccharides: Polysaccharides are among the most common natural immunomodulators extracted from mushrooms. Their mechanisms of action may include binding to cellular receptors. For example, a glucuronoxylomannan (TAP-3) obtained from Naematelia aurantialba (syn. Tremella aurantialba ) has been shown to promote the secretion of NO, IL-1β, and TNF-α from macrophages. 2 Similarly, a polysaccharide (CCP) from Craterellus cornucopioides enhances the phagocytic function of macrophages and increases cytokine expression through activation of the TLR4–NFκB pathway. 2 In general, high-molecular-weight polysaccharides tend to exhibit greater bioactivity and act by binding to cellular receptors, while low-molecular-weight polysaccharides can penetrate immune cells and exert stimulatory effects from within. The structure of polysaccharides, particularly the presence of a 1,3-β-D-glucan backbone with short 1,6-β-linked branches, is often associated with immunomodulatory activity. Some β-D-glucans, such as lentinan, schizophyllan, and PSK, adopt a triple-helical conformation, which is important for their cytokine-stimulating activity. Chemical modifications such as sulfation can also enhance the immunomodulatory activity of fungal polysaccharides.

• Lectins: Fungal lectins mediate their immunomodulatory effects through recognition and interaction with various carbohydrates/glycoproteins on the cell surface. This interaction can lead to several immune responses, including stimulation of nitrite production, increased expression of TNF-α and interleukins, activation of lymphocytes, and promotion of the production of macrophage-activating factors. For example, two lectins extracted from Leucocalocybe mongolica (syn. Tricholoma mongolicum ), TML-1 and TML-2, stimulate the production of nitrite and TNF-α. The lectin from Clitocybe nebularis (CNL) induces the maturation and activation of dendritic cells (DCs) and stimulates several proinflammatory cytokines such as IL-6, IL-8, and TNF-α.

• Fungal Immunomodulatory Proteins (FIPs): FIPs exert their immunomodulatory effects primarily through binding to Toll-like receptors (TLRs)10. This binding stimulates antigen-presenting cells and leads to the release of cytokines such as NO and IL-1210. FIPs can also activate p38/MAPK phosphorylation and increase NF-κB production, thereby promoting the proliferation and differentiation of T helper (Th0) cells into Th1 and Th2 cells, activating macrophages and B cells, and producing a variety of cellular factors (see Figure 5)10. For example, FIP-fve from Flammulina velutipes can increase the expression of intercellular adhesion molecules on the surface of T cells through p38/MAPK phosphorylation and activate Th1 cells to produce IL-2 and IFN-γ10. FIP-gts from Ganoderma tsugae can stimulate human peripheral blood monocytes to produce IFN-γ and activates the PI3K/Akt10 signaling pathway.

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Terpenes and Terpenoids: Although the mechanisms of action and structure-activity relationships of terpenes and terpenoids are still poorly understood, they have been suggested to modulate immune system function by stimulating the expression of genes encoding proteins in the nuclear factor (NF)–κB pathway and mitogen-activated protein kinases. Triterpenoids from Ganoderma species have shown immunomodulatory and anti-infective activities.

In summary, the immunomodulatory effects of medicinal mushrooms are mediated by a complex interplay of diverse bioactive compounds that affect various components and pathways of the innate and adaptive immune system. Polysaccharides often interact with cell-surface receptors and activate intracellular signaling pathways; lectins recognize specific glycosylated structures and can trigger various immune responses; FIPs bind to TLRs, initiating signaling cascades that lead to cytokine production and immune cell activation; and terpenes/terpenoids appear to influence gene expression involved in the immune response.

https://pmc.ncbi.nlm.nih.gov/articles/PMC7712035/

Edible and medicinal mushrooms have been used for centuries in various cultures for their nutritional and therapeutic properties. Recently, scientific attention has focused on their immunomodulatory effects , that is, their ability to modulate and enhance the immune system's response.

Bioactive Compounds in Mushrooms

Mushrooms are rich in bioactive compounds that contribute to their immunomodulatory properties:

• Polysaccharides , especially β-glucans : These polysaccharides are known for their ability to modulate the immune system. Mushroom β-glucans have a structure characterized by β-1,3-glucan main chains with β-1,6 branches, which are recognized by immune cell receptors, giving them specific immunomodulatory properties. PMC
  
  

• Fungal immunomodulatory proteins (FIPs) : These proteins influence the activity of immune cells, modulating the immune response.
  
  

• Terpenes and terpenoids : Compounds that modulate the immune system by stimulating the expression of genes involved in the immune response, as well as having anti-inflammatory, antioxidant, and antitumor properties. PMC
  
  

• Lectins : proteins that bind specifically to certain sugars, influencing cellular interactions and modulating immune activity.
  
  

Mechanisms of Action

Fungal β-glucans interact with specific receptors on immune cells, such as Dectin-1 , CR3 , and TLR-2/6 , activating macrophages, neutrophils, monocytes, NK cells, and dendritic cells. This interaction modulates both the innate and adaptive immune responses, enhancing phagocytosis and cytokine production. BioMed Central

Clinical Efficacy and Scientific Studies

Numerous studies have explored the clinical efficacy of medicinal mushrooms:

• Ganoderma lucidum (Reishi) : Rich in terpenoids, it modulates the immune system by stimulating the expression of genes involved in the immune response and has anti-inflammatory and anti-tumor properties. PMC
  
  

• Trametes versicolor (Turkey Tail) : Used as a non-specific immune modulator, it has shown in clinical studies the ability to improve immune function in cancer patients.
  
  

• Lentinula edodes (Shiitake) : contains β-glucans which stimulate phagocytosis and enhance the innate immune response.
  
  

Additionally, mushroom extracts such as Maitake have been studied for their potential anti-tumor and immune-boosting properties.

Final Considerations

Incorporating edible and medicinal mushrooms into the diet or as supplements can offer significant immunomodulatory benefits. However, it is essential to consult a healthcare professional before starting any supplement regimen, especially for individuals with pre-existing medical conditions or taking other medications. Further research is needed to fully understand the mechanisms of action and optimize the therapeutic use of medicinal mushrooms.

https://jhoonline.biomedcentral.com/articles/10.1186/1756-8722-2-25

https://pmc.ncbi.nlm.nih.gov/articles/PMC7826851/

https://pmc.ncbi.nlm.nih.gov/articles/PMC8623785