Ergothioneine: The Mushroom-Sourced Antioxidant

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] I was amazed to learn that 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. The more I read, the more powerful I've come to realize these unassuming fungi are.



What's all the hype around antioxidants?


During the conversion of food to fuel for energy, 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, vitamin C, metal-binding proteins, and enzymes like superoxide dismutase (SOD) and glutathione peroxidase.[2] In particular, glutathione (GSH) is crucial, a major antioxidant in mammals. It detoxifies a wide range of toxic compounds, including carcinogens. GSH 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, causing a lot of damage to cells, proteins, lipids, and DNA. They can disrupt enzymes and cell walls and can eventually kill cells. This process, called oxidative stress, can be exacerbated by environmental factors like poor nutrition, fried food, alcohol, tobacco smoke, radiation, certain drugs (e.g. cisplatin), hyperoxia, pesticides, and atmospheric pollution.[2]


Mitochondria generate hydroxyl radicals (.OH) and superoxide anion (O2-) during respiration.[1]

Mitochondria are particularly vulnerable to damage because their DNA lacks two things nuclear DNA employs to protect itself: histone proteins and efficient DNA repair mechanisms. The mitochondria becomes a target of its own production. ROS can cause nicks, breaks and mutations in mitochondrial DNA (mtDNA). A region of the 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 extent of damage can be measured by degree of amplification.[1]


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 cognitive, joint, eye, and skin health.


Examples of reactive oxygen species, some of the molecules behind aging. Others (not shown) include hypochlorous acid (HOCl), peroxynitrite (ONOO−), and nitric oxide (NO). ONOO- can cause lipid peroxidation, damage protein and DNA and deplete intracellular antioxidants; it is extensively implicated in many disorders.[3]

What are the key nutrients found in mushrooms?


Nutrients can be found in the fruit bodies (caps), mycelium, and, to a lesser extent, the stems. Mushrooms are an excellent source of:

  • 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 and chitin

  • Polysaccharides, phenols, carotenoids, ergosterol[2]

  • Antioxidants: glutathione (GSH), B-glucans (a component of the cell wall), and ergothioneine[3]

Artist: Jessica Roux

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.

  • Liver, kidneys, whole blood, erythrocytes (RBCs), bone marrow, mitochondria, eye lens and cornea, and semen[3]

  • Spleen, lung, heart, intestines, brain tissues[4]

  • CD14+ macrophages and monocytes[1]

  • Accumulates at sites of tissue injury, in particular in fatty liver disease, liver fibrosis, pressure overloaded and infarcted hearts and pre-eclampsia.[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.


Variants in OCTN1 are associated with susceptibility to Crohn’s disease (CD) and rheumatoid arthritis.[6] Additionally, the OCTN1 transporter is found to be downregulated in ulcerative colitis, further supporting the important role of EGT in reducing gut inflammation in the healthy gut. OCTN1 knockout animals display increased oxidative stress.


Conversely, OCTN1 is expressed in inflamed joints in rheumatoid arthritis and in ileal mucosa of CD patients; it is suggested to promote survival of inflamed tissues and contribute to inflammation.[5] More research is needed to definitively establish the role of EGT in healthy and inflamed tissues.


Pharmacokinetics and Pharmacodynamics


The body tends to absorb and retain EGT, leading scientists to suggest it has therapeutic properties.[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]


Toxicity: EGT has EFSA approval in the EU and is recognized as generally safe by the FDA as a supplement.


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, suggesting it is beneficial for the baby.[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 (LCMS) revealed that mushrooms, by far, contain the highest levels of EGT of any dietary source. Mushrooms with exceptionally high levels of antioxidants, including ergothioneine, are ranked from highest to lowest and include:

  • Boletus edulis

  • King oyster

  • Golden/yellow oyster[8]

  • Shiitake

  • Wild porcini[3]

  • Pioppini[8]

  • Portabella

  • Lion’s mane

  • Reishi

  • White button[9]

  • Brown button

  • Maitake


Boletus edulis - crown champion in ergothioneine content; boasts triple the levels of the next runner-up

king oyster mushrooms
King oyster mushrooms

Yellow oyster mushrooms
Yellow oyster mushrooms

Pioppini mushrooms
Pioppini mushrooms

Lion's mane mushroom
Lion's mane mushroom

Reishi mushroom
Reishi mushroom - also known as the 'mushroom of immortality' or the 'divine mushroom' in China

White button, brown button (baby bella), cremini, and portobella mushrooms are all the same species (Agaricus bisporus) at different stages of ripening. White buttons are the youngest.

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 (cepes 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 and Therapeutic Effects of EGT


  • Protects DNA and proteins: scavenges free radicals; dose-dependently prevents DNA breaks and mutations; prevents oxidation and carbonylation of proteins[1]

  • Inhibits pro-inflammatory cytokines like IL-6, IL-8 and TNF-α in alveolar macrophages and epithelial cell cultures[1, 3]

  • Protects cells: inhibits apoptosis and promotes growth by activating p38 MAPK and JNK signaling pathways[3]

  • Helps host antioxidants: can induce GSH synthesis by induction of the Nrf2/ARE-mediated signaling pathway[8]

  • Chelates metal ions: sequestering them from generating ROS. EGT form complexes with copper (Cu2+), mercury (Hg2+), zinc (Zn2+), cadmium (Cd2+), cobalt (Co2+), iron (Fe2+), and nickel (Ni2+), the most stable being the copper complex. Protects against DNA and oxidative damage. Was shown to protect sperm motility from the harmful effects of copper[3]


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 are good for patients with diabetes, as they improve glucose tolerance.


Maitake mushrooms
Roasted maitake mushrooms

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]


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 re