Edible or macrofungi have a worldwide distribution and have long been used for food and medicine by humans. They are taxonomically placed in two phyla, the Basidiomycota (class Agaricomycetes) and Ascomycota (class Pezizomycetes). The Greek physician Hippocrates in 450 BCE, used the amadou mushroom (Fomes fomentarius) to cauterize wounds and as an anti-inflammatory.^1,2 Medical mushrooms have been used for thousands of years in China, dating back to the 29th century BCE. The use of the famous medical mushroom lingzhi (Ganoderma lucidum) or reishi and others were recorded in the Shennong Bencao Jing (the Divine Farmers Materia Medica). The Bencao Gangmu, published in 1578, is a three-volume compendium of Materia Medica and comprehensively describes 1892 medicinal substances, of which 444 were animal, 1094 were herbs, 275 were mineral substances, and described 20 species of medicinal mushrooms.³ Ötzi (the Ice Man), a corpse that was discovered in 1991 in a field near the Austrian-Italian border, attracted worldwide attention. He was estimated to have lived between 3300 and 3100 BCE and was found with a tethered pouch that contained the fragments of the birch polypore mushroom (Piptoporus betulinus) and amadou/true tinder bracket (Fomes fomentarius), which many speculate helped him to survive in the Alps of northern Italy.⁴ It is estimated that there are 140,000–160,000 known species of mushrooms, with approximately 2000 that are edible mushroom species and around 700 of those reported to have medicinal properties. Most newly described fungi are from the tropics, and it is estimated that in various tropical areas, 22–55% (in some cases, up to 73%) of mushroom species have not yet been identified.^5-9 China was the first country to cultivate mushrooms beginning in 600–1000 ACE and is currently the highest producer of mushrooms in the world, followed by Poland, the Netherlands, Italy, and the United States.⁹ Although mushrooms have long been used by many different cultures, only recently has modern research focused on the study of the medicinal properties and pharmacological potential of edible/medicinal, wild, and cultivated mushrooms for standardized clinical application.

Coriolus versicolor (turkey tail), Hericium erinaceus (lion’s mane), Ganoderma lucidum (reishi), Grifola frondosa (maitake), Lentinula edodes (shiitake), Inonotus obliquus (chaga), Agaricus blazei murrill (sun mushroom), and Cordyceps sinensis/militaris (Chinese caterpillar fungus) are all considered medical mushrooms because these and many other mushrooms produce a variety of types of high- and low-molecular-weight primary and secondary metabolites. The pharmacological effects of medicinal plants depend on their phytochemical/active constituents, known as secondary metabolites. These biologically active constituents include polysaccharides, polysaccharide-protein/peptides, peptidoglycans, polyketides, proteins, phenolics, terpenoids, alkaloids, lectins, lipids, ribosomal and non-ribosomal peptides, steroids, and others.^5-7,9 Medical mushrooms have been reported to have more than 130 different therapeutic effects, including immunomodulatory, antitumor, antioxidant, radical scavenging, anti-inflammatory, antioxidant, antiviral, antibacterial, antifungal, antiparasitic, antiplatelet, antiviral, cytotoxic, hepatoprotective, cardioprotective, hypocholesterolemic, anti-diabetic, neuroregenerative, and microbiome restorative and have become the recent focus for new drug discovery.^5-7,9 The vast majority of studies and research to date focus on the immunomodulatory activity of mushrooms and the identification of bioactive substances in mushrooms for the treatment of cancer, neurodegenerative diseases, and immune deficiency.

Polysaccharides are one of the most important constituents in medical mushrooms. Due to their structural variability, polysaccharides have the highest capacity or ability for carrying biological information compared to biopolymers, such as proteins and nucleic acids and are produced by a vast number of species. Numerous bioactive polysaccharides or polysaccharide-protein complexes from medicinal mushrooms appear to enhance innate and cell-mediated immune responses and exhibit anti-neoplastic activity in animals and humans. Their mechanism of action is still not completely understood; however, stimulation and modulation of host immune responses by these mushroom compounds appear central.^9-12 This is why medical mushrooms are often described as biological response modifiers. A polysaccharide found in all medical mushrooms is beta-glucan (β-glucan), which makes up a large portion of the fungal cell wall and is divided into β-1,3-glucan and β-1,6-glucan. β-glucans are considered to be the main active constituents in most medical mushrooms, whose primary biological target is modulation of the immune system. Mushroom polysaccharides produce immunomodulatory effects by activation of cytotoxic macrophages, monocytes, neutrophils, natural killer (NK) cells, dendritic cells, and chemical messengers (cytokines, such as interleukins, interferons, and colony-stimulating factors) that trigger immune responses. These polysaccharides are also able to induce gene expression of various immunomodulating cytokines and cytokine receptors. Cytokines are molecules (small proteins, peptides, or glycoproteins) secreted by specific cells of the immune system that act as chemical messengers for cell-to-cell communication in immune responses. Cytokines can stimulate the movement of cells toward sites of trauma, inflammation, and infection and can stimulate the differentiation of immune T cells and immune B cells towards a primarily cell-mediated or humoral-mediated immune response. Activation of macrophages removes pathogens and also promotes the secretion of cytokines and the expression of phagocyte markers (CD40, CD80, and CD86) and major histocompatibility complex (MHC) to enhance the innate immune response.^11-17

Some mushroom polysaccharides prevent oncogenesis, show direct antitumor activity against a variety of tumors, and prevent tumor metastasis. The antitumor action of polysaccharides requires normal T cell function, and their activity is mediated through a thymus-dependent immune mechanism.^12-17 Polysaccharides, such as β-glucans and other mushroom metabolites, are thought to promote T cell dominance which is critical to prevent tumor growth. A balance between cellular and humoral immunity is essential for restraining tumor growth and development. National healthcare systems in Japan, China, Korea, Russia, and several other countries have developed and use mushroom-derived preparations as an adjunct for the treatment of patients with cancer and undergoing chemotherapy.^18,19 Two of the best-known commercial polysaccharide-protein complexes are polysaccharide krestin (PSK) and polysaccharopeptide (PSP) obtained from the mycelia of turkey tail (Coriolus versicolor) that has strong immunological properties and is currently in use as an adjuvant for cancer treatment with no known side effects.^14-19 There are many peer-reviewed studies on turkey tail, and it has been used for over 3000 years in China, where it is known by the name yunzhi or cloud mushroom.

Many in vivo and in vitro studies have shown that mushroom polysaccharides (primarily β-glucans in fungal cell walls) have a prebiotic effect after reaching the large intestine and colon. After ingestion, the gut flora breaks down and metabolizes mushroom polysaccharides that can cause significant beneficial changes in the microbial composition of the gut. Mushroom polysaccharides decrease the pH, which promotes the proliferation and growth of beneficial intestinal bacteria and increases the concentration of total short-chain fatty acids (SCFA), which play a regulatory role in intestinal homeostasis and immune response. For example, in one study, it was shown that polysaccharides from G. lucidum increased the abundance of Bacteroidetes, Ruminococcaceae, Bifidobacteriaceae, and Lactobacillaceae and decreased the abundance of Firmicutes, Enterobacteriaceae, and Lachnospiraceae.^20-21 As many systemic and localized diseases are associated with dysbiosis, any dysfunction in the microbiome can result in a decline in overall wellness and the development of a variety of diseases, both local and remote in the body. A healthy microbiome is necessary for optimal health, and mushroom polysaccharides can play an important role by increasing the abundance and diversity of normal intestinal flora in the treatment of dysbiosis.

Medical mushrooms produce many other secondary metabolites, in addition to polysaccharides, that not only stimulate the immune system but also modulate specific cellular responses by inhibiting specific transduction pathways. For example, Agaricus bisporus (button/cremini mushroom), Lentinula edodes (shiitake), and Phellinus linteus (sanghuang) produce the caffeic acid phenethyl ester (CAPE), which inhibits the DNA binding of nuclear factor kappa light-chain enhancer of activated B cells (NF κB) with good results in human breast cancer MCF 7 cells.^6-22 CAPE is a natural phenolic antioxidant (also found in other plants and in honey bee propolis) that has been shown to inhibit the stimulation of prostaglandin (PG) synthesis in cultured human oral epithelial cells and in a murine model of acute inflammation.

Nuclear factor-B (NF-B) is a family of inducible transcription factors that regulate genes involved in cellular growth, apoptosis, and immune and inflammatory responses and mediate transcription of target genes by binding to a specific DNA element. In another study, a methanol extract of F. fomentarius was reported to inhibit inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX) expression due to the downregulation of NF κB binding activity to DNA.^6,23 Other examples of biologically active substances in medical mushrooms include cordycepin (adenosine analogue of fungal origin) in Cordyceps, hispidin and hispolon (polyphenols) in chaga, and ganoderic acids (triterpenoids) in reishi (Ganoderma).

Medical mushrooms have broad-spectrum effects, and each species will have its own unique properties, biological targets, and physiological effects. Researchers have discovered that certain plants and fungi, including some medical mushrooms, can function as adaptogens. Adaptogens increase the body’s resistance to stressors (physical, biological, chemical, and environmental) and promote normal physiologic function through modulation of the immune and neuroendocrine systems. The body’s stress response is complex and involves multiple systems of the body, particularly the hypothalamic-pituitary-adrenal (HPA axis), which is the body’s main stress response system. The primary function of the HPA axis is to release glucocorticoids, which activate the stress response.²⁴ Adaptogens primarily work by influencing the HPA axis, enhancement of cellular energy transfer, and help the body utilize oxygen, glucose, lipids, and proteins more effectively to promote resistance to stress, decrease recovery time, prevent disease, and restore balance (homeostasis). The most common adaptogenic mushrooms include lion’s mane, reishi, and Corydceps. It is important to note that all medical mushrooms have tonic effects, but not all medical mushrooms are adaptogens. Due to time limitations, only the most commonly used mushrooms and their applications in veterinary medicine will be discussed in this lecture.

Common Medical Mushrooms Used in Veterinary Medicine

• Turkey tail (yunzhi), Coriolus versicolor/Trametes versicolor)
• Ganoderma/reishi (lingzhi), Ganoderma lucidum
• Cordyceps (dong chong xia cao), Cordyceps sinensis
• Lion’s mane, Hericium erinaceus
• Shiitake (xiang gu), Lentinula edodes
• Maitake (hui shu hua), Grifola frondosa
• Chaga, Inonotus Obliquus
• Agaricus blazei Murrill (sun mushroom)

There are several types of medical mushroom and dietary supplement products available on the market today. These include naturally grown dried mushroom fruit bodies in the form of capsules or tablets; artificially and cultivated fruit body powders; hot water or alcohol extracts of fruit bodies; dried and pulverized preparations of combined substrate, mycelium, and mushroom primordial; spores and their extracts; and biomass or extracts from mycelium. Approximately 80–85% of all medicinal mushroom products, commercially farmed or collected from the wild, are derived from the fruiting bodies, and 15% of all products are based on extracts from mycelia, such as PSK and PSP from T. versicolor.^6-8,26 Mushroom products should contain only the most potent medicinal parts of the fungi with no added fillers or starches. Many mushroom supplements sold in the U.S. and other countries contain only the mycelium (not the fruiting body or mushroom itself) and the grain on which the mycelium is grown. These products may have little to no β-glucan content or other active constituents and, therefore, lack the medicinal properties required for a therapeutic effect.

Administration of Medical Mushrooms

Both edible and medicinal mushrooms are lion’s mane, Cordyceps, maitake, and shiitake. These mushrooms can be put directly in the pet’s food. Others, such as reishi, chaga, and turkey tail, are technically considered edible; however, they don’t taste good and are commonly given in capsule form to dogs and cats. Horses, as they are strict herbivores, will take some of the aforementioned medical mushrooms mixed with sweet grain.

When using whole dried mushrooms, hot water extraction is required to extract the active components (β-glucans and other active components) from the mushrooms. Whole mushrooms are often added to bone broth to make a soup or stew that can be added to the pet’s food. The indigestible carbohydrates and soluble fibers in mushrooms support the health of the microbiota and also contain antioxidants like ergothioneine and glutathione. Fresh mushrooms are 90% water and are most often used to boost the nutritional value of the food and act as a preventative health and wellness measure. In the treatment of medical conditions, certified/standardized organic mushroom products without additives, fillers, starch, grains, or mycelium are recommended, and those list the total β-glucan content are considered to be the best indicators of quality and therapeutic benefit. The dosage of medical mushrooms is variable and depends on the product used, any other medications given, and the condition being treated.

Where to Purchase Quality Medical Mushroom Products

• Health Concerns (www.healthconcerns.com)
• Mayway Chinese Herbs (www.mayway.com)
• Evergreen Herbs (http://w.evherbs.com/herbal-products)
• Pure Encapsulations (www.pureencapsulations.com)
• Real Mushrooms (Canada, Roberts Creek, BC, www.realmushrooms.com)
• iHerb (USA, CA, www.iherb.com)
• Fungi Perfecti (Olympia, WA, www.fungi.com)
• Ommush-rooms (Carlsbad, CA, www.ommushrooms.com)
• Time Health (UK, www.timehealth.co.uk)
• Zipvit (UK, Staffordshire, www.zipvit.co.uk)

References

1.  Szychowski KA, Skóra B, Pomianek T, Gmiński J. Inonotus obliquus–from folk medicine to clinical use. eJTCM. 2021;11(4):293–302.

2.  Stamets P, Zwickey H. Medicinal mushrooms: ancient remedies meet modern science. IMCJ. 2014;13(1):46.

3.  Lee KH, Morris-Natschke SL, Yang X, et al. Recent progress of research on medicinal mushrooms, foods, and other herbal products used in traditional Chinese medicine. eJTCM. 2012;2(2):1–12.

4.  Poder R. The Ice man’s fungi: facts and mysteries. International Journal of Medicinal Mushrooms. 2005;7(3).

5.  Wasser SP. Medicinal mushrooms as a source of antitumor and immunomodulating polysaccharides. Appl Microbiol Biotechnol. 2002;60:258–274.

6.  Wasser SP. Medicinal mushroom science: Current perspectives, advances, evidences, and challenges. Biomed J. 2014;37(6).

7.  Badalyan SM, Barkhudaryan A, Rapior S. Recent progress in research on the pharmacological potential of mushrooms and prospects for their clinical application. Medicinal Mushrooms: Recent Progress in Research and Development. 2019;1–70.

8.  Lindequist U, Niedermeyer TH, Jülich WD. The pharmacological potential of mushrooms. Evid base Compl Alternative Med. 2005;2:285–299.

9.  Bhambri A, Srivastava M, Mahale VG, Mahale S, Karn SK. Mushrooms as potential sources of active metabolites and medicines. Front Microbiol. 2022;13:837266.

10.  Zhao S, Gao Q, Rong C, et al. Immunomodulatory effects of edible and medicinal mushrooms and their bioactive immunoregulatory products. J Fungi (Basel). 2020;6(4):269.

11.  Garcia J, Rodrigues F, Saavedra MJ, Nunes FM, Marques G. Bioactive polysaccharides from medicinal mushrooms: a review on their isolation, structural characteristics and antitumor activity. Food Bioscience. 2022;101955.

12.  Kiddane AT, Kim GD. Anticancer and immunomodulatory effects of polysaccharides. Nutr Canc. 2021;73(11–12):2219–2231.

13.  Chakraborty I, Sen IK, Mondal S, et al. Bioactive polysaccharides from natural sources: a review on the antitumor and immunomodulating activities. Biocatalysis and Agricultural Biotechnology. 2019;22:101425.

14.  Krishnakumar NM, Ramesh BT, Ceasar SA. Medicinal mushrooms as potential sources of anticancer polysaccharides and polysaccharide–protein complexes. Studies in Natural Products Chemistry. 2023;76:113–148.

15.  Hyder MS, Dutta SD. Mushroom-derived polysaccharides as antitumor and anticancer agent: a concise review. Biocatalysis and Agricultural Biotechnology, 2021;35:102085.

16.  Narayanan S, de Mores AR, Cohen L, et al. Medicinal mushroom supplements in cancer: a systematic review of clinical studies. Curr Oncol Rep. 2023;25(6):569–587.

17.  Jeitler M, Michalsen A, Frings D, et al. Significance of medicinal mushrooms in integrative oncology: a narrative review. Frontiers Pharmacol. 2020;11:580656.

18.  Panda SK, Luyten W. Medicinal mushrooms: clinical perspective and challenges. Drug Discov Today. 2022;27(2):636–651.

19.  Zhang X, Cai Z, Mao H, Hu P, Li X. Isolation and structure elucidation of polysaccharides from fruiting bodies of mushroom Coriolus versicolor and evaluation of their immunomodulatory effects. Int J Biol Macromol. 2021;166:1387–1395.

20.  Fernandes A, Nair A, Kulkarni N, Todewale N, Jobby R. Exploring mushroom polysaccharides for the development of novel prebiotics: a review. International Journal of Medicinal Mushrooms. 2023;25(2).

21.  Yu Y, Liu Z, Song K, Li L, Chen M. Medicinal value of edible mushroom polysaccharides: a review. Journal of Future Foods. 2023;3(1):16–23.

22.  Michaluart P, Masferrer JL, Carothers AM, et al. Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation. Canc Res. 1999;59(10):2347–2352.

23.  Park YM, Kim IT, Park HJ, et al. Anti-inflammatory and anti-nociceptive effects of the methanol extract of Fomes fomentarius. Biol Pharm Bull. 2004;27(10):1588–1593.

24.  Winston D. Adaptogens: Herbs for Strength, Stamina, and Stress Relief. Simon and Schuster; 2019.

25.  Isokauppila T, Sigmatic F. Healing Mushrooms: A Practical and Culinary Guide to Using Mushrooms for Whole Body Health. Penguin; 2017.

26.  Dawadi E, Magar PB, Bhandari S, Subedi S, Shrestha S, Shrestha J. Nutritional and post-harvest quality preservation of mushrooms: a review. Heliyon. 2022.