Medicinal Mushrooms – Going Viral

Mushrooms have been used as both food and medicine since antiquity. One of my favorite poems, discovered in an ancient Egyptian temple, illustrates this history: “Without leaves, without buds, without flowers, yet from fruit; as food, as tonic, as medicine: the entire creation is precious.” At a time when viral epidemics are inevitable and the current COVID-19 pandemic has presented in most of the world, antiviral therapies are possibly being investigated now more than ever before.  This paper explores the use of medicinal mushrooms as antivirals in in vivo (human and animal) and in vitro (petri dish) experiments and how these experiments may inform us on the utilization of these fungi as antiviral therapies.

Medicinal mushrooms are known as biological response modifiers. This physiologic modification is largely a result of the interaction of various mushroom constituents, primarily polysaccharides, with the immune system. Therefore, to understand the role that medicinal mushrooms play as antiviral agents, it is imperative to understand the happenings of the immune system in response to a viral pathogen and the interplay between mushrooms, their constituents, and this system. Unlike pharmaceutical antivirals, the actions of medicinal mushrooms are not straightforward, and there is no absolute rule that mushrooms stimulate or depress immunity. Mushrooms contain many constituents and are dynamic in their interplay with the human body.

Overview of anti-viral immunity 

The initial immune response to a new pathogen is facilitated by the innate immune system (innate meaning inborn or natural). This is our first response to non-self organisms, and requires no other stimulation than the pathogen itself. It is the response that is ready to go at all moments in the day and persistently protects the human body from infection. It is easy to imagine that an altered or defective innate immune response can have a detrimental effect on the ability to fight disease.

The innate immune response to a virus is multidimensional. There is a massive amount of cell-to-cell communication and different chemicals (called cytokines) are released to make this communication possible. Once an epithelial cell (cells that make up the surface of different body tissues like skin, lungs, etc) is infected with a virus, Type 1 Interferon (Interferon-α, a cytokine) is released and has three major functions: to induce resistance to viral replication in all cells, to increase expression of ligands for receptors on natural killer (NK) cells, and to activate NK cells to kill virus infected cells. NK cells are lymphocytes (a small white blood cell that is found primarily in the lymphatic system) that defend against viral infections and tumor cells via cytokine stimulation and direct killing of infected cells. NK cells provide such a vital role in antiviral immunity that people deficient in NK cells suffer from persistent viral infections. These functions of NK cells are important in regards to understanding medicinal mushrooms and their role in antiviral immunity.

Imagine the immune response to a newly inhaled viral particle. This virus enters the healthy person’s lungs and invades the lung epithelium. Once an epithelial cell is infected, it releases Type 1 Interferon, which turns circulating NK cells into cytotoxic effector NK cells (NK cells primed to seek out and kill virally infected cells). The cytotoxic effector NK cells promptly start the process of seeking out infected cells and the innate immune response commences. At the same time, there are resident macrophages in the respiratory epithelium and throughout the body. These macrophages (“big eaters”), are also major players in the innate immune response. Their role is to consume these virus particles and produce chemicals (cytokines and chemokines) that attract and engage more NK cells and also T cells. An important cytokine engaged in this process is interleukin-12 (IL-12), which stimulates NK cells to not become cytotoxic, but rather effector NK cells. Unlike cytotoxic effector NK cells, these effector NK cells stimulate an inflammatory response via Type 2 Interferon (IFN-γ), at the site of infection. This inflammatory cascade consists of IL-1, IL-6, TNF-α, and IL-12, and is essential for viral eradication. It is only when this response is out of control that it becomes problematic and detrimental to the host.1,2,3,4 If this initial response is not primed for viral combat, viral particles continue to proliferate and infect more healthy cells. It is in this phase that medicinal mushrooms can have a great impact to prevent viral infections from taking over the host.

Cytokine Source Role
IFN-α Virus infected epithelium Circulating NK cells –>Cytotoxic effector NK cells
IL-12 Macrophage post virus consumption NK cells –> effector NK cells
IFN- γ Effector NK cells Macrophages –> inflammatory cytokines (TNF-α, IL-2, IL-1, IL-6)
TNF- α Macrophages Induces blood vessels more permeable, enabling effector cells to enter infected tissue
IL-1 Macrophages Induces blood vessels more permeable, enabling effector cells to enter infected tissue
IL-6 Macrophages Induces fat and muscle cells to metabolize, make heat and raise temperature of infected tissue
IL-12 Macrophages Recruits and activates NK cells –> secrete more cytokines that strengthen macrophage response to infection
IL-10 Toxic substances secreted by macrophages–> TH2 Suppress macrophage activation
IL-4 Toxic substances secreted by macrophages–> TH2 Suppress macrophage activation

 

COVID-19 is an excellent example of these two main immune responses.5 The first stage of infection is the less severe incubation phase. The previously mentioned immune response is imperative to eliminate the virus and keep disease from progressing to later, more severe stages. It is in the incubation stage that immune-stimulating therapies are most indicated. In more severe stages, the protective immune response is impaired and the virus will spread and destroy healthy cells. Because damaged cells induce inflammation, immune stimulation is less indicated and it is more favorable to treat with anti-inflammatory therapies. It is at this stage of disease, characterized by severe lung inflammation, that life-threatening respiratory disorders occur and the feared cytokine storm is initiated. The cytokine storm is an influx of inflammatory cytokines. It is an overdramatic immune response that is harmful to the host and can often lead to acute respiratory distress syndrome. The inflammatory cytokines that are so important for stage one of the disease ( IL-1, IL6, TNF-α, and IL-12) are now abundant, destructive and out of control.6,7

The two phase division of the immune response is very important . The first immune response is protective and a response that can be altered through diet and lifestyle: our base response when initially combating infection. As mentioned previously, this is the phase where medicinal mushrooms are most indicated. They are primers of the first response to viral particles.

 

Antiviral immunity in healthy adults

The most informative studies exploring the interaction of medicinal mushrooms and the immune response are done on healthy human adults. In these studies it is ideal to see cytokine and NK cell levels before and after mushroom intake in healthy people to get a good idea of how exactly the mushrooms are priming our innate response. There are not many studies of this kind, but there are a few.

Healthy Korean men who took 1.5g/day of powdered extract of Cordyceps militaris brown rice culture for four weeks had their blood analyzed before and after treatment. Levels of NK cells, IFN-y and IL-12 were examined in blood samples before and four weeks after therapy began. There was a significant increase in NK cells and IFN-y and no difference in IL-12.8 Cordyceps sinensis mycelium extract, in combination with the endoparasitic fungus that commonly exists with C. sinensis, Paecilomyces hepialid, also had immune-stimulating activity in healthy adults. In this study, people were given 1.43g/day and after eight weeks the cytotoxic activity of NK cells was significantly higher than at baseline (before therapy.)9 Wild fruiting bodies of Cordyceps species are incredibly expensive and are therefore rarely, if ever used in research. However, It is likely that cultivated fruiting bodies have similar medicinal qualities.10,11,12

Another study with 52 healthy males and females aged 21-41 consumed either 5g or 10g of Lentinus edodes (shiitake mushroom) daily for four weeks. Eating the Shiitake for four weeks led to increased proliferation of NK cells and IgA, decreased CRP (a marker of inflammation), and an increase in IL-4, Il-10, TNF-α and IL-1. Serving size had no impact on cytokine levels, except that two servings of Shiitake increased serum IL-4.13 Shiitake is a good example of the dynamic effects that some mushrooms have on the immune system. Shiitake both increased inflammatory cytokines (IL-1, TNF-α) and anti-inflammatory cytokines (IL-10 and IL-4) simultaneously, illustrating the use of the term immunomodulatory: it is neither a pure stimulator nor a depressor of the immune system. This may mean that immune modulating mushrooms are safe and effective to take during both phases of the viral immune response, and in fact, may have inhibitory effects during the cytokine storm of acute respiratory distress syndrome.

Grifola frondosa (Maitake) also exhibits this modulating activity.  G. frondosa fruiting body extract produced both immune stimulatory IL-2, TNF-α and IFN-γ and suppressive IL-10 in breast cancer survivors taking 5-7g/kg per day of mushrooms extract for three weeks.14

The combination formula of Trametes versicolor(Turkey tail) and Salvia miltiorrhiza IMG_7864(Red sage root, or Dan Shen) given at 50mg/kg and 20mg/kg respectively for four months showed significant immunomodulatory effects in healthy adults. There was a significant increase in PBMC (peripheral blood mononuclear cells – NK, B and T cells) gene expression of IL-2 receptor, increase in T helper cells and the ratio of T helper cells to cytotoxic T cells. There is also a significant increase in IFN-γ.15 There is little information in western herbal and mycological medicine about the use of plant and mushroom combination formulas. Dan Shen is known to ‘move the qi of the blood’ and in combination with the immune stimulating activity of Turkey tail, has promise as a very useful combination for immune therapy.

Not all fungi are created equally as immune modulators. When the β-glucan isolate, lentinax, from L. edodes mycelium was administered to healthy adults, there was no difference seen in NK cells and inflammatory cytokines between treatment and control groups.16 This juxtaposes the previous Shiitake study where the subjects consumed whole mushrooms and did have immune stimulatory effects. Contrary to what has been suggested in in vitro research 17,18 a mushroom that showed no benefit in vivo was Agaricus blazeii. Healthy elderly women consumed 300mg of A. blazeii fruiting body extract three times daily for 60 days, and there was no change in levels of IFN-γ, IL-6 and TNF-α after administration.19 Perhaps the dose was too low in this study, further research is needed.

Mushroom Cytokine response Immune response (simplified) Phase of viral response most applicable
Grifola frondosa (Maitake) IL-10

IL-2, TNF-α, IFN- γ

Anti-inflammatory

Pro-inflammatory

Possibly severe phase

Prevention/incubation phase

Lentinus edodes (Shitake) IL-4, IL-10

TNF-α, IL-1

Anti-inflammatory

Pro-inflammatory

Possibly severe phase

Prevention/incubation phase

Cordyceps spp. IFN- γ Pro-inflammatory Prevention/incubation
Trametes versicolor (Turkey tail) with Salvia miltiorrhiza (Red sage) IL-2, IFN- γ Pro-inflammatory Prevention/incubation 


Mushrooms as immune-modulators

The increases seen in IL-10 and IL-4 after Maitake, Shiitake, and Cordyceps mycelium intake are important as they relate to TH2 immune responses. TH2 responses are anti-parasitic and anti-allergic, but through the lens of viral immunity and inflammation, are anti-inflammatory. In fact, IL-10 is considered an anti-inflammatory master regulator. 20,21,22,23 IL-10 is essential for defending the host from tissue destruction during acute phases of immune responses, though it is not as desirable in the initial phase of infection, where a higher TH1 (inflammatory) response is required. At this stage, IL-10 can downregulate antigen presentation in macrophages and dendritic cells and can lead to chronic infection.24 During the later stages of infection, however IL-10 levels can determine host survival and higher concentrations of IL-10 have been associated with better outcomes in patients with acute respiratory distress syndrome.25Cancer Cell Interactions

This is immune modulation. As depicted, mushrooms are neither solely inflammatory, nor anti-inflammatory, and so should be utilized as such. The safety of medicinal mushroom use at different phases of the immune response is debatable. It is most likely that if mushrooms and mushroom extracts are consumed as preventative medicine, and the immune response is primed, the host won’t succumb to infection in the first place. There is some concern that if IL-10 is too high during the initial phase, the infection will become chronic, but since the mushrooms are simultaneously stimulating inflammatory cytokines, this isn’t likely.

  TH1 TH2
Associated cytokines IL-2, IL-12, IFN-γ, TNF-α IL-4, IL-10, IL-5, IL-6, IL-13, IL-9

 

Mushroom Derived β-glucans and the Immune Response

The most studied immune-stimulating constituents derived from medicinal mushrooms are 1,3/1,6-β-glucans. β-glucans, or polysaccharides, are present in all mushrooms as they are an integral component of the mushroom cell wall. Macrophages in the gut have specific receptors for β-glucans, most significantly Dectin-1, complement receptor 3 and TLR-2.26,27 When β-glucans bind to these receptors, an immune response is initiated. Because of this, in most studies, polysaccharides have been deemed the ‘active’ constituents in regards to immune activation.  Therefore, isolation and administration of these compounds is most commonly seen in the literature.

Pleuran, a polysaccharide derived from Oyster mushrooms

There are a number of human trials exploring the use of pleuran, a polysaccharide extracted from Pleurotus ostreatus (Oyster mushroom) as a therapeutic agent in respiratory infections. As respiratory infections are most commonly of viral origin,28 it seems appropriate to discuss this research here. In a double-blinded, placebo-controlled, randomized multicentric study, 175 children treated with pleuran  experienced a significant reduction in the frequency of recurrent respiratory tract infections.29 These findings agreed with a Spanish study investigating 166 children aged one to ten years old who were also treated with pleuran for recurrent respiratory infection.30

Advantageous respiratory effects of pleuran are also observed in adult athletes. A study IMG_6690of 50 athletes treated with pleuran over a three month period found a significant reduction in the frequency of upper respiratory tract infections compared to athletes treated with placebo. Blood samples of the athletes showed significantly higher levels of circulating NK cells in the pleuran group as compared to the placebo group.31

Oyster mushrooms contain almost 33% polysaccharides,32 so we can deduce from these studies that consuming whole Oyster mushrooms and/or Oyster mushroom aqueous extracts could be beneficial for the prevention of respiratory infections.

Immune-stimulating polysaccharides in late stage cancer patients

The polysaccharides isolated from Ganoderma lucidum, also known as ‘Ganopoly’, were administered at 1800mg three times daily in late stage cancer patients, and there was a significant increase in NK cells, IL-1, IL-6 and IFN-γ after administration.33 Another isolate, polysaccharide krestin (PSK), is a protein-bound polysaccharide derived and isolated from Trametes versicolor. In a phase one clinical trial, breast cancer patients consumed 6 or 9g of PSK for six weeks, leading to an increase in CD8 T cells and NK cells.34 Another isolated polysaccharide, Maitake D fraction (derived from the fruiting body of G. frondosa), was administered to patients with stage 2-4 cancer aged 46-84 at doses between 40 and 150mg twice daily. IL-2 and NK cell activity was detected through peripheral blood draw and both were significantly increased after administration35 The research on isolated, mushroom-derived polysaccharides was intended to prove anti-cancer activity, but because of the close similarities of anti-cancer and antiviral immunity,36 it also suggests that polysaccharides support antiviral immunity in late stage cancer patients.

In vivo healthy animal trials

Polysaccharides from G. lucidum, L. edodes and G. frondosa administered to healthy mice significantly increase macrophage phagocytosis and NK cell activity.37 Other studies have demonstrated similar immune-enhancing effects on healthy mice with G. frondosa and L. edodes extracts exhibiting increases in IL-12, IL-6, and IFN-γ. In this study, the combination of the G. frondosa and L. edodes extracts have a stronger effect than either extract alone.38 Maitake D fraction increases IL-12 and IFN-γ in healthy mice along with a significant decrease in IL-4 and IL-10.39 C. militaris extract also increases IL-12 and TNF-α cell activity in H1N1 infected mice.40

In vivo animal cancer models

A number of in vivo animal trials explore different mushroom extracts with similar immune effects. Many of these animal studies are cancer models, so they will be mentioned briefly. Agaricus hot water extracts increase IFN-γ, IL-6 and IL-1,41,42 Reishi polysaccharide and triterpene extracts increase inflammatory NFkB, TNF- α, IL1-b, IL-2, IFN-γ 43,44,45,46 Maitake extract increases IL-12, IFN-γ and TNF-α, IL-147,48 and PSK increases IL-12.49 Ganoderma polysaccharides increase NK cells and cytotoxic T cells, IL-1, IL-6 and IL-1.50,51

Because these are cancer models, so it is not completely clear if the same effects would take place in healthy animal models, though we can deduct from other experiments using healthy volunteers and healthy animals that it is likely that similar immune effects would occur.

In vitro antiviral activity

There are a number of fungal constituents that have antiviral activity in-vitro, including polysaccharides, indole alkaloids, terpenoids, polyketides and lignan derivatives.  Agaricus subfruescens and Grifola frondosa act directly on viral particles, β-glucan protein from A. subfruescens inhibits viral adsorption into the cell,  polysaccharides from A. subfruescens and polysaccharopeptide from T. versicolor inhibit viral replication, and triterpenes from Ganoderma spp directly kill virus proteins.52

The fruiting body ethanol-water extract of T. versicolor extract increases the TH1-related cytokines IL-2, IL-12, IL-18 and IFN-γ.53,54 As most of the research done on T. versicolor is with an isolated constituent, PSK, it is significant that this study, which used whole fruiting body extract, exhibits immune stimulating qualities.

Maitake fruiting body extract does not show direct antiviral activity to influenza A but does exhibit antiviral activity through macrophage activation and an increase in TNF-α production. 55

L. edodes mycelium directly inhibits influenza virus growth at early phases of infection, possibly during the entry process of viral particles to host cells. The in vivo administration stimulated an increase in innate immunity as well, suggesting that Shiitake mycelium has antiviral effects through both inhibition of initial viral replication and immune stimulation.56

A little known mushroom, Cryptoporus volvatus, the Cryptic Globe Fungus, has shown cryptanti-viral activity through multiple mechanisms. Aqueous extracts of the fruiting body inhibit porcine respiratory syndrome virus infection by repressing viral entry, viral RNA expression, possibly viral protein synthesis, cell-to-cell spread, and the release of virus particles from the host cell. C. volvatus also inhibits influenza virus replication in vitro and in vivo.57,58,59

The aqueous extract of Phellinus igniarius, or Fire Sponge, shows virucidal activity against influenza A and B viruses, including 2009 pandemic H1N1, human H3N2, avian H9N2, and oseltamivir-resistant H1N1 viruses. The study concludes that this extract may interfere with one or more early events in the viral replication cycle, including viral attachment to the target cell. 60

In vitro research is what propels in vivo research forward, but it is important to take this information with a grain of salt and understand this is what may happen in the human body, and not necessarily what will happen.

Anti-neuraminidase activity

A highly valued antiviral action in pharmaceuticals is neuraminidase inhibition. This is the mechanism of the commonly known antivirals Tamilflu and Rilenza. Neuraminidase is found on the surface of influenza viruses and allows viruses to be released from the host cell so they can then infect other healthy human cells. Neuraminidase inhibitors have been shown to improve the outcome of patients with leukemia and influenza. 61 Medicinal mushrooms and their constituents have been shown to have neuraminidase phimg_7902inhibitory activity in vitro and in vivo. Ganoderic acids, triterpenes found in Ganoderma species, have broad spectrum inhibition against influenza neuraminidases, specifically H5N1 andH1N1.62,63 Both the fruiting body and mycelial extracts of Phellinus spp. have neuraminidase inhibiting actions as well. 64,65,66  While there is still more research needed in this area, it is possible that Reishi and Phellinus species could be beneficial in treating viruses that utilize neuraminidase.

This paper focuses on mushrooms as antiviral therapies for enveloped, influenza-like viruses, but there is in vitro evidence to suggest medicinal mushrooms have antiviral activity towards many different viruses.67,68 Ganoderma lucidum has shown to be active against enterovirus, 69 human papillomavirus (HPV),70,71 herpes simplex virus (HSV)72,73,74,75 hepatitis B (HBV)76 and Epstein Barr virus (EBV).77 Cordyceps militaris has anti-hepatitis C (HCV) activity.78 Trametes versicolor is active against human immunodeficiency virus HIV.79.80 Grifola frondosa is active against HSV-181 and HBV.82 Inonotus obliquus has anti-HSV, 83,84 anti-HCV 85and anti-HIV86 activity and Lentinula edodes has anti-HBV 87 and anti-HSV 88 activity. Although not explored in this paper, these antiviral actions are interesting and worth considering for further dissection in future research.

Having a basic understanding of our complex immune system is important in understanding the role that mushrooms play as antivirals. As we have seen, mushrooms are immune modulators and can stimulate inflammatory and anti-inflammatory responses simultaneously. Mushrooms are most likely to be useful as preventative medicine before infection occurs, though if there is an initial infection, Cordyceps, Maitake, Shiitake, Turkey tail and Oyster mushroom may prevent infection from becoming more severe. If infection does become severe, the mushrooms that also stimulate IL-10 – Maitake, Cordyceps and Shiitake, could also be beneficial. In the wake of the current viral pandemic, these mushrooms should be further explored and utilized as medicine. Further research is essential in elucidating their potential effects.

antiviral mechanisms of medicinal mushrooms

 

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  43. Zhang S, Nie S, Huang D, Li W, Xie M. Immunomodulatory effect of Ganoderma atrum polysaccharide on CT26 tumor-bearing mice. Food Chem. 2013;136(3-4):1213-1219.
  44. Wang G, Zhao J, Liu J, Huang Y, Zhong JJ, Tang W. Enhancement of IL-2 and IFN-gamma expression and NK cells activity involved in the anti-tumor effect of ganoderic acid Me in vivo. Int Immunopharmacol. 2007;7(6):864- 870.
  45.  Wang PY, Zhu XL, Lin ZB. Antitumor and immunomodulatory effects of polysaccharides from broken-spore of Ganoderma lucidum. Front Pharmacol. July 2012;3:135.
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  48. Masuda Y, Murata Y, Hayashi M, Nanba H. Inhibitory effect of MD-Fraction on tumor metastasis: involvement of NK cell activation and suppression of intercellular adhesion molecule (ICAM)-1 expression in lung vascular endothelial cells. Biol Pharm Bull. 2008;31(6):1104–1108. doi:10.1248/bpb.31.1104
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  50. Zhu XL, Chen AF, Lin Z Bin. Ganoderma lucidum polysaccharides enhance the function of immunological effector cells in immunosuppressed mice. J Ethnopharmacol. 2007;111(2):219-226. doi:10.1016/j.jep.2006.11.013
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  54. Jeong SC, Yang BK, Kim GN, et al. Macrophage-stimulating activity of polysaccharides extracted from fruiting bodies of Coriolus versicolor (Turkey tail mushroom). J Med Food. 2006;9(2):175-181. doi:10.1089/jmf.2006.9.175
  55. Obi N, Hayashi K, Miyahara T, et al. Inhibitory effect of TNF-α produced by macrophages stimulated with Grifola frondosa extract (ME) on the growth of influenza A/Aichi/2/68 Virus in MDCK cells. Am J Chin Med. 2008;36(6):1171-1183. doi:10.1142/S0192415X08006508
  56. Kuroki T, Lee S, Hirohama M, et al. Inhibition of Influenza Virus Infection by Lentinus edodes Mycelia Extract Through Its Direct Action and Immunopotentiating Activity. Front Microbiol. 2018;9:1164. doi:10.3389/fmicb.2018.01164
  57. Gao L, Sun Y, Si J, et al. Cryptoporus volvatus extract inhibits influenza virus replication in vitro and in vivo. PLoS One. 2014;9(12). doi:10.1371/journal.pone.0113604
  58. Gao L, Zhang W, Sun Y, et al. Cryptoporus volvatus Extract Inhibits Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) In Vitro and In Vivo. PLoS One. 2013;8(5). doi:10.1371/journal.pone.0063767
  59. Ma Z, Zhang W, Wang L, et al. A novel compound from the mushroom Cryptoporus volvatus inhibits porcine reproductive and respiratory syndrome virus (PRRSV) in vitro. PLoS One. 2013;8(11). doi:10.1371/journal.pone.0079333
  60. Lee S, Kim JI, Heo J, et al. The anti-influenza virus effect of Phellinus igniarius extract. J Microbiol. 2013;51(5):676–681. doi:10.1007/s12275-013-3384-2
  61. Chemaly RF, Torres HA, Aguilera EA, et al. Neuraminidase Inhibitors Improve Outcome of Patients with Leukemia and Influenza: An Observational Study. Clin Infect Dis. 2007;44(7):964-967. doi:10.1086/512374
  62. Zhu Q, Bang TH, Ohnuki K, Sawai T, Sawai K, Shimizu K. Inhibition of neuraminidase by Ganoderma triterpenoids and implications for neuraminidase inhibitor design. Sci Rep. 2015;5(AUGUST):13194. doi:10.1038/srep13194
  63. Zhu T, Kim S-H, Chen C-Y. A Medicinal Mushroom: Phellinus Linteus. Curr Med Chem. 2008;15(13):1330-1335. doi:10.2174/092986708784534929
  64. Kim J, Kim D, Hwang BS, et al. Mycobiology Neuraminidase Inhibitors from the Fruiting Body of Phellinus igniarius. 2016:117-120.
  65. Yeom JH, Lee IK, Ki DW, Lee MS, Seok SJ, Yun BS. Neuraminidase inhibitors from the culture broth of Phellinus linteus. Mycobiology.2012;40(2):142-144. doi:10.5941/MYCO.2012.40.2.142
  66. Song AR, Sun XL, Kong C, et al. Discovery of a new sesquiterpenoid from Phellinus ignarius with antiviral activity against influenza virus. Arch Virol. 2014;159(4):753–760. doi:10.1007/s00705-013-1857-6
  67. Teplyakova T V. antiviral activity of polyporoid mushrooms (higher basidiomycetes) from Altai Mountains (Russia). 2012:37-45.
  68. Krupodorova T, Rybalko S, Barshteyn V. Antiviral activity of Basidiomycete mycelia against influenza type A (serotype H1N1) and herpes simplex virus type 2 in cell culture. Virol Sin. 2014;29(5):284-290. doi:10.1007/s12250-014-3486-y
  69. Zheng DS, Chen LS. Triterpenoids from Ganoderma lucidum inhibit the activation of EBV antigens as telomerase inhibitors. Exp Ther Med. 2017;14(4):3273-3278. doi:10.3892/etm.2017.4883
  70. Hernández-Márquez E, Lagunas-Martínez A, Bermudez-Morales VH, et al. Inhibitory activity of Lingzhi or Reishi medicinal mushroom, Ganoderma lucidum (higher Basidiomycetes) on transformed cells by human papillomavirus. Int J Med Mushrooms. 2014;16(2):179–187. doi:10.1615/intjmedmushr.v16.i2.80
  71. Donatini B. Control of oral human papillomavirus (HPV) by medicinal mushrooms, Trametes versicolor and Ganoderma lucidum: a preliminary clinical trial. Int J Med Mushrooms. 2014;16(5):497–498. doi:10.1615/intjmedmushrooms.v16.i5.80
  72. Eo SK, Kim YS, Lee CK, Han SS. Possible mode of antiviral activity of acidic protein bound polysaccharide isolated from Ganoderma lucidum on herpes simplex viruses. J Ethnopharmacol. 2000;72(3):475–481. doi:10.1016/s0378-8741(00)00266-x
  73. Oh KW, Lee CK, Kim YS, Eo SK, Han SS. Antiherpetic activities of acidic protein bound polysacchride isolated from Ganoderma lucidum alone and in combinations with acyclovir and vidarabine. J Ethnopharmacol. 2000;72(1-2):221–227. doi:10.1016/s0378-8741(00)00254-3
  74. Hijikata Y, Yamada S, Yasuhara A. Herbal mixtures containing the mushroom Ganoderma lucidum improve recovery time in patients with herpes genitalis and labialis. J Altern Complement Med. 2007;13(9):985–987. doi:10.1089/acm.2006.6297
  75. Eo SK, Kim YS, Lee CK, Han SS. Antiherpetic activities of various protein bound polysaccharides isolated from Ganoderma lucidum. J Ethnopharmacol. 1999;68(1-3):175–181. doi:10.1016/s0378-8741(99)00086-0
  76. Li YQ, Wang SF. Anti-hepatitis B activities of ganoderic acid from Ganoderma lucidum. Biotechnol Lett. 2006;28(11):837–841. doi:10.1007/s10529-006-9007-9
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  88. Santoyo,Susana, Ramirez-Anguiana Ana, christina Aldaris-Garcia L et al. Antiviral activities of Boletus edulis, Pleurotus ostreatus and Lentinus edodes extracts and polysaccharide fractions against Herpes simplex virus type 1. Phys Rev Lett. 2002;88(12):4. doi:10.1103/PhysRevLett.88.126404

 

 

 

 

 

 

 

 

 

 

Oxalates and Fungi

Cause for concern?

The most common manifestation of kidney stones is without a doubt, calcium oxalate stones – 80% of stones, to be exact. For this reason, people who are prone to stones tend to avoid high oxalate-containing foods. The most popular oxalate-rich delicacies: spinach, beets greens, chard, chocolate, tea, nuts, grains, and yes, some mushrooms. It is important to keep in mind that not all oxalate-rich foods will lead to kidney stones – chemistry is much more complex than that.

There was a recent report1 about an older Japanese woman with liver cancer who consumed 4-5 tsp of Chaga mushroom per day for 6 months, and happened to get nephrotoxicity. The postulated culprit: Chaga mushroom. Unfortunately, in this study, there was neither mention of the source of the Chaga, if this was the canker or mycelium, nor if the Chaga powder was an extract or not. This case report concluded that it must have been the high oxalate content in the Chaga mushroom that induced this nephrotoxicity.  Is this a true cause or simply a correlation? Should consumers be concerned about the oxalate content in in all Chaga products?

My hope is that this post will be educational, and readers will walk away with some answers to these questions.

This report got me thinking, about Chaga and oxalates and wondering, could this really be? I mean, they do look so similar. Could this be an example of the doctrine of signatures or is it possible that if you crush any golden substance into small enough pieces it may resemble calcium oxalate fragments? (No offense to the doctrine of signatures)

Some education about oxalates

First, not all oxalates are created equal. There are soluble and insoluble oxalates. Insoluble oxalates are already bound to minerals, for example: calcium oxalate, magnesium oxalate and iron oxalate. The insoluble oxalates in foods pass right into the GI and come out in feces. They will not be absorbed in the blood stream, and so they are not a concern for causing hyperoxaluria (high urine oxalates). Examples of soluble oxalates are potassium and sodium oxalate. Unlike soluble oxalates, these acids release free oxalate anions which can pass into the blood stream. Free oxalate can then bind with free calcium and make calcium oxalate crystals;

This distinction is important to keep in mind when considering high oxalate foods.

Mushrooms and Oxalates

White button mushroom and Shiitake mushroom are both very high in oxalates, but 99% of them are insoluble! So, don’t fret about these mushrooms – the oxalate will all come out in your shiit(ake).2

Screen Shot 2019-12-01 at 8.20.41 AM

Oyster mushrooms, on the other hand, are moderately high in oxalates, and 90% of them are soluble. They contain a comparable amount to chocolate, almonds, and grains.2 So if you can eat more oyster mushrooms than you can chocolate, you are my hero and you may want to eat them with some calcium containing foods – more about this later.

Pleurotus ostreatus

Lucky for kidney stone formers, they can continue to consume large quantities of Lion’s Mane (Hericium erinaceus), Cauliflower mushroom (Sparassis spp) and Reishi (Ganoderma spp). There are no soluble oxalates found in any of these mushrooms.2

Remember, for an organism to take the time and energy to make a molecule, the molecule must serve some purpose for that organism; oxalates are not made to cause kidney stones in humans. I hope to find more on this subject in relation to mushrooms, but for now, I found one study. According to this study, calcium oxalate crystals form in response to toxic metal stress.3 So perhaps mushrooms growing in environments where there are more toxic metals will in turn have a higher calcium oxalate load than those same species growing elsewhere.

Oxalates and Chaga

Oxalate samples were assessed in Chaga samples from Russia, Finland and Thailand. A hot water extract was made of the Chaga canker (the growth coming out of the tree, traditionally used as medicine) and oxalate content was assessed. Researchers found that for 1 gram of the Russian Chaga extract there was 97.6mg of soluble oxalic acid and 24mg of insoluble oxalic acid. The Finnish Chaga extract contained 55.62mg/g of soluble oxalates and 9.5mg/g of insoluble oxalates. Japan Food Research Laboratories measured oxalate content of the mushroom powder and concentrations of 11.2g total oxalate in 100g of powder. Another test from this laboratory on a separate Chaga sample was 2.8g/100g.1

Some perspective: These amounts are higher than most edible mushrooms, similar to the amount in almonds, peanuts, cereal grains and chocolate, and much lower than what is found in high oxalate foods like spinach, rhubarb and beet greens.4

Cooking and Oxalates

Oxalate load was compared in a 10g sample of dried mushrooms cooked versus not cooked. This study found that cooking slightly decreases oxalates, but also seems to increase them in certain cases. Interestingly, levels of soluble oxalate from forest harvested mushrooms was generally lower than cultivated mushrooms.2

Concerned about your mushroom intake and risk of kidney stones?

Here is some food for thought:

Calcium intake and oxalate absorption

People with low calcium diets can benefit from consuming calcium-containing foods along with oxalate-containing foods to decrease oxalate absorption. One study found that exogenous (dietary) calcium leads to a linear reduction of oxalate absorption within the range of daily intake of 200-1200mg of calcium.  This case has been documented in numerous studies5,6,7 and calcium supplements have been shown to lower the oxalate absorption. One study assessed this theory using 1000mg calcium supplement given simultaneously with soluble oxalates. They concluded that this technique will reduce oxalate absorption by 10%, however this is mostly effective if the person already has a low calcium diet.  When calcium is supplemented to an already high calcium diet, there is only a 1% decrease in oxalate absorption.

coffeemilk

Perhaps this is an excellent reason to add milk to tea and coffee and of course, to your favorite mushroom drink. To give some perspective, 1 cup of dairy milk has about 305mg of calcium and 1 cup of fortified almond milk has about 300mg of calcium.

The microbiome and oxalate absorption

Within the microbiome resides a bacteria known as Oxalobacter formigenes.8  This superlative gut bacteria degrades oxalates and helps to prevent hyperoxaluria and kidney stones. So, for those concerned about the oxalate content in the mushrooms discussed, perhaps this little bacteria is your ally. Studies looking at oral intake of Oxalobacter  have shown less urinary oxalate excretion following administration of an oxalate heavy food load compared to when there was no Oxalobacter administered. Unfortunately, this bacteria is susceptible to antibiotic use. Specifically, clarithromycin and doxycycline have been shown to annihilate this little probiotic, leaving the human left behind to be more susceptible to kidney stones.

oxalobacter.png

Representation of Oxalobacter formigenes activity. Utilizes oxalate as a source of energy through the oxalate-formate antiporter.9

This is all very interesting and something most people do not need to worry about. Though I would say, if you are an oxalate kidney stone former: don’t eat a ton of oyster mushrooms or drink multiple cups of Chaga tea per day. Do make sure to drink plenty of water and eat a diet with adequate amounts of calcium, and hope that antibiotic use hasn’t eradicated all of your Oxalobacter.

 

Work Cited

  1. Kikuchi Y, Seta K, Ogawa Y, et al. Chaga mushroom-induced oxalate nephropathy. Clin Nephrol. 2014;81(6):440-444. doi:10.5414/CN107655
  2. Savage GP, Nilzen V, Österberg K, Vanhanen L. Soluble and insoluble oxalate content of mushrooms. Int J Food Sci Nutr. 2002;53(4):293-296.doi:10.1080/09637480120057000
  3. Jarosz-Wilkolazka A, Gadd GM. Oxalate production by wood-rotting fungi growing in toxic metal-amended medium. Chemosphere. 2003;52(3):541-547. doi:10.1016/S0045-6535(03)00235-2
  4. Glamočlija J, Ćirić A, Nikolić M, et al. Chemical characterization and biological activity of Chaga (Inonotus obliquus), a medicinal “mushroom.” J Ethnopharmacol.2015;162:323-332. doi:10.1016/j.jep.2014.12.069
  5. Von Unruh GE, Voss S, Sauerbruch T, Hesse A. Dependence of oxalate absorption on the daily calcium intake. J Am Soc Nephrol. 2004;15(6):1567-1573.doi:10.1097/01.ASN.0000127864.26968.7F
  6. Bong WC, Vanhanen LP, Savage GP. Addition of calcium compounds to reduce soluble oxalate in a high oxalate food system. Food Chem. 2017;221:54-57. doi:10.1016/j.foodchem.2016.10.031
  7. Brogren M, Savage GP. Bioavailability of soluble oxalate from spinach eaten with and without milk products. Asia Pac J Clin Nutr. 2003;12(2):219-224.
  8. Duncan SH, Richardson AJ, Kaul P, Holmes RP, Allison MJ, Stewart CS. Oxalobacter formigenes and its potential role in human health. Appl Environ Microbiol.2002;68(8):3841-3847. doi:10.1128/AEM.68.8.3841-3847.2002
  9. Corica, Domenico & Romano, Claudio. (2015). Renal Involvement in Inflammatory Bowel Diseases. Journal of Crohn’s & colitis. 10. 10.1093/ecco-jcc/jjv138.
  10. Oxalates in Chaga – A Potential Health Threat By Michael W. Beug, Chair NAMA Toxicology Committee
  11. Mitchell T, Kumar P, Reddy T, et al. Dietary oxalate and kidney stone formation. Am J Physiol Renal Physiol. 2019;316(3):F409–F413. doi:10.1152/ajprenal.00373.2018

Lion’s Mane: a Psychosomatic Psychobiotic

I know you immediately think of the brain, but follow the vagus nerve from brain to gut and let’s just stay there for a while…

annalion

This mushroom is incredibly popular right now. Very hip. Very trendy.

Also of grand popularity are afflictions of the stomach, intestines and the colon. Many people have a visceral response to this overstimulating existence of modernity, and the most common viscera affected – the gut. Not only is the entire weight of the world living there, but the once-prolific community of microorganisms that once inhabited this space, and that would normally support the gut with the physiological burden that comes with this weight, has been significantly depleted. The reasons for this lack of microbial support are many, though we can just call it an unhealthy obsession with purity. The problem here is that this physiological burden that comes with the stress of the world, more often than not, becomes a pathology. Lion’s Mane extracts infiltrate the gut and the associated lymphoid tissue, regulating inflammation, decreasing oxidative damage, feeding the residing microbiota and modulating the immune system – all desired actions for healing, and hopefully avoiding, this potential pathology. Before being known as a nootropic medicinal, this mushroom was used in Traditional Chinese Medicine as a digestive tonic and to support gastrointestinal health. I have gone through the most current research to support the use of Lion’s Mane for gut health, and so overall human health.

Warning – most all of the research has been done on rats or mice. This is just the reality of most in vivo research and that is all we get until human clinical studies, which are incredibly difficult to find funding for – especially with natural products that don’t have potential to be synthesized into pharmaceuticals – can be done. So if you need to blame someone, blame capitalism and big pharma.

Rodent studies exploring Hericium Extracts and inflammatory bowel disease (IBD)

There have been many studies exploring variations of Lion’s Mane extracts and the effects of these extracts on rodents with chemically induced inflammatory bowel disease (I know it is fucked up). In one study1, mice were exposed to 2% dextran sulfate sodium (DSS) for 7 days to induce acute intestinal inflammation. These mice were then administered an ethanol extract of Hericium at a dose of 250mg/kg/day (This is a very big dose). Results showed that the treated mice had significant improvement in body weight, colon length and overall decreased intestinal bleeding compared with control mice. After administration of the extract, there was suppressed production of inflammatory mediators (TNF-alpha, IL-1â and IL-6) in colon tissue, as well as a decrease in oxidative damage potentiators (nitric oxide production, malondialdehyde, and superoxide dismutase). Overall, Lion’s Mane decreased inflammation and oxidative stress, leading to a decrease in mucosal damage and protection of mucosal epithelium.

Another in vivo study2 induced colitis in mice using this same DSS solution, and found similar results with Hericium polysaccharides.  In this study, researchers tested markers of inflammation and oxidative stress before and after administration of the polysaccharides. Similar to the previously described study, there was a marked improvement in clinical symptoms postulated to be due to the decrease in nitric oxide, malondialdehyde, superoxide dismutase and myeloperoxidase. There was also a significant reduction in inflammatory cytokines TNF alpha, IL-1ß, and IL-6. Other notable markers decreased after polysaccharide administration include COX-2 and iNOS. COX-2 is an important enzyme in the prostaglandin synthesis pathway and the target of NSAIDs (like aspirin). Reduction or inhibition of this enzyme leads to decreased pain and inflammation. Intriguingly, this extract also blocked phosphorylation of NF-kappaB, p56 and also reversed DSS- induced gut dysbiosis and maintained intestinal barrier integrity. NF-kappaB is the major transcription factor for inflammatory cytokine production and if it is not phosphorylated it will not be active, and so less overall inflammation. (I realize I am really driving home the idea that we want to reduce inflammation, and inflammation is NOT always bad, but in a condition like inflammatory bowel disease, where the inflammation is causing significant damage to the mucosa and destroying a person’s quality of life, inflammation is not desirable).

Another method of inducing colitis in rats is with a trinitrobenzene sulfonic acid (TNBS) enema. To further explore the therapeutic potential of various Hericium extracts on inflammatory bowel disease, another study3 had to be done, using rats with this TNBS induced colitis. After the TNBS enema, the rats exhibited symptoms of reduced activity, lethargy, weight loss, ruffled fur, and bloody stool. After 14 days of Lion’s Mane extract treatments, there was significant improvement in all symptoms. Serum levels of inflammation were also monitored during this time, and decreased significantly after treatment. The proportion of FOXP3 and IL-10 positive cells significantly increased, especially in the rats receiving the alcoholic extracts compared with the model group. FOXP3 is the transcription factor for T-regulatory cells, and T regulatory cells secrete IL-10, so increased levels indicate improved immune regulation.

Prebiotic activity: Another study4 using an IBD rat model explored immunomodulatory activity of the water soluble fungal protein, HEP3, extracted from the mushroom fruiting body. The mechanism proposed: regulation of the gut microbiota. The study explained that HEP3 is a protein, and its digestion and absorption is reliant on proteases and peptidases extracted from bacteria. The nitrogenous degradation products of protein digestion also serve as important nutrient and energy sources for some anaerobic organisms. Knowing this, HEP3 can significantly influence the diversity, structures, and metabolism of organisms and microorganisms. Evidence suggests that the diversity of gut microbiota is reduced in IBD patients, so finding treatments that can target both inflammation and increase biodiversity is ideal. In this study, after HEP3 administration, Bifidobacterium abundance increased significantly and the colon tissue damage, inflammation, other prebiotics and diversity and structures improved significantly. Bifidobacterium is a beneficial genus of bacteria, associated with enhanced gut health and overall human health. This study concluded that HEP3 improves the immune system via regulation of the structure and metabolism of gut microbiota. The researchers postulate that through this prebiotic role, HEP3 activates the proliferation and differentiation of T cells and stimulates antigen presenting cells.

This prebiotic activity was also found in a hot water extract of the fruiting body.5 The preparation method was to simmer dried and ground mushroom in water (1:10, w:v) for 8 hours followed by pouring ETOH over the extract and leaving overnight. The alcohol was used to precipitate the polysaccharides which were then collected and used as the treatment in question. This method of precipitating polysaccharides out with alcohol is typically how polysaccharides are extracted in a laboratory setting, and so when people say that alcohol will destroy the polysaccharides in your mushroom extract, that is simply not true. This study found that Lactobacillus plantarum was the probiotic most affected by the Hericium polysaccharides. At first, after administration of the polysaccharides, the bacterial population rapidly increased after 6h. Also, the molecular weight of the polysaccharide decreased due to the loss of glycosidic bonds from gastrointestinal digestion, leading researchers to suppose that digestion is vital for the bioactivity of these polysaccharides in the GI system.

 Immune modulation: Not only are these polysaccharides food for our gut bacteria, but they are also the primary constituent involved with immune modulation. There are many receptors in the phagocytes associated with mucosal immunity and the most often discussed regarding mushroom 𝛃-glucans is Dectin-1. Interestingly, one study6 found evidence that that the major pattern recognition receptors for Hericium polysaccharides are TLR2 and mannose receptor rather than Dectin-1. (fangfang wu 2017) In an in vivo mouse study assessing Hericium polysaccharides and their effect on cell mediated immunity (T-cells and phagocytes), humoral immunity (B-cells, complement and antimicrobial peptides), phagocytic capacity of peritoneal cavity phagocytes, and NK cell activity, results showed that Hericium polysaccharides improve immune function by functional enhancement of all of the above.

lionbraingut

Neuroimmunity: mucosal immunity and vagus nerve regulation

The vagus nerve, the 10th cranial nerve and the queen of the parasympathetic response. This is the rest and digest, the chill and feel, the relax and pass response. The Vagus nerve also innervates the majority of our digestive organs, hence the ‘digest’ and ‘pass’ parts of the aforementioned idioms. Therefore, the mucosal immunity described previously, is also innervated by this nerve. Studies show that when vagus is dysfunctional, there is more GI inflammation and an overall dysregulated mucosal immunity.7,8 There is evidence for stress-induced alterations in gut flora and an associated increase in inflammatory markers in the gastrointestinal tract. Does it go both ways? If there is less stress, then there is less GI inflammation, but if there is more regulation of gut inflammation, increased intestinal integrity and a more diverse microbiome, will there be a more regulated stress response? Are we stimulating vagus by stimulating mucosal immunity, therefore eliciting a parasympathetic response? Is this actually the mechanism by which Lion’s Mane decreases depression and anxiety in post-menopausal women?9

Bidirectional gut-brain communication: One route of this communication is thought to begin through sensory information from the GI tract, and subsequent activation of neural, hormonal, and immunological signals. These signals can independently or cooperatively relay information to the central nervous system (CNS).10,11,12 There are a number of studies described in this review regarding increased probiotic intake associated with increased mood and less anxiousness. Specifically, probiotic supplementation with Lactobacillus helveticus and Bifidobacterium longum showed less self-reported negative mood and decreased urinary cortisol.13 A similar effect was also observed in healthy participants who consumed a mixture of Bifidobacterium bifidum and Bifidobacterium lactis, and Lactobacillus acidophilus, Brevibacillus brevis, Brevibacterium casei, Bifidobacterium salivarius, and Lactococcus lactis 14 Allen et al.15 found that healthy individuals fed Bifidobacterium longum had attenuated levels of cortisol and reduced subjective anxiety in response to the socially evaluated cold stress pressor test.  It does indeed seem to go both ways: decreasing inflammation and regulating the gut microbiome reduces anxiety and stress, and reduced anxiety and stress decreases inflammation and regulates the gut microbiome.

Lion’s Mane mushroom is more than one constituent that increases nerve growth factor synthase (the myopia of this mushroom’s medicine). Lion’s Mane, like all things living, is made up of many synergistic compounds that work together to keep this mushroom living and producing. These compounds also happen to play a major role in human health. This field of neuroimmunology is growing and the physiological effects of Lion’s Mane are an excellent example of the mechanisms of bidirectional gut-brain communication. Lion’s Mane is, in fact, the ultimate psychosomatic medicine, in the true meaning of the word – relating to the interaction of mind and body, the psyche and the soma, and a true psychobiotic.

*Psychobiotic is actually a word, I did not invent it. It is a medicine that affects the psyche by regulating the gut microbiome.

 

Disclaimer: Information from this post is not meant to diagnose or treat any disease.

 

 

Work Cited

  1. Qin M, Geng Y, Lu Z, Xu H, Shi JS, Xu X, Xu ZH. Anti-Inflammatory Effects of Ethanol Extract of Lion’s Mane Medicinal Mushroom, Hericium erinaceus (Agaricomycetes), in Mice with Ulcerative Colitis. Int J Med Mushrooms. 2016;18(3):227-34. doi: 10.1615/IntJMedMushrooms.v18.i3.50. PubMed PMID: 27481156.
  2. Ren Y, Geng Y, Du Y, et al. Polysaccharide of Hericium erinaceus attenuates colitis in C57BL/6 mice via regulation of oxidative stress, inflammation-related signaling pathways and modulating the composition of the gut microbiota. J Nutr Biochem. 2018;57:67-76. doi:10.1016/j.jnutbio.2018.03.005
  3. Diling C, Xin Y, Chaoqun Z, et al. Extracts from Hericium erinaceus relieve inflammatory bowel disease by regulating immunity and gut microbiota. Oncotarget. 2017;8(49):85838-85857. doi:10.18632/oncotarget.20689
  4. Diling C, Chaoqun Z, Jian Y, et al. Immunomodulatory activities of a fungal protein extracted from Hericium erinaceus through regulating the gut microbiota. Front Immunol. 2017;8(JUN). doi:10.3389/fimmu.2017.00666
  5. Yang Y, Zhao C, Diao M, et al. The Prebiotic Activity of Simulated Gastric and Intestinal Digesta of Polysaccharides from the Hericium erinaceus. Molecules. 2018;23(12):1-14. doi:10.3390/molecules23123158
  6. Sheng X, Yan J, Meng Y, Kang Y, Han Z, Tai G, Zhou Y, Cheng H. Immunomodulatory effects of Hericium erinaceus derived polysaccharides are mediated by intestinal immunology. Food Funct. 2017 Mar 22;8(3):1020-1027. doi:10.1039/c7fo00071e. PubMed PMID: 28266682.
  7. Shea-Donohue T, Urban JF Jr. Neuroimmune Modulation of Gut Function. Handb Exp Pharmacol. 2017;239:247-267. doi: 10.1007/164_2016_109. Review. PubMed PMID: 28035531.
  8. Bailey MT. Psychological Stress, Immunity, and the Effects on Indigenous Microflora. Adv Exp Med Biol. 2016;874:225-46. doi: 10.1007/978-3-319-20215-0_11. Review. PubMed PMID: 26589222.
  9. Nagano M, Shimizu K, Kondo R, Hayashi C, Sato D, Kitagawa K, Ohnuki K. Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake. Biomed Res. 2010 Aug;31(4):231-7. PubMed PMID: 20834180.
  10. Lach G, Schellekens H, Dinan TG, Cryan JF. Anxiety, Depression, and the Microbiome: A Role for Gut Peptides. Neurotherapeutics. 2018;15(1):36-59. doi:10.1007/s13311-017-0585-0
  11. Matteoli G, Boeckxstaens GE. The vagal innervation of the gut and immune homeostasis. Gut. 2013;62(8):1214-1222. doi:10.1136/gutjnl-2012-302550
  12. Fonseca RC, Bassi GS, Brito CC, et al. Vagus nerve regulates the phagocytic and secretory activity of resident macrophages in the liver. Brain Behav Immun. 2019;81(December 2018):444-454. doi:10.1016/j.bbi.2019.06.041
  13. Messaoudi M, Violle N, Bisson J-F, Desor D, Javelot H, Rougeot C. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes 2011;2:256– 261.
  14. Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun 2015;48:258–264.
  15. Allen AP, HutchW, Borre YE, et al. Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Transl Psychiatry 2016;6:e939.

 

 

 

 

 

 

 

 

 

 

Fall Transitions

Fall. The quintessential season of the mushroom. I very outwardly and not so secretly love when summer comes to an end. The giant ball of fire in the sky, reflecting off of the far too many reflective surfaces throughout the city like laser beams in a diamond shop, is finally going to be shrouded by clouds. What a treat. Although a creature of habit, I have a deep love for transition – seasons of transition, symbols of transition, momentous occasions initiating transition, etc. Perhaps this is why I love Fall, and perhaps this is why I have a tattoo of an ouroboros on my right arm, and most definitely why I love mushrooms. As the rains come and wash away the summer, this can be a time of deep introspection and with that, inevitable discomfort. Shorter days and a generally darker existence is not desirable to most people, but can be especially valuable for the psyche. So rather than seeking herbs or mushrooms to bring more ‘light’ during this time, how about seeking out plant and mushroom allies to support and encourage transition. I think of deciduous trees during this time, trees that innately hold the energy of transformation – the ability to move through seasons in different forms and continue to grow stronger each year. The tannins in the leaves of the Birch, Willow, Poplar and Aspen oxidize from green to brilliant yellow, red, and brown. They stand bare through winter – vulnerable, nude, yet with tremendous stature and strength. Imaginably, this is the medicine that these trees share, and the energy that we can cultivate. Look for patterns in nature to understand the medicine in nature.  Is it grace through transition that you desire? Look closer at the natural world that surrounds you. This grace encompasses you already.

 

Oyster Mushroom

Pleurotus ostreatus

“side of the body” and “resembling oyster” 

I am apt to write about the polypores – the often overlooked wizened and ancient ‘conks’ of the forest –  that require more time to age, to collect, to process. I am stepping back and writing about the medicine of the familiar gilled Oyster Mushroom. They are as common in the forest as in the grocery store, and what better medicine to write about than medicine that is so accessible that the forest dwellers as well as the grocery store goers may benefit.

The fruiting Oysters will be found on hardwoods mostly – the Cottonwoods, Oaks and Alder – fruiting from their carnivorous mycelia in the spring. The carnivory is real – watch the mycelia digest a nematode in this video

Pleurotus ostreatus

Spore print

White

Known active constituents

Pleuran (polysaccharide), chrysin, ergothioneine, lovastatin, GABA

Nutritional information

Nutritional constituents estimated per 100 g dry weight include protein (29.3 g), carbohydrate (62.97 g), crude fat (0.91 g), ash (6.82 g) and crude fiber (12.3 g).

Energy value of this mushroom was about 297.5 kcal/100 g dry weight

Major mineral components estimated include Ca, Fe, and Mg with highest level of 505.0, 109.5 and 108.7 mg/100 g respectively.

Therapeutic actions

Immune modulating, antiatherogenic, neuroprotective, antioxidant, inflammation modulating

 Some laboratory findings

Antiatherogenic

There are many factors that aggregate and result in atherosclerosis. These include and are not limited to hypertension, hyperglycemia, hypercholesterolemia and lipid peroxidation. Oyster mushroom research has demonstrated protection against all of those factors. In an animal study, rats were administered chrysin-rich Pleurotus extract. After administration there was a significant decrease in mean blood serum levels of glucose, lipid profile parameters, and hepatic marker enzymes and a simultaneous increase in enzymatic and nonenzymatic antioxidant parameters.2

 P. ostreatus is the richest known source of ergothioneine, containing 118.91mg/kg. As mentioned previously, ergothioneine protects against DNA damage and lipid oxidation. For hypertension, Oyster mushroom water extract inhibits angiotensin converting enzyme (ACE) – a common mechanism in hypertensive medication.

Oyster mushroom also contains lovastatin, a naturally occurring statin compound that reduces LDL cholesterol through inhibition of HMG-CoA reductase.

Some human findings

Atopic dermatitis

In a split-body study of 80 patients, topical P. ostreatus-based β-glucan cream application resulted in improvement of both subjective and objective symptoms of atopic dermatitis. The patients applied the cream on one segment of the body with atopic dermatitis and no treatment on another atopic dermatitis segment. On the application site there was a significant decrease in the number of days and severity of atopic dermatitis. 4

You can make your own Oyster mushroom cream by following my mushroom cream recipe hereThe aqueous part of the cream will be an Oyster mushroom decoction.

Respiratory Disease

Pleuran extract from Oyster mushrooms has clinical evidence for application with various respiratory diseases. In a human study, chronic obstructive pulmonary disease (COPD) patients treated with 100mg Pleuran, 60mg vitamin C, and 5mg Zinc, had significantly lower incidence and shorter duration of exacerbations compared to the control (60mg vitamin C and 5mg Zinc).5

In another double-blinded, placebo-controlled, randomized multicentric study, 175 children were treated with either pleuran or placebo over a 12-month period. Children treated with pleuran experienced a significant reduction in the frequency of recurrent respiratory tract infections. 1,6 These findings agreed with a Spanish study investigating 166 children aged one to ten years old who were also treated with Pleuran for recurrent respiratory infection.7

Advantageous respiratory effects of pleuran were also observed in adult athletes. A study included 50 athletes treated with pleuran over a three month period of time and found a significant reduction in the frequency of upper respiratory tract infections as compared to athletes treated with placebo. Blood samples of the athletes showed significantly higher levels of circulating NK cells in the pleuran group as compared to the placebo group.8

Antihyperlipidemic

20 subjects were randomized to take either one portion of soup containing 30g dried oyster mushrooms or a tomato soup (placebo) on a daily basis for 21 days. Standardized blood concentrations of lipid parameters and oxidized LDLs were measured at baseline and after 21 days. Treatment with Oyster mushroom soup decreased both triacylglycerol and oxidized low density lipoprotein levels significantly, and showed a significant tendency towards lowering total cholesterol values. 9

Pleurotus ostreatus Syrup Recipe

for upper respiratory support

Ingredients

30g dried Oyster mushrooms, chopped

120mL raw honey

130mL Water (up to 300mL if not using pressure cooker)

Kitchen Tools Needed

Boiling pot or Pressure cooker (Instant pot)

Cheese cloth

Potato ricer

Bowl

Directions

Pressure cooker: pressure cook dried mushrooms with 130mL water for 45 minutes

Boiling pot: boil for 1.5 hours, strain mushroom from decoction, dispose of mushrooms, put aqueous extract back on heat and reduce liquid down to 120mL

Once you have 120mL of mushroom aqueous extract, stir in 120mL of raw honey

Store in jar and refrigerate

Final product should be 240mL 1:8 (1gram of mushroom in 8mL liquid)

1g mushroom =  about .5g Pleuran

Some math:

Pleurotus ostreatus is about 50% Polysaccharide, and the best way to extract these polysaccharides is through a boiling process. We have 30g of dried Pleurotus ostreatus and for a child who weighs 27kg, we would dose them with 270mg Pleuran, and so about 540mg dried oyster mushroom, or .5g. We want there to be .5g in 1 tsp (4mL) of extract. Since we will add 1part honey to 1part mushroom decoction, we will want the decoction to be a 1:4 and the final product to be a 1:8.

Pediatric Dose: 4mL (~.25g Pleuran)

IMG_6545

Work Cited

  1. Jesenak M, Hrubisko M, Majtan J, Rennerova Z, Banovcin P. Anti-allergic Effect of Pleuran ( b -glucan from Pleurotus ostreatus ) in Children with Recurrent Respiratory Tract Infections. 2014;474(March 2013):471-474.
  2. Anandhi R, Annadurai T, Anitha TS, Muralidharan AR, Najmunnisha K, Nachiappan V, Thomas PA, Geraldine P. Antihypercholesterolemic and antioxidative effects of an extract of the oyster mushroom, Pleurotus ostreatus, and its major constituent, chrysin, in Triton WR-1339-induced hypercholesterolemic rats. J Physiol Biochem. 2013 Jun;69(2):313-23. doi: 10.1007/s13105-012-0215-6. Epub 2012 Oct 27. PubMed PMID: 23104078.
  3. Hamdi M, Abidin Z, Abdullah N, et al. Therapeutic properties of Pleurotus species ( oyster mushrooms ) for atherosclerosis : A review Therapeutic properties of Pleurotus species ( oyster mushrooms ). Int J Food Prop. 2017;20(6):1251-1261. doi:10.1080/10942912.2016.1210162.
  4. Jesenak M, Urbancek S, Majtan J, Banovcin P, Hercogova J. b -Glucan-based cream ( containing pleuran isolated from pleurotus ostreatus ) in supportive treatment of mild-to-moderate atopic dermatitis. 2016;6634(4):351-354. doi:10.3109/09546634.2015.1117565.
  5. Minov J, Bislimovska-karadzhinska J, Petrova T, Vasilevska K, Stoleski S. Effects of Pleuran ( Β – Glucan from Pleurotus Ostreatus ) Supplementation on Incidence and Duration of COPD Exacerbations. 2017;5(7):893-898.
  6. Jesenak M, Urbanclkova I, Banovcin P. Respiratory Tract Infections and the Role of Biologically Active Polysaccharides in Their. Nutrients. 2017:1-12. doi:10.3390/nu9070779.
  7. Pico Sirvent L, Sapena Grau J, Morera Ingles M, Rivero Urgell M. Effect of supplementation with β–glucan from Pleurotus ostreatus in children with recurrent respiratory infections. Ann Nurr Metab. 2013; 63 (1): 1378.
  8. Bergendiova K, Tibenska E. Pleuran ( b -glucan from Pleurotus ostreatus ) supplementation , cellular immune response and respiratory tract infections in athletes. 2011:2033-2040. doi:10.1007/s00421-011-1837-z.
  9. Schneider, I.; Kressel, G.; Meyer, A.; Krings, U.; Berger, R.G.; Hahn, A. Lipid Lowering Effects of Oyster Mushroom (Pleurotus Ostreatus) in Humans. Journal of Functional Foods 2011, 3(1), 17–24. DOI:http://Dx. Doi.Org/10.1016/J.Jff.2010.11.004

 

Ergothioneine: The Elusive Amino Acid

 

Proving that mushrooms are an essential part of the human diet 

 

 

Definitions to consider while reading:

Antioxidant­: Compounds that mitigate oxidation. Oxidation is a reaction that can produce free radicals, leading to cellular damage. Antioxidants such as thiols and ascorbic acid (vitamin C) terminate these reactions by donating electrons. To balance oxidative states, living organisms maintain systems with overlapping antioxidants such as glutathione, catalase, superoxide dismutase.

 Blood-brain barrier: a filtering mechanism of the capillaries that carry blood to the brain and spinal cord tissue, blocking the passage of certain substances.

Cation chelator: a type of bonding of ions and molecules to metal ions. There is application of this in removing toxic metals from the body. 

Glutathione: Glutathione is a tripeptide (cysteine, glycine, and glutamic acid) found in surprisingly high levels—5 millimolar—concentrations in most cells. Responsible for the following actions in the body: (Pizzorno)

  1. Direct chemical neutralization of singlet oxygen, hydroxyl radicals, and superoxide radicals
  2. Cofactor for several antioxidant enzymes
  3. Regeneration of vitamins C and E
  4. Neutralization of free radicals produced by Phase I liver metabolism of chemical toxins
  5. One of approximately 7 liver Phase II reactions, which conjugate the activated intermediates produced by Phase I to make them water soluble for excretion by the kidneys
  6. Transportation of mercury out of cells and the brain
  7. Regulation of cellular proliferation and apoptosis
  8. Vital to mitochondrial function and maintenance of mitochondrial DNA (mtDNA)

Lipid peroxidation: The oxidative degradation of lipids. It is the process in which free radicals “steal” electrons from the lipids in cell membranes, resulting in cell damage. (Wik)

Oxidative stress: disturbance in the balance between the production of reactive oxygen species (free radicals) and antioxidant defenses (Betteridge)

IMG_4412
Pleurotus ostreatus – Oyster Mushroom

 

‘Constituentism’

I am not necessarily a fan of isolation and ‘constituentism’ in supplemental medicine – especially when a constituent has been isolated from its synergistic community of molecules from the whole plant or whole mushroom and is considered supposedly different than a pharmaceutical. Though, I do love to understand the individual constituents in organisms and how they work independently, in order to better understand how they work synergistically. There is also a greater understanding to be had of how animals, plants, fungi and bacteria all evolved together when we can explore specific plant and fungi constituent mechanisms with specific cellular receptors and transporters in the animal organism. A specific example of this is a compound called Ergothioneine (ERG). ERG is an amino acid derivative, specifically a crystalline betaine, derivative of histidine – the etymology explains; ergot- (found in ergot (fungus) thione- (double bond to a Sulphur) and  -ine (amine containing)—basically a sulphur containing amine found in fungi. ERG is also found in Actinobacteria (gram positive bacteria that behave similar to fungi in soil, helping to decompose the organic matter of dead organisms so the molecules can be taken up by new plants, they even grow extensive mycelium like fungi and were in fact long believed to be fungi) and Cyanobacteria, commonly known as blue-green algea, (another abnormal bacteria that can actually obtain their energy from photosynthesis – they are the only photosynthetic prokaryote able to produce oxygen). (blankenfeldt)

 

Specific ERG transporters in the animal

We have evolved so closely with mushrooms that we have specific transporters and receptors uniquely for mushroom compounds. ERG is no exception.  While we have a specific receptor for ERG, we cannot synthesize this molecule ourselves, and as I will describe later, we are discovering this compound is extremely important for human health.  The ERG transporter, OCTN1, (gene: SLC22A4) is found specifically on erythrocytes, fetal liver and bone marrow, ileum of the small intestine, trachea, kidney, cerebellum, lung, monocytes, seminal vesicles and the lens and cornea of the eye (Halliwell). Interestingly, ERG transporter is concentrated in the mitochondria of cells – suggesting a role in protecting mitochondrial components from DNA damage (Paul, Halliwell). This transporter’s only known role is to sequester as much ERG within the cells as is available, and only cells with this transporter can absorb, distribute, and retain this compound (Grundermann). Researchers explored the effects when cells were depleted of this transporter, the results being that cells were more susceptible to oxidative stress, leading to mitochondrial damage, protein oxidation, and lipid peroxidation. Once taken up into the cell, ERG is extremely bioavailable and is retained for up to a month within the body.

 IMG_4117

Bioavailability of ergothioneine from mushroom consumption

Once consumed in the diet, whether it be the isolated molecule or from whole mushrooms, ERG is quickly absorbed into the blood stream. Human erythrocytes (red blood cells, RBC) contain 2-9 fold more ERG than plasma. Interestingly, concentration is lowest in early life (1-10yo), increases between 11-18yo and reaches maximum value of 3.7mg/100mL by age 18. In this study, subjects consumed 8g and 16g of mushrooms and increases in red blood cell ERG were observed. After 1 and 4hr of consumption, the 16g mushroom dose increased RBC ERG concentration compared to the control, and after only 2 hrs of 16g of mushroom consumption, RBC ERG concentration was significantly higher than the control. Variability in bioavailablity was due to genetic variations in the SLC22A4 gene (Heller, Kris-etherton, Beelman). Interestingly, mutations in the ERG transporter have been identified as a susceptibility factor for autoimmune disorders, such as rheumatoid arthritis and Crohn’s disease, as well as neurodegenerative disorders, such as dementia and Parkinson’s (Paul, Snyder). 

IMG_0914

Why do we care – Once ergothioneine is in the cell, then what happens?

Ergothioneine as an antioxidant and cytoprotectant: The distribution of ERG transporters may seem random, but on closer inspection, they seem to be present in tissues predisposed to high levels of oxidative stress and inflammation (Halliwell). In animal studies, animals who were completely deficient in ERG had higher levels of reactive oxygen species and were therefore more susceptible to oxidative stress. In vitro, ERG is a powerful scavenger of hydroxyl radical and has been shown to deactivate singlet oxygen at a higher rate than glutathione (Hseu, Servillo). Similar results were proven in vivo – rats supplemented with ERG had lower levels of lipid peroxidation and higher levels of glutathione and alpha-tocopherol. As one might surmise, ERG and glutathione seem to have an intimate relationship within the cell. Glutathione is considered the major intracellular antioxidant in almost all organisms and has important functions in detoxification and immune function. It has been proposed, based on current research, that ERG can help maintain GSH levels in the presence of oxidative burden by interacting with other cellular defense systems. The maintenance of glutathione tissue levels is important in maintaining health as depletion will impair immune function. Conveniently, mushrooms contain both glutathione and ERG. In fact, mushrooms have been observed to have higher GSH amounts than any vegetable or fruit. Grifola frondosa (Maitake), Hericium erinaceus (Lions mane), Pleurotus ostreatus (Oyster mushroom), Boletus edulis (porcini) and Lentinus edodes (shitake) containing the most, respectively (Kalaras). Considering the relationship between ERG and GSH in mushrooms, a correlation analysis found that mushrooms high in GSH were also high in ERG, specifically the caps or pileus of the mushrooms (kalaras). All this said, mushrooms are an important source for cellular antioxidants.

Cation chelator: ERG chelates divalent metal cations – specifically, Cu2, hg, Zn, Cd, Co, Fe, and Ni (Cheah, Song, Kerley). Binding these cations in the body may help prevent their participation in the generation of reactive oxygen species. For example, EGT has been found to protect DNA and protein against copper induced oxidative damage through formation of a redox-inactive EGT-Cu complex. Interestingly, the high levels of ERG in semen – due to the high concentration of ERG OCTN1 transporter on the seminal vesicles- have been shown to prevent Cu inhibition of sperm motility. There is more to be explored between the relationship of ERG and semen viability.

Ergothioneine, aging, and cognitive decline: As we age, we are more vulnerable to the oxidative stress and environmental toxins that slowly damage our DNA, making us more susceptible to neurodegeneration – one of many conditions associated with DNA damage from oxidative stress. Low levels of glutathione have been linked to certain neurodegenerative diseases including Parkinson’s disease (Wei, Shah). ERG was able to dose dependently enhance glutathione activity in the rat liver cytosol—leading researchers to postulate that declining ERG may play a role in age related decline of GSH and glutathione peroxidase. Furthermore, ERG levels were found to be lower in the elderly with early stages of dementia and in PD patients relative to age matched healthy controls (Cheah). In animal studies, oral administration of ERG protected neurons and preserved cognitive function following administration of toxic amyloid beta cisplatin or D-galactose. It is now understood that the presence of Octn1 transporter in the blood brain barrier is responsible for these neuroprotective actions. Captivatingly, researchers found that there is a direct relationship between whole blood and brain ERG levels following consumption (Cheah). It is rare for compounds to be bioavailable in this way and transported across the blood brain barrier so readily – even glutathione needs to be taken intranasal for treatment of neurodegeneration.

Ergothioneine human trial: uptake metabolism and effects

While there is undeniably a lack of human trials exploring the in vivo effects of ERG, a recent study from 2017 explored ERG uptake, metabolism, and effects on biomarkers of oxidative damage and inflammation in healthy human subjects (cheah, Tang). One of the most interesting aspects of ERG discussed in this particular article is that ERG is a tautomer. This means that it exists in two forms – thione and thiol. The thiol is a single bond to sulfur and the thione is a double bond to sulfur. The article explains that in animal physiologic conditions, ERG primarily exists as the thione tautomer – under circumstances of low stress in the body, ERG remains in its thione tautomer form and is not the first choice as an antioxidant, rather endogenous antioxidants like glutathione are preferred (glutathione is a primary antioxidant thiol in the body). When the cells undergo higher levels of oxidative stress, ERG transforms into its thiol tautomer form and is then used for extra support. Additionally, under levels of elevated stress, tissues have increased amounts of the ERG, supposedly by upregulating expression of the OCTN1 ERG transporter in response to inflammatory cytokines.

This study also found that ERG can be stored in the cells for up to a month. It is theorized that ERG is stored for an extended period of time following consumption until it is required as a stronger defense mechanism.

During administration of ERG, plasma levels significantly elevated, while whole blood levels steadily increased for up to four weeks after administration stopped (red blood cells could continue to take ERG up as needed), and the excretion of ERG in the urine remained low, indicating that ERG is absorbed and retained in the body after oral administration. While this study used pure ERG, other studies previously mentioned (Heller) prove this same high bioavailability of ERG from dietary mushrooms, and so I will consider this as true for dietary ERG.

IMG_1993

Mushroom analyses of ergothioneine: Fruiting body or mycelium? Gilled mushrooms or polypore mushrooms?

ERG was highest in the fruiting body of Pleurotus ostreatus and in the mycelium of Pleurotus eryngii. Generally, fruiting bodies and mycelium contained different amounts of ERG, with Pleurotus genus containing the highest amounts overall (Chen). Among simple mushrooms, fruiting body of White Button had the least (1.4mg erg per 85g mushroom) and Portabella the highest (2.7mg erg per 85g mushroom). While among specialty mushrooms, Maitake had the least (16.3mg erg per 85g mushroom) and oyster the highest (26.4mg per 85g mushroom) (Dubost).

Fruiting bodies of gilled mushrooms, specifically the cap, contain the most ERG, while polypore mushrooms contain very small amounts. Interestingly, the mycelium of Ganoderma contains more ERG than the fruiting body, but still not as much as the fruiting bodies of Shitake, Matsutake, Oyster, and Maitake (Lee, Wang).

Extraction:

Hot water extraction is sufficient to extract ERG from mushrooms.

In a study that explored water extraction – temperature of water, ratio of water to mycelium and the extraction rate of ERG, the following information was found:

Most notable: at 85°C and 20:1 ratio of mycelium to water, the extraction rate of ERG was 91.2% – the least effective yield of ERG was at 78°C and a 20:1 ratio of mycelium to water. There was no difference in ERG concentration between 5 minutes and 120 minutes, so a long boil to extract EGR is not necessary (Zhang).

In Summary:

Ergothioneine is a water soluble compound that is most abundant in Oyster mushrooms. There are transporters on different tissues in the body that are highly specific to ergothioneine. Ergothioneine is readily absorbed into the blood after consumption of mushrooms and stored in tissues for up to 1 month. In times of excessive oxidative stress, ergothioneine is taken up by those tissues and used as an antioxidant. Of note: there are transporters on the blood brain barrier and there is an association with low ergothioneine and age-related cognitive decline. In a world full of environmental toxins that are mostly impossible to escape, we might as well eat more mushrooms and get some extra protection.

How to apply this information to your life:

Eat a lot of mushrooms, especially Oyster mushrooms.

Oyster Mushroom Recipes

Resources for ergothioneine rich mushrooms around the Seattle area:

Cascadia Mushrooms

Sno-Valley Mushrooms

Work Cited

Antonicelli F, Aruoma OI. Ergothioneine inhibits oxidative stress- and TNF- a -induced NF- j B activation and interleukin-8 release in alveolar epithelial cells. 2003;302:860-864. doi:10.1016/S0006-291X(03)00224-9.

Aruoma OI, Spencer JPE, Mahmood N. Protection Against Oxidative Damage and Cell Death by the Natural Antioxidant Ergothioneine. 1999;37.

Aruoma OI, Whiteman M, England TG, Halliwell B. Antioxidant Action of Ergothioneine : Assessment of Its Ability to Scavenge Peroxynitrite. 1997;391(231):389-391.

Aubert DIRKT. Dietary Sources and Antioxidant Effects of Ergothioneine. 2007:6466-6474. doi:10.1021/jf071328f.

Benson KF, Ager DM, Landes B, Aruoma OI, Jensen GS. Improvement of joint range of motion ( ROM ) and reduction of chronic pain after consumption of an ergothioneine-containing nutritional supplement. Prev Med (Baltim). 2018;54(2012):S83-S89. doi:10.1016/j.ypmed.2012.02.001.

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