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…

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.

Neuroimmunity: mucosal immunity and vagus nerve regulation

The vagus nerve, the 10^th 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.