Immunomodulating properties of beta glucans derived from shiitake mushroom
Lentinula edodes, better known by its Japanese name – shiitake mushroom, is a wood rot fungus that grows on fallen tree trunks or tree stumps. An edible mushroom with a long history of use in East Asian medicine, shiitake is one of the most cultivated mushroom species worldwide.1 It is a popular food due to both its taste and nutritional value, and a valued medicine owing to its anti-fungal, anti-bacterial, anti-viral, hepatoprotective, anti-tumour and immunomodulatory activity.2,3
Traditionally shiitake mushroom was adopted as a tonic that could alleviate the aches, pains and fatigue associated with ageing. It was also used for conditions affecting the heart and lungs, for intestinal worms and for various cancers.4 Contemporary research has focused on the immunomodulatory role exerted by shiitake mushroom.
Some of the reported bioactive constituents of shiitake mushroom include; phenolic compounds, arabinoxylan, syringic acid, vanillic acid, and the high molecular weight polysaccharide, lentinan.5,6 Mushroom polysaccharides, which exist as a structural component of the cell wall, are thought to account for the majority of its clinical effects. Polysaccharides such as shiitake mushroom's lentinan, are beta glucans with a 1,3/1,6 glycosidic linkage pattern and belong to a class of molecules known as biological response modifiers (BRM), a term used to describe immunoactive compounds which mobilise the body’s own defences against tumorigenesis, infection and other diseases.3,7
Whilst rice bran arabinoxylan compound (RBAC) is considered to be the ’gold-standard’ biological response modifier in oncology support due to its wealth of clinical data and practitioner feedback; an increasing amount of research suggests that polysaccharides from Lentinula edodes are also able to improve quality of life, reduce the side effects of various cancer treatments and improve immune function in immunosuppressed cancer patients, and may be a useful adjunct to treatment alongside RBAC.
Mechanism of Action
Mushroom derived beta 1,3/1,6 glucans are recognised by receptors on host immune cells as a pathogen associated molecular patterns (PAMPs). Immune cells such as macrophages detect PAMPs through various Pattern Recognition Receptors (PRR’s) such as toll-like receptor-2, dectin-1, complement receptor-3, lactosylceramide and others.7 Subsequently, identification of beta glucans as non-self molecules by mammalian cells induces beneficial innate and adaptive immune responses, which modulate inflammatory, antimicrobial and anti-tumour activities, see figures 1 and 2.7
Adaptive immune responses play an important role in cancer resistance. In the course of cancer progression, there appears to be a marked deregulation in the balance of Th1 and Th2 immune responses, with a progressive loss of Th1 type responses. Therapies which reduce the Th2 dominant responses and increase Th1 responses could therefore improve cancer resistance. In vivo studies demonstrate that mushroom derived beta glucans induce Th1 cell development, and play an important role in maintaining the balance between Th1 and Th2 responses, see figure 2.7
Broad clinical applications
Mushrooms produce antibacterial and antifungal compounds so that they can survive in their natural environment, and these substances could produce beneficial effects in humans. Actives from Lentinula edodes have demonstrated an antibacterial effect against Staphylococcus aureus and antiprotozoal effect against Paramecium caudatum. Antiviral effects have also been demonstrated from whole extracts and isolated compounds of various mushroom species. These direct antimicrobial effects are likely complemented by indirect antimicrobial activity by immune stimulating polysaccharides, or other complex molecules.8 Preliminary clinical data also supports the use of shiitake mushroom as a hypolipidaemic, hypoglycaemic and hepatoprotective agent.9-12
Clinical data: In vitro and in vivo models
Polysaccharides from Lentinula edodes extract have demonstrated a significant antioxidant effect in vivo, with high molecular weight polysaccharides increasing the activity of antioxidant enzymes, and reducing the level of malondialdehyde in most tested organs.13 Other antioxidant and phenolic compounds from shiitake mushroom have also been identified.5
Various experimental models using shiitake mushroom have demonstrated immunomodulatory effects, including reduced immunosuppression and enhanced anti-tumour effect of cancer therapy. Animal studies also demonstrate that administration of shiitake extract leads to a decrease in tumour inducing Treg cells and TGF-ß.6,14
Human clinical data: Chemotherapy related side effects
Chemotherapy produces significant adverse effects such as haematotoxicity, nausea, vomiting and hair loss, and whilst the use of 5-HT3 receptor antagonists allow some degree of control of late onset nausea, patients continue to experience fatigue and a decrease in their activity and daily quality of life (QOL). In addition, although host immunity is known to affect recurrence rate of certain cancers, chemotherapies commonly have adverse effects on immune function.15 Reducing side effects from chemotherapy treatment may extend the time patients are able to tolerate treatment, and importantly, improving immune competence post-chemotherapy may also prevent cancer recurrence or extend lifespan.5 Consequently there is a need for treatments that can maintain and/or improve the QOL and immune function of patients undergoing chemotherapy.15
Along with RBAC, shiitake mushroom has the potential to improve the QOL in a broad range of cancer treatments, with positive results seen in both chemotherapy and immunotherapy treatments, as well as post-operative hormonal treatments in human clinical trials, see table 1.
The mechanism by which shiitake mushroom is able to improve QOL and reduce side effects during cancer treatment is not fully understood. It is known that antioxidants can reduce chemotherapy related side effects; however the antioxidant activity of shiitake mushroom is not thought to play a predominant role. Rather the immunoactive polysaccharides or combined synergy of all active constituents are believed to mediate the positive results seen in clinical trials.5
Chemotherapy induced immunodysfunction
Considering the importance of the role of host immunity in cancer progression, shiitake mushroom could offer a novel treatment adjunct to other well-studied biological response modifiers such as RBAC compound, in preventing or extending the time to cancer relapse.
Research has demonstrated shiitake mushroom exerting a beneficial effect on interferon and interleukin immune parameters associated with cancer progression, along with preventing white blood cell depression, and increasing natural killer cell activity during treatment with chemotherapy.14,16,17 Shiitake possesses a high safety profile, with a no observed adverse effect level (NOAEL) considered to be greater than 2000mg/kg in animal models.18
Co-administration of shiitake mushroom with anthracycline based chemotherapies was effective in alleviating decreases in QOL scores, particularly regarding patients physical condition and functional activity.15
Co-administration of shiitake mushroom with chemotherapy was effective in alleviating decreases in QOL scores. Immunological and haematological parameters were also maintained or improved by concomitant use of shiitake mushroom.16
Co-administration of shiitake mushroom significantly improved total QOL scores and immune parameters in those with immune deficiency.14
Table 1: Shiitake mushroom extracts: results from human clinical trials.
|Anthracycline based chemotherapies (5-fluorouracil, cyclophosphamide, epirubicin and doxorubicin/pirarubicin)||Co-administration of shiitake mushroom with anthracycline based chemotherapies was effective in alleviating decreases in QOL scores, particularly regarding patients physical condition and functional activity.15|
|5-fluorouracil, cyclophosphamide, epirubicin||Co-administration of shiitake mushroom with chemotherapy was effective in alleviating decreases in QOL scores. Immunological and haematological parameters were also maintained improved by concomitant use of shiitake mushroom.16|
Hormone therapies (tamoxifen, anastrozole,
|Co-administration of shiitake mushroom significantly improved total QOL scores and immune parameters in those with immune deficiency.14|
|Various types (advanced progression)|
|Immunotherapy (dendritic cell-based cancer vaccine or CD3-activated T-lymphocyte therapy)||Co-administration of shiitake mushroom with immunotherapy significantly improved the total symptom score, and tended to improve the global QOL scores.6|
|Breast and gastrointestinal (gastric, oesophageal, colorectal)|
|Chemotherapy (EC, TS-1, UFT, FOLFIRI)||Co-administration of shiitake mushroom significantly improved total QOL scores and NK cell activity.17|
|Colorectal and gastric cancer (advanced progression)|
|Chemotherapy (5-florouracil, irinotecan, uracil and tegafur, levofolinate, mitomycin or taxol)||Co-administration of shiitake mushroom reduced incidence of nausea and abdominal pain.5|