The Turkey Tail Mushroom (Coriolus versicolor); A thousand year story from Energising Tea to Cutting-Edge Anti-Cancer Agents.

By Jaydon Inott

Coriolus versicolor, known as ‘Turkey Tail’ for its appearance, is an inedible saprophytic fungus of the Basomycedes class, appearing on the trunk and logs of nearby hardwood trees. In this monograph, we trace the medicinal use of Coriolus versicolor from ancient China, to its’ promise as one of the first examples of cancer immunotherapy. We outline the history, use and identification of Coriolus versicolor to then provide a brief, critical review of its extracts used in acclaimed anticancer therapies in the East. The monograph reveals the promising bioactivities and safety profile of Coriolus versicolor extracts, which have largely alluded attention for medicinal use in the West.

Popular History and Contemporary Use

When you hear the word ‘fungus’, you would be forgiven for immediately thinking of the invasive species, which we work to keep at bay in the garden. The same is true in the clinic, where a physician may immediately think of fungi for their pathogenic nature. Yet, we also know that the kingdom of fungi is a diverse group inhabiting a wide range of ecological niches, forming intimate symbiotic relationships with our trees and living complex lifecycles; as a group, they may provide a rich source of functional properties and biochemical pathways to the gardener and physician alike.

The use of medicinal mushrooms is limited in Western medicine, but they have enjoyed a long history in Eastern medical systems. The Reishi mushroom (Ganoderma lucidum) has been known as the mushroom of immortality and appeared in depictions of emporers’ tea ceremonies (Figure 1). While Coriolus versicolor did not enjoy such an illustrious position as the Reishi mushroom (Ganoderma lucidum) in the East, it has featured in the Chinese Materia Medica since around 200 BC (Han Dynasty).

The 15th century Materia Medica (Ben Cao Gang Mu) listed Coriolus versicolor, then drunk as a tea, to be beneficial to the spirit (Shen), vital energy (Chi) and able to strengthen bone and tendon. Since the 1960s, extracts from Coriolus versicolor have been used in Japan and China for the treatment of various types of cancer, gathering clinical experience as licensed medicinal products. As a result, the extracts from Coriolus versicolor have become the most extensively researched of the mushroom extracts (Kidd, 2000).

Preliminary investigations into the bioactivity of Coriolus versicolor began in Japan the 1960s following a case of remission in an individual with metastatic cancer. These investigations led to the isolation of β-d-glucan Polysaccharide-K (PSK), a heteropolysaccharide. A hot water extraction technique was refined, and a programme of clinical trials launched with Polysaccharide-K appearing under the trade name of Krestin (Oriveda; Accessed 16Mar18). By the 1970s, positive results led some Japanese institutions to add Polysaccharide-K to their chemotherapy protocols by virtue of their immunostimulating activity (Kaibura et al., 1976). In 1983, the closely related Polysaccharide-Peptide (PSP) was isolated in China and eventually approved by The Chinese Medicines Authority as adjuvant therapy in Lung and Gastrointestinal Cancer. These developments appear to be the first application of ‘immuno-oncology’, a concept that is now at the forefront of cancer research. Immuno-oncology recognises the role of the immune system in providing a defence against cancer. A range of novel molecules are being researched and used, aiming to prevent malignant cells from evading the immune system (Chen and Melman, 2003). There is evidence that the β-glucans from mushrooms, as we will see through the example of Turkey Tail, stimulate the immune system and pose an enticing complement to the latest therapies.

In the West, only a few preliminary clinical trials have been performed, and there is little recognition of medicinal mushrooms in conventional medical practice (Tsang et al., 2003; Smith et al., 2002). Meanwhile, whole mushroom powders are appearing as nutritional supplements in health stores said to support energy levels and immune function (Reis et al., 2017). Mushroom extracts are, however, added to some complementary treatment regimens used by practitioners of Integrative Oncology (Guggenheim et al., 2014). The increased recognition of immuno-oncology and integrative practices may draw more attention to these humble mushrooms appearing in our forests.

Biological Characteristics and Identification

Coriolus versicolor is a widely distributed, saprophytic polypore fungi belonging to the Basidiomycetes class. They are very widely distributed, found living on tree trunks and logs in the forests of tropical, temperate and boreal zones. Consequently, they have an array of common names: Turkey Tail (North America), Yun Zhi (China), Kawaratake (Japan), and also several Latin synonyms: Trametes Versicolor, Polyporus versicolor (Mycobank; accessed 22Mar18). Although none were seen in the Mecklenburgh Square Gardens at the time of writing, they are likely to appear on the trunks of hardwood trees in the garden, or nearby.

The mushroom has a tough, leathery surface, which renders it inedible. The surface alternates between hairy, smooth and coloured zones. The coloured zones are predominantly shades of white, brown and orange. Occasional lines of green, blue and maroon pigments are seen. Pores are often white, but sometimes yellow. Layers of overlapping fruiting bodies are found clinging to a dead log in a shelf-like formation (Figure 2; Kuo, 2017)

Identification of the species can be difficult, 15 sister species have been found in Canada and the USA. There have, however, been no records of poisonous species within the Coriolus or Trametes genus (MAMI, Accessed: 21Mar18). Work has been done to genetically identify strains of Coriolus versicolor and enable more precise identification for medicinal purposes, but the wide distribution and pigmentation is likely to confer a diverse range of properties within the species (Lee, 2006).

Phytochemistry

Polysaccharide-K and Polysaccharide-peptide are very similar; large molecules composed of approximately 62% polysaccharide and 38% is peptide. Both are heteropolysaccharides, containing a diverse set of saccharide units bound by 1→3 and 1→6-β-d-glycosidic bonds (Ruthes et al., 2015a). Polysaccharide-Peptide is found exclusively in the mycelia, containing rhamnose and arabinose. Polysaccharide-K is extracted from the fruiting body, containing fucose. A series of long-chain polysaccharides may be bound to the peptide at one terminus with long, branched polysaccharides trailing behind, likely forming a complex structure (Ruthes et al., 2015b).

Animal studies have investigated the activity of a wide range of mushroom polysaccharides and found comparative bioactivity in molecules with very different saccharide units (Ramberg et al., 2010). As a result, it is hypothesised that their characteristic branched form (1->6- β-d-glycosidic bonds) or high molecular weight is responsible for their bioactivity (Figure 3, Ruthes et al., 2015a).

Polysaccharide-K and Polysaccharide-Peptide are partially digested in the gastrointestinal tract, with smaller molecules found in the blood soon after ingestion. Larger fractions have been observed four hours after ingestion, suggesting that longer molecules are absorbed by slower processes (Masanori et al., 1988). There are, therefore, molecules of varying length in the blood, which may confer different actions or potency (Bohn & Bemiller, 1995).

Whole Mushroom Composition

The whole mushroom contains an array of steroids, triterpenes, organic acids and alkaloids (Reis et al., 2017). Ergosterol (provitamin D2) derivatives are found and, like many mushrooms, they are a good source of dietary fibre. Collectively, these properties may lead to some activity as antioxidants and pro-biotics (Cheung, 2013; Aida et al., 2009). The Coriolus versicolor triterpenes, a promising group of compounds for bioactivity, remain relatively unexplored at the time of writing but supplements are found on the market advertising triterpene content as a benefit. The exploration of mushroom triterpenes has predominantly focused on Ganoderma luciderm, which is seen as a richer and more varied source (Wu et al., 2013).

Preclinical Data

A 2015 review of preclinical studies found that 15 out of 17 studies supported immunostimulatory and anti-cancer effects of Polysaccharide-K (Fritz et al., 2015). Several immune cells, namely the dendritic and natural killer cells, have been found in higher concentrations after administration of Polysaccharide-K (Kariya et al., 1992). These cells, which form the front line of the immune system, are suspected to interact directly with Polysaccharide-K or Polysaccharide-Peptide, setting off a cascade of immuno-modulating signals, cytokines (Pedrinaci et al., 2009). There have been a range of cytokine responses to Polysaccharide-K, but the cascade of events is thought to augment the activity of natural killer and dendritic cells, also activating other cytotoxic immune cells (Saleh, 2017; Tsujitani et al., 2008).

It may not be surprising to learn that ingesting mushrooms stimulates our immune systems; defence from pathogenic fungi would confer an evolutionary advantage. There are indications, however, that the stimulatory effect of β -glucans does not just increase activity, but promotes a shift in the immune state.

Some immunologists think of the immune system as a balance between two or more distinct arms, characterised by the activation of T-Helper 1 (Th1) and T-Helper 2 (Th2) cells (Corey, 2014). Activation of the Th1 arm leads to a higher population of cytotoxic T-cells, which may engage with malignant cells (Knutson and Disis, 2005). On the other hand, overstimulation of Th2 is implicated in chronic inflammation; a condition thought to favour tumour growth (Yu, 2006). The direct interaction of β-glucans with dendritic cells could assist in shifting the balance to a Th1-dominant state, providing conditions favourable to attacking cancer cells (Powell, 2014). Some studies indicate that administration with β-glucans shifts immune sytem towards Th1 activity by measuring white blood cell counts and chemical (cytokine) profiles following ingestion (Saleh, 2017). Polysaccharide-K and Polysaccharide-Peptide may also support an environment conducive to tumour suppression by acting as anti-oxidants either directly or stimulating biochemical pathways leading to antioxidant activity (Wei, 1996).

Efficacy- Human Studies

After more than 40 years of experience with Polysaccharide-K and Polysaccharide-Peptide in Japan and China, the evidence for the anticancer activity appears compelling at first sight (Wasser, 2017; Kidd, 2000; Fritz et al., 2015). Some sources list all of the studies to date, but do not highlight the challenges of interpreting the results (See supplement, Table 1, for a list of general observations during our review). For these reasons, and many more, the information should not be seen as a substitute for guidance from a Medical Oncologist and Turkey Tail should in no way be considered a replacement therapy. It is worth noting that many of the studies are over 30 years old, and the research and treatment of cancer is rapidly evolving. Consequently, the older studies may not provide results that are easily compared to current standards of care. Also, in all studies, Polysaccharide-K and Polysaccharide-peptide were given as an addition to standard chemotherapy, radiotherapy and surgical approaches rather than a replacement therapy.

With this caution in mind, we draw focus to recent trials that have avoided methodological traps and to meta-analyses, which allows us to look at larger datasets and offset some of the shortcomings of individual studies to see trends.

Lung Cancer

Tsang et al., 2003 showed a statistically significant improvement in clinical symptoms, immune system markers and quality of life measures in patients with stage I to III Lung Cancer who received Polysaccharide-Peptide or placebo for 28 days following standard chemotherapy. This study was relatively small (116 patients) and short in duration, only measuring clinical markers rather patient outcomes (6 weeks of treatment) but provides recent evidence to support the proposed mechanism of action. A systematic review of trials was conducted in 2015, indicating a statistically significant difference in 5-year survival outcomes for patients receiving Polysaccharide-K in two trials covering 301 patients (Ikeda et al., 1986; Hayakawa et al., 1997). Of the 11 studies reviewed, only Tsang et al.,2003 met the highest standard for clinical trial design (JADAD score) and occurred in the last 20 years. However, taking the evidence from old and new studies together, the authors concluded that there is a favourable signal for Polysaccharide-K activity against lung cancer across the trials (Fritz et al., 2015).

Gastro-Intestinal Cancer

A recent meta-analysis of 23 studies covered 10,684 cases of Gastro-intestinal Cancer where Polysaccharide-K or Polysaccharide-peptide had been given to patients in addition to standard therapies. The combined analysis indicated that the addition of Polysaccharide-K or Polysaccharide-peptide to conventional chemotherapy regimes, led to a statistically significant improvement of three and five-year survival rates, but minimal impact was seen on seven-year survival rates (Ma et al., 2017).

Toxicology

Polysaccharide-K and Polysaccharide-peptide appear well tolerated in the clinical trials referenced above, commonly using 3g per day. Side effects were mild gastrointestinal symptoms and darkening of the fingernails, occurring uncommonly (≥ 1 in 1000 to < 1 in 100 of cases) (Maehere et al., 2012; Fritz et al., 2015; Ma et al., 2017). Interestingly, patients receiving Polysaccharide-K have a lower incidence of fatigue and adverse haematological parameters such as neutropenia, indicating that Polysaccharide-K may attenuate the toxicity from standard chemotherapy (Kidd, 2000). On the other hand, the safety of the whole mushroom, including the full myriad of fungal compounds, is only supported by anecdotal evidence and its use in Traditional Chinese Medicine.

Importantly, the safety profile has been observed with older chemotherapy agents and may not correlate to their concomitant use with novel treatments. Additionally, the immune system is eminently complex. There is a chance that stimulation of the immune system could predispose patients to a higher risk of autoimmune reactions, where the immune system may attack normal cells. So, the immunogenicity of β –glucans propels the agenda for research but raises questions about their use in long-term or prophylactic treatment.

Conclusion

Turkey Tail (Coriolus versicolor) is a widely distributed mushroom, long believed to provide benefits to energy and vitality in Chinese Medicine. These claims may be supported by the immunostimulatory action of the β –glucan polysaccharides, Polysaccharide-K and Polysaccharide-peptide, as explored in pre-clinical and clinical research. Overall, Polysaccharide-K and Polysaccharide-peptide extracts demonstrate some activity in lung and gastrointestinal cancers, moderately improving survival time. More trials are needed, however, given issues with the design of earlier trials and a rapidly evolving clinical landscape.

There is a demonstrable elevation in immune activity following the ingestion of Polysaccharide-K and Polysaccharide-peptide in pre-clinical and clinical studies, possibly supporting their role as add-on therapy in contemporary immunotherapy regimes. It is important to note that these β –glucans should only be considered as an add-on therapy, requiring a detailed consultation with a health care practitioner. They should not be considered a replacement to therapies recommended by your healthcare practitioner, or hinder the ability of an individual to take other, more efficacious options. It is also important to note that the Turkey Tail has been consumed as a tea or extract throughout its history, it is considered inedible and tests have not been performed on consumption of raw material. Despite the favourable safety profile of Turkey Tail extract, close medical observation is needed, especially when taken with other medications targeting the immune system. The combined effect of Turkey Tail β –glucans and novel immunotherapy treatments have, so far, not been tested. However, the body of evidence goes some way to merge knowledge from East and West, raising awareness of the potential for medicinal mushrooms as an avenue for further research.

Supplemental Information

General Observations Clinical Trial Data

Table 1: List of observations leading to studies being discounted as conclusive evidence based on those listed in Wasser (2017). See Pilkington et al., 2016 for a comprehensive list of considerations.

The Author:

Jaydon Inott holds a Bachelor of Biotechnology and has over ten years experience of clinical research operations in the pharmaceutical sector. He is also an advocate for sustainable development, ecological food production and functional nutrition; interlinking topics explored through his travels, volunteer work and academic studies. Jaydon is currently pursuing a Masters of Environment and Sustainable Development at University College London. He now brings his experience and interests together with a focus on natural medicines within the School of Pharmacy.

Disclaimer:

In this essay we do not to advise or recommend herbs for medicinal or health use. This information is intended for educational purposes only and should not be considered as a recommendation or an endorsement of any particular medical or health treatment. The use of any such product should be based on the appropriate advice of a health care professional or based on the information available in the patient information leaflets.

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