August 5, 2020

Ergothioneine and Citrus Metabolites Reduce Risk of Cardiovascular Disease

Results from a Swedish prospective cohort study
A recent population-based, prospective study looked at plasma metabolites, including ergothioneine, to identify a link between health-conscious food patterns and reduced cardiometabolic morbidity and mortality.


Smith E, Ottosson F, Hellstrand S, et al. Ergothioneine is associated with reduced mortality and decreased risk of cardiovascular disease. Heart. 2020;106(9):691‐697.

Study Objectives

Study objectives were 2-fold: to identify plasma metabolites associated with the health-conscious food pattern (HCFP) and to assess whether these metabolites predict cardiometabolic disease and mortality


Baseline examination of a Swedish population-based prospective cohort study, the Malmö Diet and Cancer (MDC) study


The original MDC study consisted of 28,098 participants, all of whom underwent baseline examinations between 1991 to 1996. From this cohort, a cardiovascular cohort (MDC-CC) to study carotid artery disease was randomly chosen (n=6,103). From this MDC-CC cohort, a random sample of 3,833 were chosen to provide baseline measurement of plasma metabolites.

Exclusionary criteria included participants with prevalent coronary artery disease (CAD, n=80), stroke history (n=26), and/or type 2 diabetes (n=348) at baseline, as well as those with incomplete data on covariates (n=43) or dietary intake (n=120). This left 3,236 participants who qualified for the study, of whom 2,513 had sufficient information on adherence to the HCFP for investigators to assess its relation to measured plasma metabolites.

The 2,513 participants analyzed in this study were aged 57.4 (±6.0) years on average, were 60% female, and had an average body mass index (BMI) of 25.3 kg/m2.

Study Parameters Assessed

The MDC study measured 112 plasma metabolites in participants at study baseline. HCFP was determined using validated methods: a combination of 7-day food history record and an extensive diet history questionnaire done through interviews. Metabolites associated with the HCFP were determined using liquid chromatography–mass spectrometry (LC-MS) techniques.

Incident CVD, diabetes mellitus, and death from any cause were tracked over the follow-up period of 21.4 years using the Swedish national registries: Swedish Hospital Discharge Register, the Swedish Cause of Death Register, and the Swedish Coronary Angiography and Angioplasty Registry (SCAAR).

Primary Outcome Measures

Cardiometabolic morbidity and mortality were the primary outcome measures. Using Cox proportional hazard models, the researchers investigated the relationship of 5 plasma metabolites that associated closely with a healthy dietary intake to cardiometabolic diseases and mortality to determine if they were independent biomarkers of risk.

Key Findings

There were 5 metabolites that closely associated with the HCFP at baseline (P<0.004): ergothioneine, proline betaine, methylproline, acetylornithine, and pantothenic acid.

Ergothioneine was the most strongly associated with HCFP, and its levels were associated with lower risk of coronary disease as determined per standard deviation increment (HR=0.85, P=0.01), cardiovascular mortality (HR=0.79, P=0.002), and overall mortality (HR=0.86).

Ergothioneine in circulation was an independent marker of cardiovascular disease and mortality.

Practice Implications

Metabolomics is broadly defined as the comprehensive measurement of all metabolites and low-molecular-weight molecules in a biological specimen. In this study, the correlation of particular metabolites and a healthy diet was established, with ergothioneine the only metabolite that was an independent marker for disease and mortality. A metabolite that is high in citrus fruit, proline betaine, was also highly correlative.1

In this study, ergothioneine had the strongest association with a lower risk of CAD, cardiovascular mortality, and overall mortality.

Citrus foods have been associated with positive health for many years, and higher consumption of citrus fruits has been associated with a decreased risk of coronary heart disease (CHD).2 Citrus is a great source of dietary flavonoids that may reduce the risk of cardiovascular disorders. In a single-blind, randomized crossover study of 22 healthy subjects, it was found that sweet orange (Citrus sinensis) juice lowered the subjects’ blood pressure.3 Citrus are a good source of essential nutrients such as vitamin C, potassium, and folate, all of which are heart-healthy nutrients. Vitamin C is an antioxidant, reducing oxidative stress in endothelial cells, which reduces the risk of atherosclerosis. Stachydrine, another metabolite tracked in this study, is a constituent found in citrus fruits that helps to promote vascular relaxation by inhibiting NADPH (nicotinamide adenine dinucleotide phosphate) oxidase.4 Additionally, grapefruit (Citrus paradisi) has been shown to have hypolipidemic effects.5 There is also an association with daily intake of citrus fruits (oranges, grapefruit, orange juice, grapefruit juice) and a 22% lower risk of endometriosis.6

In this study, ergothioneine had the strongest association with a lower risk of CAD, cardiovascular mortality, and overall mortality. Ergothioneine is a sulfur-containing amino acid produced in non-yeast fungi (Basidiomycetes primarily) and some bacteria (Actinomycetales and cyanobacteria including spirulina, Arthrospira maxima7) but in neither plants nor mammals.8 It is highest in mushrooms but also found in some organ meats, black and red beans, and oat bran. However, in 1 prospective study, ergothioneine was associated with fish, shellfish, and alcohol intake,9 which may reflect incidental consumption, as ergothioneine is sometimes added to fish to reduce discoloration.10

When absorbed by humans, ergothioneine accumulates at relatively high concentrations in erythrocytes, liver, seminal fluid, bone marrow, eye lens, cornea, brain, spleen, intestines, heart, and kidneys through a highly specific transporter, OCTN1.11,12 Often compared to glutathione, ergothioneine has been shown in preclinical data to be effective at scavenging hydrogen peroxide, superoxide ion, singlet oxygen, lipid peroxides, hydroxyl radical, and reactive nitrogen species (RNS) while protecting nitric oxide from destruction.13 In the article “Ergothioneine Antioxidant Function: From Chemistry to Cardiovascular Therapeutic Potential,” Servillo and team in Italy have shown that ERGO reduces proinflammatory cytokine production (interleukin-1 beta [IL-1β] and tumor necrosis factor alpha [TNF-α]), downregulates vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin adhesion molecules, inhibits monocyte binding to the endothelium, and has positive modulation of sirtuin 1 (SIRT1) and sirtuin 6 (SIRT6) signaling pathways.13 There is also preclinical data showing that ergothioneine and an ergothioneine-containing mushroom extract inhibited myeloperoxidase (MPO),14 a predictor of plaque progression and likelihood of adverse events.15

Mushrooms contain more ergothioneine than plants, but it is still at relatively low concentrations. Researchers have been working to create a cost-effective source of ergothioneine through bacterial fermentation.16 Initial reports were that the yield was still very low, and the costs remained high. Newer techniques incorporate multiple bacterial enzymes for improved synthesis.17 Plus, ergothioneine has been granted Generally Recognized as Safe (GRAS) status from the FDA,18 and Novel Food status by the European Union.19 It will be interesting to see what the future holds for clinical applications of ergothioneine, a potential naturally derived intervention for cardiovascular support.

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