Ergothioneine supplementation in people with metabolic syndrome (ErgMS): protocol for a randomised, double-blind, placebo-controlled pilot study

Xiaoying Tian, Giorgia Cioccoloni, Joanna H Sier, Khalid M Naseem, James L Thorne, J Bernadette Moore, Xiaoying Tian, Giorgia Cioccoloni, Joanna H Sier, Khalid M Naseem, James L Thorne, J Bernadette Moore

Abstract

Background: Ergothioneine is a naturally occurring metabolite of histidine found in many foods and in high amounts in mushrooms. In vivo, ergothioneine acts as an antioxidant and is widely distributed in most mammalian tissues. While ergothioneine is sold as a dietary supplement for its antioxidant and anti-inflammatory properties, to date there are no published intervention trials examining its health benefits in humans. The aim of this work was to develop a study protocol for a pilot interventional trial that will establish the primary and secondary outcomes, and the power required, for a definitive randomised controlled trial to test the hypothesis that ergothioneine supplementation is beneficial for people with metabolic syndrome.

Methods: We have designed the ErgMS study as a single-centre, randomised, double-blind, placebo-controlled, 3-arm parallel, pilot intervention trial, which aims to supplement participants with either placebo, 5 or 30 mg/day ergothioneine for 12 weeks. Measurements of metabolic syndrome risk factors, serum markers of oxidative stress (lipid peroxidation), inflammation, blood platelet function and liver function will take place at baseline, and after 6 weeks and 12 weeks of supplementation. In addition, we will examine if there are any changes in the serum metabolome in response to ergothioneine supplementation. Linear regression and two-way ANOVA will be utilised to analyse the association between ergothioneine and measured variables.

Discussion: The ErgMS study will be the first study to address the question does ergothioneine supplementation have health benefits for people with metabolic syndrome. Study results will provide preliminary data as to which dose may improve inflammatory markers in adults with metabolic syndrome and will inform dose and primary outcome selection for a definitive randomised controlled trial.

Trial registration: ISRCTN, ISRCTN25890011 Registered February 10th, 2021.

Keywords: ALT; Ergothioneine; Inflammation; Metabolic syndrome; Metabolome; Oxidative stress; Supplementation.

Conflict of interest statement

The authors declare no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
ErgMS Study design. BMI body mass index, BP blood pressure, FFQ food frequency questionnaire, TAG triacylglyceride, HDL-C high-density lipoprotein-cholesterol

References

    1. Ey J, Schomig E, Taubert D. Dietary sources and antioxidant effects of ergothioneine. J Agric Food Chem. 2007;55(16):6466–6474. doi: 10.1021/jf071328f.
    1. Halliwell B, Cheah IK, Tang RMY. Ergothioneine—a diet-derived antioxidant with therapeutic potential. FEBS Lett. 2018;592(20):3357–3366. doi: 10.1002/1873-3468.13123.
    1. Cheah IK, Halliwell B. Ergothioneine; antioxidant potential, physiological function and role in disease. Biochim Biophys Acta. 2012;1822(5):784–793. doi: 10.1016/j.bbadis.2011.09.017.
    1. Borodina I, Kenny LC, McCarthy CM, Paramasivan K, Pretorius E, Roberts TJ, et al. The biology of ergothioneine, an antioxidant nutraceutical. Nutr Res Rev. 2020;33(2):190–217. doi: 10.1017/S0954422419000301.
    1. Cheah IK, Halliwell B. Ergothioneine, recent developments. Redox Biol. 2021:101868. 10.1016/j.redox.2021.101868.
    1. Smith E, Ottosson F, Hellstrand S, Ericson U, Orho-Melander M, Fernandez C, et al. Ergothioneine is associated with reduced mortality and decreased risk of cardiovascular disease. Heart. 2020;106(9):691–697. doi: 10.1136/heartjnl-2019-315485.
    1. Grundemann D, Harlfinger S, Golz S, Geerts A, Lazar A, Berkels R, et al. Discovery of the ergothioneine transporter. Proc Natl Acad Sci U S A. 2005;102(14):5256–5261. doi: 10.1073/pnas.0408624102.
    1. Kato Y, Kubo Y, Iwata D, Kato S, Sudo T, Sugiura T, et al. Gene knockout and metabolome analysis of carnitine/organic cation transporter OCTN1. Pharm Res. 2010;27(5):832–840. doi: 10.1007/s11095-010-0076-z.
    1. Tschirka J, Kreisor M, Betz J, Grundemann D. Substrate selectivity check of the ergothioneine transporter. Drug Metab Dispos. 2018;46(6):779–785. doi: 10.1124/dmd.118.080440.
    1. Yee SW, Buitrago D, Stecula A, Ngo HX, Chien HC, Zou L, et al. Deorphaning a solute carrier 22 family member, SLC22A15, through functional genomic studies. Faseb J. 2020;34(12):15734–15752. doi: 10.1096/fj.202001497R.
    1. Cheah IK, Tang RM, Yew TS, Lim KH, Halliwell B. 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):193–206. doi: 10.1089/ars.2016.6778.
    1. Tang RMY, Cheah IK, Yew TSK, Halliwell B. Distribution and accumulation of dietary ergothioneine and its metabolites in mouse tissues. Sci Rep. 2018;8(1):1601. doi: 10.1038/s41598-018-20021-z.
    1. Pfeiffer C, Bach M, Bauer T, Campos da Ponte J, Schomig E, Grundemann D. Knockout of the ergothioneine transporter ETT in zebrafish results in increased 8-oxoguanine levels. Free Radic Biol Med. 2015;83:178–185. doi: 10.1016/j.freeradbiomed.2015.02.026.
    1. Paul BD, Snyder SH. The unusual amino acid L-ergothioneine is a physiologic cytoprotectant. Cell Death Differ. 2010;17(7):1134–1140. doi: 10.1038/cdd.2009.163.
    1. Ames BN. Prolonging healthy aging: longevity vitamins and proteins. Proc Natl Acad Sci U S A. 2018;115(43):10836–10844. doi: 10.1073/pnas.1809045115.
    1. Cheah IK, Ong RL, Gruber J, Yew TS, Ng LF, Chen CB, et al. Knockout of a putative ergothioneine transporter in Caenorhabditis elegans decreases lifespan and increases susceptibility to oxidative damage. Free Radic Res. 2013;47(12):1036–1045. doi: 10.3109/10715762.2013.848354.
    1. EFSA Panel on Dietetic Products N, Allergies. Turck D, Bresson J-L, Burlingame B, Dean T, et al. Safety of synthetic l-ergothioneine (Ergoneine®) as a novel food pursuant to Regulation (EC) No 258/97. EFSA J. 2016;14(11):e04629.
    1. USFDA . Re: GRAS Notice No. GRN 000734. 2018.
    1. Cheah IK, Mahendran R, Halliwell B. Investigating the efficacy of ergothioneine to delay cognitive decline. ; 2018.
    1. Midwest Center for Metabolic and Cardiovascular Research . Effects of ergothioneine on cognition, mood, and sleep in healthy adult men and women. ; 2020.
    1. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640–1645. doi: 10.1161/CIRCULATIONAHA.109.192644.
    1. Mahjoub S, Masrour-Roudsari J. Role of oxidative stress in pathogenesis of metabolic syndrome. Caspian J Intern Med. 2012;3(1):386–396.
    1. Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200–207. doi: 10.7326/0003-4819-158-3-201302050-00583.
    1. Eldridge SM, Chan CL, Campbell MJ, Bond CM, Hopewell S, Thabane L, et al. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. Pilot Feasibility Stud. 2016;2:64. doi: 10.1186/s40814-016-0105-8.
    1. Stallard N. Optimal sample sizes for phase II clinical trials and pilot studies. Stat Med. 2012;31(11-12):1031–1042. doi: 10.1002/sim.4357.
    1. Teare MD, Dimairo M, Shephard N, Hayman A, Whitehead A, Walters SJ. Sample size requirements to estimate key design parameters from external pilot randomised controlled trials: a simulation study. Trials. 2014;15(1):264. doi: 10.1186/1745-6215-15-264.
    1. Schoenfeld D. Statistical considerations for pilot studies. Int J Radiat Oncol Biol Phys. 1980;6(3):371–374. doi: 10.1016/0360-3016(80)90153-4.
    1. Bub A, Malpuech-Brugère C, Orfila C, Amat J, Arianna A, Blot A, et al. A dietary intervention of bioactive enriched foods aimed at adults at risk of metabolic syndrome: protocol and results from PATHWAY-27 pilot study. Nutrients. 2019;11(8):1814. doi: 10.3390/nu11081814.
    1. Bredin C, Naimimohasses S, Norris S, Wright C, Hancock N, Hart K, et al. Development and relative validation of a short food frequency questionnaire for assessing dietary intakes of non-alcoholic fatty liver disease patients. Eur J Nutr. 2020;59(2):571–580. doi: 10.1007/s00394-019-01926-5.
    1. Hindle MS, Spurgeon BEJ, Cheah LT, Webb BA, Naseem KM. Multidimensional flow cytometry reveals novel platelet subpopulations in response to prostacyclin. J Thromb Haemost. 2021;19(7):1800–1812. doi: 10.1111/jth.15330.
    1. Moore JB. Non-alcoholic fatty liver disease: the hepatic consequence of obesity and the metabolic syndrome. Proc Nutr Soc. 2010;69(2):211–220. doi: 10.1017/S0029665110000030.
    1. Moore JB. From sugar to liver fat and public health: systems biology driven studies in understanding non-alcoholic fatty liver disease pathogenesis. Proc Nutr Soc. 2019;78(3):290–304. doi: 10.1017/S0029665119000570.
    1. Cheah IK, Tang R, Ye P, Yew TS, Lim KH, Halliwell B. Liver ergothioneine accumulation in a guinea pig model of non-alcoholic fatty liver disease. A possible mechanism of defence? Free Radic Res. 2016;50(1):14–25. doi: 10.3109/10715762.2015.1099642.
    1. Tang Y, Masuo Y, Sakai Y, Wakayama T, Sugiura T, Harada R, et al. Localization of xenobiotic transporter OCTN1/SLC22A4 in hepatic stellate cells and its protective role in liver fibrosis. J Pharm Sci. 2016;105(5):1779–1789. doi: 10.1016/j.xphs.2016.02.023.
    1. Salama SA, Omar HA. Modulating NF-κB, MAPK, and PI3K/AKT signaling by ergothioneine attenuates iron overload-induced hepatocellular injury in rats. J Biochem Mol Toxicol. 2021;35(5):e22729. doi: 10.1002/jbt.22729.
    1. Dare A, Elrashedy AA, Channa ML, Nadar A. Cardioprotective effects and in-silico antioxidant mechanism of L-ergothioneine in experimental type-2 diabetic rats. Cardiovasc Hematol Agents Med Chem. 2021. 10.2174/1871525719666210809122541.
    1. Wang T, Xu J, Fu L, Li L. Hypertriglyceridemia is associated with platelet hyperactivation in metabolic syndrome patients. Int J Clin Pract. 2020;74(7):e13508. doi: 10.1111/ijcp.13508.
    1. Barale C, Russo I. Influence of cardiometabolic risk factors on platelet function. Int J Mol Sci. 2020;21(2):623. doi: 10.3390/ijms21020623.
    1. Aune D, Keum N, Giovannucci E, Fadnes LT, Boffetta P, Greenwood DC, et al. Dietary intake and blood concentrations of antioxidants and the risk of cardiovascular disease, total cancer, and all-cause mortality: a systematic review and dose-response meta-analysis of prospective studies. Am J Clin Nutr. 2018;108(5):1069–1091. doi: 10.1093/ajcn/nqy097.
    1. Freedman JE. Oxidative stress and platelets. Arterioscler Thromb Vasc Biol. 2008;28(3):s11–s16. doi: 10.1161/ATVBAHA.107.159178.
    1. Wang CZ, Moss J, Yuan CS. Commonly used dietary supplements on coagulation function during surgery. Medicines (Basel) 2015;2(3):157–185. doi: 10.3390/medicines2030157.
    1. Olas B. Dietary supplements with antiplatelet activity: a solution for everyone? Adv Nutr. 2018;9(1):51–57. doi: 10.1093/advances/nmx014.
    1. Henning T, Weber D. Redox biomarkers in dietary interventions and nutritional observation studies - From new insights to old problems. Redox Biol. 2021;41:101922. doi: 10.1016/j.redox.2021.101922.
    1. Asbaghi O, Ghanavati M, Ashtary-Larky D, Bagheri R, Rezaei Kelishadi M, Nazarian B, et al. Effects of folic acid supplementation on oxidative stress markers: a systematic review and meta-analysis of randomized controlled trials. Antioxidants (Basel) 2021;10(6):871. doi: 10.3390/antiox10060871.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅