Ergothioneine is a rather unusual sulfur-containing, amino-acid-derived antioxidant. Synthesized only by some fungi and bacteria, this molecule is not made in the human body and can only be obtained from diet.[1] Mushrooms, by far, contain the highest levels of ergothioneine of any known food source. Ancient Egyptians believed mushrooms would grant immortality, and pharoahs proclaimed they were reserved for royalty.
This article provides a detailed overview of the state of the science regarding ergothioneine. It starts by giving an background on the causes and biomarkers of oxidative stress and introduces antioxidants as a therapeutic approach.
The body of the report discusses ergothioneine. It covers ergothioneine's pharmacokinetics and pharmacodynamics, protein interactions, mechanisms of action, and regulation of gene expression. The article goes on to outline the peer-reviewed evidence of potential therapeutic effects, covers the safety and toxicity of ergothioneine, and proposes precautions for specific populations.
It concludes with key takeaways and important considerations when implementing ergothioneine supplements into the diet or pursuing clinical applications of ergothioneine.
Ergothioneine: The Mushroom-Sourced Antioxidant
Oxidative stress: a major driver of aging-related disease
Glutathione upregulator
Safety, toxicity, and potential contraindications
Oxidative stress: a major driver of aging-related disease
During the conversion of food to energy to fuel cellular processes, our mitochondria naturally produce free radicals and reactive oxygen species (ROS), unstable molecules that contain unpaired electrons. ROS is a normal part of redox signaling, which gets balanced out in states of health.
Our bodies have their own systems for neutralizing ROS—the endogenous antioxidants, molecules that fight the formation and propagation of free radicals. These include glutathione (GSH), metal-binding proteins, and enzymes like superoxide dismutase (SOD) and glutathione peroxidase.[2] In particular, glutathione is the predominant mammalian liver antioxidant. It detoxifies a wide range of toxic compounds, including carcinogens. Glutathione depletion can impair immune function and is associated with increased risk for cancer, cardiovascular diseases, arthritis, and diabetes.
ROS production can supersede the body's defense systems. These excess ROS zoom around the body looking for bonds to stabilize themselves, damaging cells, proteins, lipids, and DNA. They can disrupt enzymes and cell walls and can eventually kill cells. This process is called oxidative stress.
Causes of oxidative stress
Oxidative stress is, in part, endogenous. Free radicals form in response to normal mitochondrial metabolism. Mitochondria generate superoxide anion (O2-) and hydroxyl radicals (.OH) during respiration.[1] Free radicals can also be generated as part of the immune response, during white blood cell-mediated inflammation.
Environmental factors can also exacerbate oxidative stress. These disease drivers include poor nutrition, fried food, alcohol, smoke and smoking (regardless of what is smoked), ionizing and non-ionizing radiation, UV light, certain drugs (e.g. cisplatin), hyperoxia (too much oxygen), pesticides, and atmospheric pollution.[2]
Biomarkers of oxidative damage
Mitochondria are particularly vulnerable to damage because their DNA lacks two self-protection mechanisms employed by nuclear DNA: histone proteins and efficient DNA repair mechanisms. Mitochondria become a target of their own production. ROS can cause nicks, breaks and mutations in mitochondrial DNA (mtDNA). A region of mtDNA, the Displacement or D-loop, is a hotspot for DNA damage. Several mutations occurring here are associated with cancers.
Damaged DNA is poorly amplified by PCR, so the extent of damage can be measured by degree of amplification.[1] Other markers of oxidative damage include 8-OH-dG (modified nucleotides), γH2AX (forms on histones when double-strand breaks occur), MDA (malondialdehyde), and HNE (one of the most common aldehyde biomarkers of lipid peroxidation).
Antioxidants as disease therapeutics
Cell damage caused by free radicals underlies aging, cancer, Alzheimer's, coronary heart (CV) disease, cataracts, immune system decline, liver diseases, diabetes mellitus, inflammation, renal failure, brain dysfunction, and stress.[2]
Replenishing antioxidants can help protect against oxidative stress while promoting the health of metabolically-demanding tissues, such as the brain, joints, eyes, and skin. This is because antioxidants are typically stable resonance structures with delocalized electrons that can afford to provide an electron and become positively charged.
What are the key nutrients found in mushrooms?
Mushrooms are an excellent source of many vitamins, minerals, and other nutrients. Nutrients can be found in the fruiting bodies, mycelium, and, to a lesser extent, the stems and include:
Vitamins: vitamin B2, other B vitamins, vitamin C, vitamin D2 (when exposed to UV light), vitamin E[2, 3]
Micronutrients: selenium, copper, potassium[3]
Dietary fiber
Chitin
Polysaccharides, phenols, carotenoids, ergosterol[2]
Antioxidants: glutathione, beta-glucans (cell wall component), and ergothioneine[3]
What is ergothioneine? Chemical structure and properties
Ergothioneine is the chief antioxidant found in mushrooms. It gets its name from the ergot fungus, Claviceps purpurea.
Where is ergothioneine found in the body?
EGT is found throughout the human body but preferentially accumulates in organs, cells, and secretions predisposed to high levels of oxidative stress and inflammation. Ergothioneine has been detected in:
Liver, kidneys, whole blood, erythrocytes (RBCs), bone marrow, mitochondria, eye lens, cornea, and semen[3]
Spleen, lung, heart, intestines, brain tissues[4]
CD14+ macrophages and monocytes[1]
Sites of tissue injury, in particular in fatty liver disease, liver fibrosis, pressure-overloaded and infarcted hearts, and pre-eclampsia[5]
Mammary epithelial cells and breastmilk[5]
Brain and urine of infants[5]
OCTN1: The Body's Transporter for Ergothioneine
The SLC22A4 gene codes for OCTN1 (organic cation transporter), a membrane transporter of ergothioneine and other compounds.[3] It is expressed in the intestine, monocytes, and activated lamina propria macrophages.
Additionally, the OCTN1 transporter is found to be downregulated in ulcerative colitis, suggesting EGT plays an anti-inflammatory role in the healthy gut. OCTN1 knockout animals display increased oxidative stress.
Conversely, variants in OCTN1 are associated with susceptibility to Crohn’s disease (CD) and rheumatoid arthritis.[6] OCTN1 is expressed in inflamed joints in rheumatoid arthritis and in ileal mucosa of CD patients.[5] Overall, further investigation is necessary to better establish the role of EGT in healthy and inflamed tissues.
Pharmacokinetics and Pharmacodynamics (PK/PD)
The body tends to absorb and retain EGT.[5] It is stable under physiological conditions and is metabolized slowly in mammalian tissues. The beneficial effects of ergothioneine can last up to a month after ingestion. It is excreted in urine at relatively low rates, under 4%.[7]
EGT can be detected in mothers' breastmilk as well as the urine and brains of infants, suggesting that EGT can cross the placenta (which expresses OCTN1). Alternatively, OCTN1 absorbs EGT in the intestines of newborns when they breastfeed. Human mammary epithelial cells express significantly greater EGT during lactation, and it may be beneficial for neonates.[5]
EGT crosses the blood-brain barrier and can be found in CSF and postmortem brain samples. A Japanese study found a correlation between increased intake of mushrooms and decreased incidence of dementia, but this data is indirect since there are multiple therapeutic compounds in mushrooms.[5]
Which foods are highest in ergothioneine?
Liquid chromatography-mass spectroscopy (LC-MS) revealed that mushrooms, by far, contain the highest levels of EGT of any dietary source. Mushrooms with exceptionally high levels of antioxidants, including ergothioneine, ranked from highest to lowest, include:
Boletus edulis, or wild porcini[3]
King oyster
Golden/yellow oyster[8]
Shiitake
Pioppini[8]
Portabella
Lion’s mane
Reishi
White button[9]
Brown button
Maitake
king oyster, yellow oyster, shiitake,
Plants with the highest levels of ergothioneine include tempeh, asparagus, and garlic. Trace amounts can be found in basil, tofu, cumin, pepper, red and black beans, Japanese seaweed, kiwi, various nuts (pistachios, almonds), oats, pomegranate, passion fruit, onions, and durian.
But even so, most of these plants contain between 1-5 mg/kg of EGT. By comparison, Boletus edulis (porcini mushroom) contains 1,812.4 mg/kg dry weight of ergothioneine. Shiitake mushrooms contain over 10 times more ergothioneine than garlic.[5]
Mechanism of Action of EGT
How does ergothioneine work? Several research studies have demonstrated EGT's potential mechanisms of action:
Protects DNA and proteins
EGT scavenges and quenches free radicals, dose-dependently prevents DNA breaks and mutations, and prevents oxidation and carbonylation of proteins.[1]
Cytokine inhibitor
EGT was shown to inhibits pro-inflammatory cytokines like IL-6, IL-8 and TNF-α in alveolar macrophages and epithelial cell cultures.[1, 3]
Apoptosis inhibitor
EGT is cytoprotective. It inhibits apoptosis and promotes growth by activating p38 MAPK and JNK signaling pathways.[3]
Glutathione upregulator
EGT can induce synthesis of glutathione by induction of the Nrf2/ARE-mediated signaling pathway.[8]
Metal chelator
EGT chelates metal ions, sequestering them from generating ROS. EGT form complexes with copper (Cu2+), iron (Fe2+), zinc (Zn2+), cobalt (Co2+), mercury (Hg2+), cadmium (Cd2+), and nickel (Ni2+), the most stable being the copper complex. This metal chelation activity protects against DNA and oxidative damage. EGT was shown to protect sperm motility from the harmful effects of copper.[3]
In fact, whereas other low molecular weight thiols in aerobic organisms are susceptible to metal-catalyzed autooxidation, the sulfur atom of EGT coordinates metal ions, thereby forming a non-redox active complex composed of two molecules of ergothioneine and one metal ion.[15]
Therapeutic Effects of EGT
Ergothioneine has demonstrated therapeutic potential for gut dysbiosis, skin aging, ischemia-reperfusion injuries, Parkinson's disease, and Alzheimer's disease. Based on cell culture and animal model research, it has been suggested to be therapeutic in other conditions, but clinical trials are needed to directly establish its safety and efficacy.
Cataracts
Oxidative damage can occur in the eyes because of their high exposure to oxygen; this process underlies eye disease. Substantial EGT is found in the eyes and is decreased in the lens and corneas of patients with cataracts.[5] EGT could help counteract eye aging.
Promotes heart health
EGT is found in high amounts in the blood and travels readily to the heart, where it neutralizes ROS and chelates metals. It may be therapeutic in myocardial ischemia-reperfusion injuries.[5]
Kidney disease
EGT is lowered in the kidneys of patients with chronic kidney disease. Knocking out OCTN1 in mice increased severity of renal fibrosis, manifested as oxidative damage.
Diabetes
Diabetes is linked to oxidative and glycative stress. EGT may help counteract the pro-oxidant effect of hyperglycemia. Maitake mushrooms have been shown to be beneficial for patients with diabetes, as they improve glucose tolerance.
Anti-aging for skin
EGT directly absorbs UV radiation and dose-dependently prevents DNA breaks and mutations.[1] EGT decreased caspase-9 (apoptotic signal) activity in keratinocytes exposed to UV radiation.[3]
Neuroprotective
Blood EGT levels significantly decline after age 60. Subjects with mild cognitive impairment, as well as patients with Parkinson’s, had significantly lower plasma EGT levels compared with age-matched subjects.[10]
Multiple studies support EGT’s neuroprotective activity in Alzheimer's disease.[11] EGT significantly prevented Aβ accumulation in the hippocampus and brain lipid peroxidation in mice. EGT also restored cognitive function and inhibited cisplatin-induced lipid peroxidation.[3] Yang et. al showed EGT can protect against Aβ-induced loss of memory and learning abilities in mice.[12] EGT was also neuroprotective against NMDA excitotoxicity in retinal rat models.[13] Further studies are needed to establish whether EGT has a therapeutic effect on Parkinson's and Alzheimer's disease in humans.
May play a role in gut health
Ergothioneine levels are significantly lower in dysbiosis mice. On the other hand, elevated EGT concentrations have been observed in injured tissues, particularly liver, heart, joint, and intestinal injury.[14] This suggests EGT could dose-dependently promote gut homeostasis and suppress inflammation.
Safety, toxicity, and potential contraindications
Ergothioneine has European Food Safety Authority (EFSA) approval in the EU and is generally recognized as safe (GRAS) by the FDA as a supplement.
Certain fungi and microorganisms make use of EGT to protect themselves from attack by host defenses (ROS/RNS). It's important to realize that diseased cells (i.e. cancer cells or abnormal immune cells) may also use EGT to promote their survival.
Research has suggested EGT is contraindicated for patients with cancer, Crohn’s disease, and rheumatoid arthritis.
Cancer
Significantly increased OCTN1 mRNA was found in thyroid, liver, and esophageal cancers. It's possible cancer cells accumulate ergothioneine to fight off/protect against the oxidative stress generated by chemotherapy. Possible therapeutic targets for cancer include depleting EGT and/or blocking the transporter.[5]
This doesn't rule out ergothioneine's potential to prevent cancer. Research is contradictory, as many mushrooms are well-recognized for their ability to fight cancer. Overall, further research is necessary to establish its activity and role in cancer.
Crohn's disease and rheumatoid arthritis
Crohn's disease and rheumatoid arthritis are two inflammatory conditions that both demonstrate alterations in the OCTN1 transporter. EGT is suggested to promote survival of inflamed tissues, thereby indirectly contributing to inflammation.
Compromised immunity
Individuals with compromised immune systems have been advised to avoid EGT.[5] Certain anti-inflammatory medications taken for autoimmune diseases can also compromise immunity.
Conclusion
Many gaps in the research remain when it comes to ergothioneine efficacy. EGT appears to be a safe, diet-derived antioxidant with promising therapeutic potential, but double-blind, placebo-controlled studies are yet to be conducted.
EGT concentrates in areas of oxidative stress. Its many intriguing properties, such as its presence in infants, absorption of UV radiation, and.metal chelating abilities point to its value in preventive medicine.
Health status should be considered before introducing a new supplement into the diet. It's important to consult your doctor before incorporating an ergothioneine supplement. A nutritionist can also provide more personalized advice.
Overall, mushrooms offer a variety of antioxidants which confer many impressive health benefits.
Further Reading
Whitmore, Clayton A et al. “Longitudinal Consumption of Ergothioneine Reduces Oxidative Stress and Amyloid Plaques and Restores Glucose Metabolism in the 5XFAD Mouse Model of Alzheimer's Disease.” Pharmaceuticals (Basel, Switzerland) vol. 15,6 742. 13 Jun. 2022, doi:10.3390/ph15060742
Wijesinghe, Printha et al. “Ergothioneine, a dietary antioxidant improves amyloid beta clearance in the neuroretina of a mouse model of Alzheimer's disease.” Frontiers in neuroscience vol. 17 1107436. 14 Mar. 2023, doi:10.3389/fnins.2023.1107436
References
Paul, B.D. and S.H. Snyder, The unusual amino acid L-ergothioneine is a physiologic cytoprotectant. Cell Death Differ, 2010. 17(7): p. 1134-40.
Sanchez, C., Reactive oxygen species and antioxidant properties from mushrooms. Synth Syst Biotechnol, 2017. 2(1): p. 13-22.
Cheah, I.K. and B. Halliwell, Ergothioneine; antioxidant potential, physiological function and role in disease. Biochim Biophys Acta, 2012. 1822(5): p. 784-93.
Tang, R.M.Y., et al., Distribution and accumulation of dietary ergothioneine and its metabolites in mouse tissues. Sci Rep, 2018. 8(1): p. 1601.
Halliwell, B., I.K. Cheah, and R.M.Y. Tang, Ergothioneine - a diet-derived antioxidant with therapeutic potential. FEBS Lett, 2018. 592(20): p. 3357-3366.
Grundemann, D., et al., Discovery of the ergothioneine transporter. Proc Natl Acad Sci U S A, 2005. 102(14): p. 5256-61.
Cheah, I.K., et al., Administration of Pure Ergothioneine to Healthy Human Subjects: Uptake, Metabolism, and Effects on Biomarkers of Oxidative Damage and Inflammation. Antioxid Redox Signal, 2017. 26(5): p. 193-206.
Kalaras, M.D., et al., Mushrooms: A rich source of the antioxidants ergothioneine and glutathione. Food Chem, 2017. 233: p. 429-433.
Adams, L.S., et al., White button mushroom (Agaricus bisporus) exhibits antiproliferative and proapoptotic properties and inhibits prostate tumor growth in athymic mice. Nutr Cancer, 2008. 60(6): p. 744-56.
Cheah, I.K., et al., Ergothioneine levels in an elderly population decrease with age and incidence of cognitive decline; a risk factor for neurodegeneration? Biochem Biophys Res Commun, 2016. 478(1): p. 162-167.
Song, T.Y., et al., Ergothioneine and melatonin attenuate oxidative stress and protect against learning and memory deficits in C57BL/6J mice treated with D-galactose. Free Radic Res, 2014. 48(9): p. 1049-60.
Yang, N.C., et al., Ergothioneine protects against neuronal injury induced by beta-amyloid in mice. Food Chem Toxicol, 2012. 50(11): p. 3902-11.
Moncaster, J.A., et al., Ergothioneine treatment protects neurons against N-methyl-D-aspartate excitotoxicity in an in vivo rat retinal model. Neurosci Lett, 2002. 328(1): p. 55-9.
Halliwell, B., I.K. Cheah, and C.L. Drum, Ergothioneine, an adaptive antioxidant for the protection of injured tissues? A hypothesis. Biochem Biophys Res Commun, 2016. 470(2): p. 245-250.
Ulrich, Kathrin, and Ursula Jakob, The role of thiols in antioxidant systems. Free Radic Biol Med, 2019. 140: p. 14-27.