Hericium erinaceus

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1. Classification

a. Higher order taxa

Hericium erinaceus is classified under the domain Eukaryota, kingdom Fungi, phylum Basidiomycetes, class Agaricomycetes, order Russulales, and family Hericiaceae [1].

2. Description and significance

Hericium erinaceus is an edible mushroom also named “Bearded Tooth Fungus,” “Lion’s Mane Mushroom,” or “Yamabushitake" for its unique macromorphology [2]. In addition to its culinary use, H. erinaceus has been prescribed as an alternative natural remedy for epigastric pain and general weakness or fatigue in traditional medicine across Asia for centuries [3,2]. The fruiting body and mycelium of H. erinaceus contain around 70 structurally different secondary metabolites [4]. Each of these compounds potentially produce various bioactive effects including antibiotic, anticarcinogenic, neuroprotective, anti-inflammatory, immunostimulatory, and antioxidative properties among others [4]. The discovery of these effects has expanded the usage of H. erinaceus across various medical specialties. Ongoing research focuses on extracting these compounds to elucidate their mechanisms of action, which are largely unknown, and thus their therapeutic potential as pharmaceutical agents for treating or curing neurological conditions, gastrointestinal disorders, and cancer [2].

3. Genome structure

The genome of H. erinaceus is 41.2 Mb in size with 10,620 predicted genes and 447 transcription factors [5]. 44.2% of the genome sequence contains protein-coding genes. Repeat sequences, or short/long patterns of DNA that can occur, account for 19.0% of the genome; tandem repeats make up 1.7% of the genome; and transposable elements account for 17.3% of the genome [5]. 341 genes encoding Carbohydrate-active enzymes (CAZymes), which build and break down complex carbohydrates and glycoconjugates, were found in the genome of H. erinaceus [5,6]. Of the 341 CAZyme genes found, 161 encode glycoside hydrolases, 59 encode glycosyl transferases, 7 encode polysaccharide lyases, 26 encode carbohydrate esterases, 4 encode carbohydrate-binding modules, and 84 encode auxiliary activities enzymes [5]. Glycoside hydrolases that are required to digest cellulose and hemicellulose were also found in the H. erinaceus genome [5].

4. Cell structure

The cell wall of H. erinaceus is mainly made up of low molecular mass polysaccharides that are water soluble and alkali-soluble [7]. The water soluble polysaccharides are mainly made up of glucose and galactose. H. erinaceus also has numerous polysaccharide-protein complexes that promote its medicinal properties [7]. The spores of H. erinaceus are ellipsoid and smooth to slightly roughened. The spores of H. erinaceus have an average size of 5.5 -- 7 × 4.5 -- 5.5 μm [8].

5. Metabolic processes

H. erinaceus contains a large percentage of polysaccharides, specifically in its cell wall. These polysaccharides act as the main bioactive compound that lend the mushroom to being beneficial to the medical and healthcare industries [7]. Furthermore, H. erinaceus contains a large variety of secondary metabolites, which can be loosely classed by characteristics of organic structure: erinacines, hericerins (aromatic compounds), glycoproteins, polysaccharides, and sterols [4]. Carbohydrate metabolism pathways – carbon metabolism, pyruvate metabolism, and glycolysis and gluconeogenesis – in two mutant strains (HEB and HEC) of H. erinaceus with higher polysaccharide production, as well as a cAMP-PKA pathway, are upregulated such that glucose availability can be used efficiently in order to promote cell growth and division [9]. Cytochrome P450 proteins are highly active in H. erinaceus and have been found to play a large role in secondary metabolite biosynthesis, amino acid transport, and energy production in the mushroom [10]. H. erinaceus's increased polysaccharide synthesis, carbohydrate metabolism, and glucose signaling, are the properties of interest in the medical community.

6. Ecology

H. erinaceus is a fungus with a mature fruiting body: a bulbous structure hidden by smooth fibrous spines dangling from the body in a radiating arrangement [2]. Generally, the spines’ characteristics vary with maturation. An immature specimen has white spines that are 1 cm or less in length, whereas a fully developed specimen’s spines are 1-4 cm and may discolor into a yellow-brown color [11]. H. erinaceus most often grows in Japan, North America, and the UK. Though overall, H. erinaceus is not common in nature, it is typically found growing from wood in sparsely populated forests with older trees [12]. It most often grows in dead wood, but also sometimes grows out of knotholes in trees or cracks in the bark of living trees. The growth of H. erinaceus indicates that it is a saprotroph, using already decaying wood as its source of nutrition rather than acting as the cause of disease in the wood [12]. It is most abundant in the northern hemisphere from the months of September to December [2]. H. erinaceus is beginning to disappear from natural habitats, perhaps indicating extinction [2].

7. Pathology

There are currently no known instances in which H. erinaceus acts as a human pathogen. A study performed on the efficacy of erinacine-A-enriched H. erinaceus mycelia and its potential adverse effects in a preclinical experimental setting found that the mycelia was considered safe for consumption within appropriate doses, and nontoxic based on prenatal developmental toxicity tests [13]. Another study orally administered aqueous extracts of H. erinaceus at different dosages and observed no mortality or morbidity in all of the treated and control rats [14]. The results from both toxicity studies conclude that the oral administration of H. erinaceus extracts is safe and relatively non-toxic under certain dosages.

8. Current Research

a. Neurodegenerative Diseases

H. erinaceus was able to ameliorate pathologies in Alzheimer’s Disease (AD) through its neuroprotective and neuritogenic properties [15]. In one study, H. erinaceus was cultured and isolated into seven separate bioactive compounds, with 4-chloro-3,5-dimethoxybenzoic methyl ester and erinacine-A having the greatest effect [15]. H. erinaceus contributed to the advancement of phosphorylation in PC12 cells, promoting the TrkA pathway which determines axonal growth. It also promoted the survival of the cell by another pathway, the ERK 1-2 pathway which regulates cellular processes such as proliferation, differentiation, and survival of the cell [15].

A 2021 study found that H. erinaceus contains bioactive compounds that counteract hyperactive oxidative stress and neuroinflammatory responses associated with symptoms of AD [16]. Using a rat model with AlCl3 injections, which simulate neurodegeneration in AD, biochemical analysis of hippocampal tissues and behavioral tests were able to demonstrate the anti-inflammatory and antioxidative properties of the mushroom [16]. H. erinaceus activates antioxidant enzymes and downregulates inflammasome pathways that produce proinflammatory proteins, reducing the plaque accumulation, neurodegeneration, and behavioral alterations caused by AD [16].

H. erinaceus mycelium (HEM) and its bioactive components, erinacine-A and erinacine-S show promising results in promoting oligodendrocyte (OL) maturation [17]. OLs are myelin producing glia that facilitate action potential propagation in neurons [17]. A research study found that OLs displayed a mature morphology with a complex and extended membranous shape after being immunostained in cell cultures treated with 0.1 and 1.0 μ/mL of crude HEM [17].

b. Spinal Cord Injuries

The bioactive compounds in H. erinaceus have recently been reported to have anti-inflammatory properties that act in both the central and peripheral nervous systems. Crude extracts from H. erinaceus (HE-CE) can ameliorate nerve injury and neuroinflammation found in both of these systems, reducing neuropathic pain [18]. Spinal nerve ligations, which tightly tie or cut the L5 nerve, were performed on rats as a model for neuropathic pain, inducing symptoms mimicking causalgia, a burning sensation resulting from injury to a PNS nerve [18]. These effects were also confirmed in an in vitro human cell line [18].

HE-CE acts as an analgesic and an anti-inflammatory by suppressing the molecular processes that initiate and transmit neuropathic pain and neuroinflammation [18]. Erinacine-S and erinacine-A were further isolated to determine which of these two major components was inducing these effects [18]. Erinacine-S produced a more potent analgesic and anti-inflammatory effect than HE-CE, while erinacine-A had little to no effect on these molecular pathways [18].

c. Depression, Anxiety, and Sleep Disorders

H. erinaceus has been shown to improve depression, anxiety, and sleep disorders in obese individuals. Previous studies and epidemiological data suggest that subjects affected by obesity have an increased risk of developing mood disorders [19]. A study investigating the effect of H. erinaceus on mood disorders using a SCL-90 test found that depression, anxiety, and sleep disorders decrease significantly in obese individuals after 8 weeks of oral supplementation with H. erinaceus [19]. After 2 months of H. erinaceus (T1) supplementation, the mean score value decreased to 43.5 ± 1.54, indicating a low degree of depression symptomatology [19]. The value remained stable after the H. erinaceus wash-out.

d. Gastrointestinal Disorders

Current research on the use of H. erinaceus extracts for treating gastrointestinal disorders include studies of how its properties can benefit the human gut microbiome. One study utilized the extracts to test if they are clinically effective for treating inflammatory bowel disease (IBD) [20]. The extracts, consisting of polysaccharide, alcoholic, and whole extracts, were prepared using solvent extraction methods, and then administered in rats with IBD for two weeks. The extracts were successful in promoting the growth of beneficial gut bacteria and improving the host immunity in vivo IBD model, showing the potential benefits of using H. erinaceus to treat IBD by regulating gut microbiota and the immune system [20].

Another study extracted and isolated polysaccharides from fruiting bodies of H. erinaceus to test whether they could alter the diversity and abundance of gut microbiota through oral administration [21]. Adult, middle-aged, and old mice were fed the polysaccharides for 28 days. Then, their feces and intestinal contents were collected to create supernatants for in vitro fermentation [21]. A control group, consisting of cells incubated with unfermented polysaccharides, were used for comparison. The study utilized Western Blots to test whether the fermentation supernatants in H. erinaceus polysaccharides activated a pathway of macrophages, finding that the polysaccharides increased the diversity and abundance of gut microbiota through oral administration [21].

e. Cancer

Research is currently being conducted on properties of H. erinaceus that may allow it to be used as a cancer treatment. Current studies are investigating peptides derived from H. erinaceus for their ability to induce death in cancerous cells, including leukemia cells and lung cancer cells [22].

Further research shows that the polysaccharides of H. erinaceus have antitumor properties. In a study conducted on human carcinoma cells, H. erinaceus was combined with doxorubicin (Dox), an antibiotic. Scientists looked at the effects that this combination had on carcinoma cells in humans. The results signified that the fusion of both H. erinaceus and Dox promoted the activation of JNK, a signal molecule that assists in cell processes like proliferation and apoptosis. H. erinaceus and Dox were used as a treatment on HepG2 cells. These treated HepG2 cells induced activation of JNK and that led to apoptosis of the cells [23]. This research contributes to the plethora of other studies using natural remedies to treat cancer.

An experiment, performed by Sangtitanu et al., introduced the idea that H. erinaceus can scavenge free radicals [24]. These free radical scavengers can either stop reactive oxygen species from being formed or remove them before they can damage the cells. In the case of H. erinaceus, F4 peptide hydrolysate sub-fraction, which is found in H. erinaceus, was the best free radical scavenger. This radical helps prevent DNA damage and can even lead to apoptosis of lung cancer cells [24].

9. References

[1] [Schoch, C. L., Ciufo, S., Domrachev, M., Hotton, C. L., Kannan, S., Khovanskaya, R., Leipe, D., Mcveigh, R., O’Neill, K., Robbertse, B., Sharma, S., Soussov, V., Sullivan, J. P., Sun, L., Turner, S., & Karsch-Mizrachi, I. (2020). Taxonomy browser (Hericium erinaceus). National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=91752]

[2] [Thongbai, B., Rapior, S., Hyde, K.D., Wittstein, K., & Stadler, M. (2015). Hericium erinaceus, an amazing medicinal mushroom. Mycol Progress, 14, 91. https://doi.org/10.1007/s11557-015-1105-4]

[3] [Gravina, A. G., Pellegrino, R., Auletta, S., Palladino, G., Brandimarte, G., D'Onofrio, R., Arboretto, G., Imperio, G., Ventura, A., Cipullo, M., Romano, M., & Federico, A. (2023). Hericium erinaceus, a medicinal fungus with a centuries-old history: Evidence in gastrointestinal diseases. World journal of gastroenterology, 29(20), 3048–3065. https://doi.org/10.3748/wjg.v29.i20.3048]

[4] [Friedman, M. (2015). Chemistry, Nutrition, and Health-Promoting Properties of Hericium erinaceus (Lion’s Mane) Mushroom Fruiting Bodies and Mycelia and Their Bioactive Compounds. Journal of Agricultural and Food Chemistry, 63(32), 7108-7123. https://doi.org/10.1021/acs.jafc.5b02914]

[5] [Gong, W., Wang, Y., Xie, C., Zhou, Y., Zhu, Z., & Peng Y. (2020). Whole Genome Sequence of an Edible and Medicinal Mushroom, Hericium erinaceus (Basidiomycota, Fungi). Genomics. (112)3. https://doi.org/10.1016/j.ygeno.2020.01.011]

[6] [Cantarel, B. L., Coutinho, P. M., Rancurel, C., Bernard, T., Lombard, V., & Henrissat, B. (2009). The Carbohydrate-Active EnZymes database (CAZy): an expert resource for Glycogenomics. Nucleic acids research, 37(Database issue), D233–D238. https://doi.org/10.1093/nar/gkn663]

[7] [Wu, D., Yang, S., Tang, C., Liu, Y., Li, Q., Zhang, H., Cui, F., & Yang, Y. (2018). Structural Properties and Macrophage Activation of Cell Wall Polysaccharides from the Fruiting Bodies of Hericium erinaceus. Polymers, 10(8), 850. https://doi.org/10.3390/polym10080850]

[8] [Sokol, S., Golak-Siwulksa, I., Sobieralski, K., Siwulski, M., & Gorka, K. (2015). Biology, Cultivation, and medicinal functions of the mushroom Hericium Erinaceus. Acta Mycologica, 50(2), 1-18. https://doi.org/10.5586/am.1069]

[9] [Gong, M., Zhang, H., Wu, D., Zhang, Z., Zhang, J., Bao D., Yang, Y. (2021). Key metabolism pathways and regulatory mechanisms of high polysaccharide yielding in Hericium erinaceus. BMC Genomics 22, 160. https://doi.org/10.1186/s12864-021-07480-x]

[10] [Chen, J., Zeng, X., Yang, Y. L., Xing, Y. M., Zhang, Q., Li, J. M., Ma, K., Liu, H. W., & Guo, S. X. (2017). Genomic and transcriptomic analyses reveal differential regulation of diverse terpenoid and polyketides secondary metabolites in Hericium erinaceus. Scientific Reports, 7(1): 10151. https://doi.org/10.1038/s41598-017-10376-0]

[11] [Brandalise, F., Roda, E., Ratto, D., Goppa, L., Gargano, M. L., Cirlincione, F., Priori, E. C., Venuti, M. T., Pastorelli, E., Savino, E., & Rossi, P. (2023). Hericium erinaceus in Neurodegenerative Diseases: From Bench to Bedside and Beyond, How Far from the Shoreline? Journal of Fungi (Basel, Switzerland), 9(5), 551. https://doi.org/10.3390/jof9050551]

[12] [Boddy, L., Crockatt, M.E., Ainsworth, A.M. (2011). Ecology of Hericium cirrhatum, H. coralloides and H. erinaceus in the UK. Fungal Ecology, (4)2, 163-173. https://www.sciencedirect.com/science/article/pii/S175450481000070X]

[13] [Li, I.C., Chen, W.P., Chen, Y.P., Lee, L.Y., Tsai, Y.T., & Chen, C.C. (2018). Acute and developmental toxicity assessment of erincine A-enriched Hericium erinaceus mycelia in Sprague–Dawley rats. Drug and Chemical Toxicology, 41:4, 459-464. https://doi.org/10.1080/01480545.2017.1381110]

[14] [Lakshmanan, H., Raman, J., David, P., Wong, K.-H., Naidu, M., & Sabaratnam, V. (2016). Haematological, biochemical and histopathological aspects of Hericium erinaceus ingestion in a rodent model: A subchronic toxicological assessment. Journal of Ethnopharmacology, 194, 1051–1059. https://doi.org/10.1016/j.jep.2016.10.084]

[15] [Zhang, C.-C., Cao, C.-Y., Kubo, M., Harada, K., Yan, X.-T., Fukuyama, Y., & Gao, J.-M. (2017). Chemical Constituents from Hericium erinaceus Promote Neuronal Survival and Potentiate Neurite Outgrowth via the TrkA/Erk1/2 Pathway. International Journal of Molecular Sciences, 18(8), 1659. MDPI AG. http://dx.doi.org/10.3390/ijms18081659]

[16] [Cordaro, M., Salinaro, A. T., Siracusa, R., D'Amico, R., Impellizzeri, D., Scuto, M., Ontario, M. L., Cuzzocrea, S., Di Paola, R., Fusco, R., & Calabrese, V. (2021). Key Mechanisms and Potential Implications of Hericium erinaceus in NLRP3 Inflammasome Activation by Reactive Oxygen Species during Alzheimer's Disease. Antioxidants (Basel, Switzerland), 10 (11), 1664. https://doi.org/10.3390/antiox10111664]

[17] [Huang, H. T., Ho, C. H., Sung, H. Y., Lee, L. Y., Chen, W. P., Chen, Y. W., Chen, C. C., Yang, C. S., & Tzeng, S. F. (2021). Hericium erinaceus mycelium and its small bioactive compounds promote oligodendrocyte maturation with an increase in myelin basic protein. Scientific reports, 11(1), 6551. https://doi.org/10.1038/s41598-021-85972-2]

[18] [Yang, P. P., Chueh, S. H., Shie, H. L., Chen, C. C., Lee, L. Y., Chen, W. P., Chen, Y. W., Shiu, L. Y., & Liu, P. S. (2020). Effects of Hericium erinaceus Mycelium Extracts on the Functional Activity of Purinoceptors and Neuropathic Pain in Mice with L5 Spinal Nerve Ligation. Evidence-based complementary and alternative medicine : eCAM, 2020, 2890194. https://doi.org/10.1155/2020/2890194]

[19] [Vigna, L., Morelli, F., Agnelli, G. M., Napolitano, F., Ratto, D., Occhinegro, A., Di Iorio, C., Savino, E., Girometta, C., Brandalise, F., & Rossi, P. (2019). Hericium erinaceus Improves Mood and Sleep Disorders in Patients Affected by Overweight or Obesity: Could Circulating Pro-BDNF and BDNF Be Potential Biomarkers?. Evidence-based complementary and alternative medicine : eCAM, 2019, 7861297. https://doi.org/10.1155/2019/7861297]

[20] [Diling, C., Xin, Y., Chaoqun, Z., Jian, Y., Xiaocui, T., Jun, C., Ou, S., & Yizhen, X. (2017). Extracts from Hericium erinaceus relieve inflammatory bowel disease by regulating immunity and gut microbiota. Oncotarget, 8(49), 85838–85857. https://doi.org/10.18632/oncotarget.20689]

[21] [Yang, Y., Ye, H., Zhao, C., Ren, L., Wang, C., Georgiev, M. I., Xiao, J., & Zhang, T. (2021). Value added immunoregulatory polysaccharides of Hericium erinaceus and their effect on the gut microbiota. Carbohydrate polymers, 262, 117668. https://doi.org/10.1016/j.carbpol.2021.117668]

[22] [Kim, S. P., Nam, S. H., & Friedman, M. (2013). Hericium erinaceus (Lion’s Mane) mushroom extracts inhibit metastasis of cancer cells to the lung in CT-26 colon cancer-tansplanted mice. Journal of agricultural and food chemistry, 61(20), 4898-4904. https://pubs.acs.org/doi/full/10.1021/jf400916c]

[23] [Lee, J. S., & Hong, E. K. (2010). Hericium erinaceus enhances doxorubicin-induced apoptosis in human hepatocellular carcinoma cells. Cancer letters, 297(2), 144–154. https://doi.org/10.1016/j.canlet.2010.05.006]

[24] [Sangtitanu, T., Sangtanoo, P., Srimongkol, P., Saisavoey, T., Reamtong, O., & Karnchanatat, A. (2020). Peptides obtained from edible mushrooms: Hericium erinaceus offers the ability to scavenge free radicals and induce apoptosis in lung cancer cells in humans. Food & function, 11(6), 4927-4939. https://pubs.rsc.org/en/content/articlehtml/2020/fo/d0fo00227e]

Written by: Madeline Tahnk, Lauren Debnam, Sophia Rodriguez, Jansi Patel, Arya Gupta, students of Dr. Jennifer Bhatnager for BI311 General Microbiology, 2023, Boston University.

Author Contributions: M.T. wrote the Classification, Pathology, and Gastrointestinal Disorders sections; L.D. wrote the Description and Significance, Neurodegenerative Diseases, and Spinal Cord sections; S.R. wrote the Genome structure, Cell structure, Neurodegenerative Diseases, and Cancer sections; J.P. wrote the Metabolic Processes and Ecology sections; A.G. wrote the Neurodegenerative Diseases and Depression, Anxiety, and Sleep Disorders sections. L.D. curated figures. M.T. and L.D. edited the final article draft.