CLINICALLY PROVEN;

• Stimulates the non-specific immune system

• Enhances Immune Alertness and Surveillance

• Activates innate anti-infective and inflammatory response

• Inhibits viral replication

• Promotes antibody production

• Promotes lymphocyte proliferation and differentiation

• Stimulates monocytes and granulocytes

• Modulate the microbiota of the intestinal tract

• Supports a healthy immune response, indicated for auto-immune conditions

• Supports prevention, treatment and post treatment recovery of cancer

• Proven anti-viral activity against Epstein-Barr, HPV, HIV, Herpes simplex virus 1 & 2

POLYSACCHARIDES

Plant polysaccharides are well known for their immune modulating abilities, through enhancing host immune defence mechanisms as well as providing potent antioxidant effects.[1] These compounds are found in a wide variety of algae, lichens, herbs, and mushrooms, including reishi and coriolus mushrooms, and astragalus root.[2]

Medicinal mushrooms have been popularly used in folk medicine and as functional foods in Asia. The non-digestible or β-linked polysaccharides, especially β-D-glucans, are well known mushroom bioactive components with various human health benefits; they are large polymeric molecules that are resistant to digestion in the small intestine and fermentable in the large intestine.[3]  

The polysaccharides present in reishi include Ganoderma lucidum proteoglycans (GLPGs),[4] while coriolus contains krestin, polysaccharide-K (PSK) and polysaccharopeptides (PSP),[5] and astragalus contains astroglucans A-C.[6]  These constituents stimulate the non-specific immune system as well as host defence mechanisms.[7]

Reishi contains a number of different compounds; more than 150 biologically active polysaccharides have been isolated from the fruiting bodies.

ENHANCED IMMUNE ALERTNESS AND SURVEILLANCE

Reishi contains a number of different compounds; more than 150 biologically active polysaccharides have been isolated from the fruiting bodies. These active constituents have been scientifically proven to have antioxidant, immune modulating, antiviral and antibacterial effects.[8] Some of the mechanisms through which GLPGs from reishi exert these effects to provide enhanced immune alertness and surveillance include:

• Binding to cell-surface receptors on the surface of immune cells, leading to alteration of the activities of macrophages, T helper and natural killer (NK) cells[9];

• Activating peripheral blood mononuclear cells, and activating an innate anti-infective and inflammatory response[10];

• Promoting lymphocyte proliferation and differentiation[11];

• Inhibiting viral replication[12]; and

• Promoting antibody production.[13]

The immunomodulatory effect of polysaccharides extracted from mushrooms has been attributed to recognition of these substances by specific receptors (Figure 2), such as Toll-like receptors (TLR), complement receptor 3 (CR3), NOD-like receptors (NLR), RIG-I-like receptors (RLR), and Dectin. These receptors initiate the immune response during an infection of fungal origin, inducing macrophages, NK cells, dendritic cells, neutrophils, and monocytes to produce cytokines.[14] These factors lead to increased immune surveillance and defence against pathogens.

EFFICIENT IMMUNE DEFENCE AND RESPONSE

Polysaccharides contained within reishi, coriolus and astragalus have been shown to modulate the microbiota of the intestinal tract, and have been heralded as effective prebiotics. The polysaccharides derived from higher fungi are reported to elicit diverse beneficial effects in numerous studies, while more recent research suggests that the beneficial health effects of fungal polysaccharides may result from their role as prebiotics.[15] 

Most polysaccharides are non-digestible in the human gut, but can be fermented and utilised by the gut microbiota, or interact with the immune cells in the gastrointestinal tract (GIT).[16]  Animal studies have found that polysaccharide administration could significantly up-regulate the expression of occludin, nuclear factor κB p65 (NF κB p65) and secretory immunoglobulin A (SIgA) in the ileum, and markedly improve the levels of interferon-γ (IFN-γ), interleukin-2 (IL-2), and interleukin-4 (IL-4).[17]  

Previous studies suggest that intestinal bacteria possess distinct polysaccharide preferences, and that these molecules may favour the growth of specific bacterial species in the gut microbiota that ameliorate dysbiosis and repair elevated intestinal permeability.[18] Furthermore, astragalus has also been shown to promote beneficial gut biota and also reduce numbers of harmful bacteria, likely due to its polysaccharide concentrations.[19]

Polysaccharides contained within reishi, coriolus and astragalus have been shown to modulate the microbiota of the intestinal tract, and have been heralded as effective prebiotics.

The gastrointestinal microbiota, in turn, affect other aspects of gastrointestinal function. It interacts closely with the immune system via the intestinal mucosal-associated lymphoid tissue (MALT), and accompanying gut-associated lymphoid tissue (GALT) which are filled with macrophages, dendritic cells and lymphocytes. The utilisation of polysaccharides by the gut microbiota and subsequent interaction with GALT are capable of taking a number of different actions:

• Improve the antioxidant activity of gut tissue[20];

• Affect the levels of secretory immunoglobulin A in the intestinal mucosa[21];

• Prevent apoptosis of intestinal epithelial cells[22];

• Modulate the function of macrophages[23];

• Induce apoptosis of inflammatory corpuscles[24];

• Modulate the levels of cytokines in intestinal mucosal lymphocytes and peripheral blood[25]; and

• Modulate the production of chemotactic factor,[26] proteins that attract phagocytes to pathogen invasion sites.[27]

GALT tissues comprise almost 70% of the entire immune system,[28]  illustrating the significance of the GIT in the maintenance of a strong, healthy immune system. Extracts of reishi and coriolus therefore have the capacity to affect both local GIT immune responses and systemic responses by improving intestinal barrier integrity, modulating intestinal immune functions and regulating the composition of intestinal microbiota.[29]

MODULATION OF IMMUNE SIGNALLING FOR APPROPRIATE RESPONSE

In conjunction with enhancing immune system defences reishi, coriolus and astragalus have demonstrated immune-modulating properties. Compounds from mushrooms have displayed anti-inflammatory properties via inhibition of NFκB, antioxidant activity, antihistamine activity, decreasing IL-1β expression, TNF-α, and other pro-inflammatory cytokines. 

This is achieved through their ability to stimulate peripheral blood mononuclear cells (PBMCs) such as lymphocytes, monocytes and granulocytes. Additionally astragalus increases the number and activity of T regulatory (Treg) cells by increasing Foxp3 activity. The transcriptional factor Foxp3 controls the differentiation of CD4 naïve T cells into Tregs, Th1, or Th17. Foxp3 is the master transcriptional factor required for the development and function of Tregs.[30] 

This results in the downstream reduction of inflammatory cytokine production, especially IFN-gamma, TNF-α and IL-17 secretion; and decreased levels of pro-inflammatory, destructive cytokines (e.g. IL-1, TNF-α, INF-y). Simultaneously, the production of anti-inflammatory cytokines (e.g. IL-10, TGF-β) is increased.[31]  

These mechanisms support a healthy immune response and help to prevent a slide into autoimmunity, by reducing inflammation and a switch to Th2 dominance. Further, Treg cells are also important for the maintenance of an intact mucosal barrier, the significance of which will be discussed further below.[32]

SUPPORT FOR RECURRENT INFECTIONS

Astragalus, reishi and coriolus are recognised as potent immune stimulants and immunomodulators in traditional Chinese medicine (TCM).[34],[35],[36] Reishi and coriolus are specific for the treatment of upper respiratory infections, and are highly prized in Eastern herbal medicine. In TCM, reishi is especially useful for upper respiratory tract infections characterised by wheezing or a chronic cough.[37],[38]Modern research has shown that reishi extracts display a wide range of antimicrobial characteristics against various bacterial, fungal and viral pathogens, with its polysaccharide components being the major antimicrobial compounds. 

Many researchers have found that the polysaccharides in reishi have antibacterial effects that are able to inhibit gram-positive and gram-negative bacteria in vitro. It has been shown that reishi extracts are more effective than antibiotics against pathogenic bacterial species such as Escherichia coli, Micrococcus luteus, Staphylococcus aureus, Bacillus cereus, Proteus vulgaris, and Salmonella typhimurium. Other research has revealed that crude and purified extracts of reishi had significant antibacterial activities in vitro against E.coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebseilla pneumonia, S. aureus, B. cereus and Actinomyces spp. Reishi extracts showed a higher activity against S.aureus and B.cereus than the antibiotics ampicillin and streptomycin. This illustrates its potential value in the treatment of recurrent bacterial infections, without risking the negative side effects associated with antibiotics.[39]

REBUILDING AFTER IMMUNE SUPPRESSION

In an animal study, rats were given polysaccharide derived from reishi to investigate the effects on intestinal barrier function, including the mechanical, immunological and biological barriers. Rats treated with reishi polysaccharide experienced a significant up-regulation of occludin, NK-kβ p65 and SIgA, illustrating its protective and regenerative value. There was also a decrease in diamine oxidase (DAO) levels, an enzyme involved in the metabolism and deactivation of histamine in the gut. Furthermore, the polysaccharide reduced the total Firmicutes:Bacteroidetes ratio, indicating its ability to regulate intestinal barrier functions, reduce inflammation and enhance immune function.[40]

Reishi extracts showed a higher activity against S.aureus and B.cereus than the antibiotics ampicillin and streptomycin…

Medicinal fungi polysaccharides have also been shown to assist with recovery and the immune deficits associated with antibiotic use. 

In a human trial, amoxicillin therapy was associated with changes in the prevalence of several bacterial genera, the most notable being an increase in Escherichia/Shigella spp. Although Escherichia/Shigella spp. bacterial groups are considered commensal, significant increases in their populations are undesirable. Analysis of microbial population shifts by discriminant analysis and biplots confirmed marked microbiome changes during antibiotic treatment that persisted after the end of the antibiotic exposure. 

Using similar analyses, the researchers found that the PSP group differed from the control and antibiotic groups at baseline, although the microbiome composition of the PSP group showed a clear change during treatment that was consistent with a prebiotic effect. This highlights the value of PSP from coriolus in supporting the body during immune suppression situations, such as during antibiotic administration, which can negatively impact the microbiota.[41]

Research also suggests that the medicinal mushrooms coriolus and reishi are valuable in the prevention, treatment and post treatment recovery of cancer. This is due to their ability to activate macrophages, T lymphocytes and NK cells. These immune cells secrete TNF-α, IFN-y, and IL-1β, which are anti-proliferative and induce apoptosis in tumour cells.[42]

PSK and PSP from coriolus have been used in Asia as chemotherapy agents in the treatment of cancer for over 30 years. Several randomised clinical trials have suggested the efficacy of PSK as an immunotherapy or biological response modifier (BRM). BRMs potentially have the ability to improve the "host versus tumour response," thereby boosting the body’s ability to defend itself from tumour progression. Interestingly, studies have also shown that PSK may actually inhibit carcinogenesis, by inhibiting the action of various carcinogens on cells. This may assist with the prevention of second primary tumours when a carcinogen (such as tobacco or asbestos) is suspected, and may also prevent second malignancies due to the carcinogenic effects of radiotherapy and cytotoxic chemotherapy.[43]

In addition to this, plant polysaccharides have also shown promise in the recovery and rehabilitation following cancer therapy, when patients are in remission. A phase I, two-centre, dose escalation study was done to determine the maximum tolerated dose of a Trametes versicolour preparation. The preparation was taken daily in divided doses for six weeks after completion of chemotherapy and radiotherapy. The primary objective of this study was to evaluate the safety and tolerability of Trametes versicolour in women with breast cancer in the post-radiotherapy setting. The secondary aim was to gather data that compared pre- and post- radiation therapy baselines, on treatment and post-treatment immunologic measures. The results indicated daily increased lymphocyte counts at an intake of 6 and 9 g/day; increased NK cell functional activity at 6 g/day and dose-related increases in CD8+T cells and CD19+ B cells, but not the CD4+ T cells or CD16+56+NK cells. 

The findings show that up to 9 g/day of a Trametes versicolour preparation is safe and tolerable in women with breast cancer, after treatment with chemotherapy and radiotherapy. It also shows promise in improving the immune status of immunocompromised breast cancer patients, following these conventional oncology regimens.[44]

RELAPSING VIRAL INFECTIONS

A randomised study investigated the efficacy of coriolus and reishi, in combination with a third medicinal mushroom, Laetiporus sulphureus (LS), on the clearance of oral human papillomavirus (HPV, serotypes 16 and 18). Among 472 patients who underwent oral swabs for gingivitis, 61 patients were positive for HPV16 or HPV18. Twenty patients were included in group 1 (LS group), and 41 patients were included in group 2 (coriolus + reishi group) for two months. Polymerase chain reaction (PCR) for HPV was performed at inclusion and again after two months. In group 1, the clearance was equal to 5% after two months of treatment. In group 2, the clearance was equal to 88% (p<0.001)[55], further indicating the value of medicinal mushrooms in the treatment of stubborn, chronic viral infections.

Persistent infection with carcinogenic HPV is linked to high-grade lesions and cervical cancer,[56] and is also responsible for a large percentage of genital warts, and anal, vaginal, and oropharyngeal cancers.[57] In a clinical trial, participants were divided into 2 groups: those with low-grade squamous intraepithelial lesions (LSIL) defined by HPV and CIN I, and those with high-grade squamous intraepithelial lesions (HSIL), defined by CIN II and CIN III. Fifty percent of the LSIL group was submitted to coriolus versicolour supplementation for a period of one year (six tablets a day, equivalent to 3 g/day). 

The remaining 50% received no supplementation or other medical treatment (control group). The second group (HSIL) was submitted to cone biopsy and, immediately after, 50% took coriolus supplementation for a period of one year (six tablets a day, equivalent to 3 g/day). Again, the remaining 50% received no supplementation or additional medical intervention. In the LSIL group, of the 11 patients who took Coriolus supplementation over the year, only 1 still showed positive cervical cytology (LSIL) after a year of follow up. Of the eight patients who did not take any supplementation, four still showed positive cervical cytology (LSIL) after a year of follow-up. 

The four patients who were HPV+ High Risk and received coriolus supplementation all reverted to HPV- High Risk status after one year. Of the three HPV+ High Risk status patients who did not receive coriolus supplementation, all remained HPV+ High Risk.[58]

GLPG inhibits viral replication by interfering with the early events of viral adsorption and entry into target cells.

Some GLPGs from reishi have shown significant HIV-1 protease activity. Other research has found that Ganoderic acids had antiviral activity against HIV and Epstein-Barr virus.[59] Additionally, a 2009 animal model observed a switch to Th1-dominant immune regulation, along with increased exercise tolerance in chronic fatigue rats who were administered with astragalus, which suggests potential benefit for the use of astragalus in post viral syndrome and chronic fatigue.[60]

GLPG exhibits strong antiviral activity against herpes simplex virus 1 (HSV1) and 2 (HSV2) in vitro. The effects may be attributed to its ability to inhibit viral replication by interfering with the early events of viral adsorption and entry into target cells. A study found that GLPG inhibits the appearance of cytopathic effects in HSV-1 infected vero cells. Twenty-four hours after infection, HSV-1 exposed vero cells started to display signs of infection characterised by cell rounding and clumping. However, in the presence of GLPG these effects were found to be inhibited. GLPG prevented cell detachment, rounding and clumping. A concentration of 1000 μg/mL of polysaccharide provided significant protection against the destruction of the cell monolayer by HSV during the experimental period, for two hours. GLPG showed strong antiviral activity against HSV-1 and HSV-2 when present before, during and after viral infection. This suggests that GLPG inhibits viral replication by interfering with the early events of viral adsorption and entry into target cells.[61]

In another trial, 36 patients suffering from chronic fatigue were recruited. Each participant had been exposed to, and had antibodies to at least one of a number of viral infections, including Epstein-Barr, Cytomegalovirus, HSV, Polio, Adenovirus and Retrovirus. The participants received 3 g of coriolus daily. T cells [CD3+CD26] showed increased activation in two thirds of the patients and a 77% activation for the T cells [CD3+HLA-DR+] at the end of the study period. NK cells were found to be low in the participants before treatment, however, after supplementation with Coriolus there was a 35% increase in these cells after 2 months of treatment.[63]

IMMUNE MODULATION RELATED TO AUTOIMMUNITY

Underlying, recurrent infections and associated chronic inflammation are thought to play a role in autoimmune pathophysiology. Therefore, in those with autoimmune diseases, potential investigation and treatment of immune imbalance, as a result of persistent infections and reduced immunity, should be conducted. As discussed, astragalus, reishi and coriolus have the capacity to improve immune alertness, surveillance and signalling to assist in these cases. 

Research indicates that these herbal remedies can also play a direct role in the treatment of autoimmune progression. Treg cells play an essential regulatory role in the pathogenesis of autoimmunity. As previously mentioned, astragalus increases the number and activity of Tregs by increasing Foxp3 activity. The induction or transplant of Treg cells leads to a reduction in disease severity in autoimmunity. In an animal study, astragalus treatment significantly reduced levels of pro-inflammatory, destructive cytokines associated with excessive T-helper cell activity - especially IFN- y, TNF-α and IL-17 secretion.[64] Additionally, Foxp3 activity was increased by astragalus application, suggesting the beneficial impact of astragalus in halting autoimmune disease activity and slowing progression.[65]

Astragalus increases the number and activity of T regulatory cells by increasing Foxp3 activity, suggesting the beneficial impact of astragalus in halting autoimmune disease activity and slowing progression.

Dysfunction of Treg cells is closely associated with the development and progression of inflammatory bowel disease. In another animal study, rats were randomly divided into groups. Colitis was induced with 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) which was followed by treatment with 400 mg/kg of astragalus polysaccharide (APS) for seven days. After treatment with APS, the weight index of the colon and colonic weight were decreased, while the colonic length was increased in comparison to the model group.[66] Additionally, levels of IL-2, IL-6, IL-17, IL-23 and RAR-related orphan receptor gamma (ROR-γt), a transcription factor which promotes thymocyte differentiation into pro-inflammatory Th-17 cells),[67] in the colonic tissues was down-regulated, but Treg cells (TGF-β and STAT5a) in intestinal Peyer’s patches were up-regulated.[68] These effects indicate the value of APS in the treatment of a wide range of conditions, particularly in those with an autoimmune element.