{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T14:37:09Z","timestamp":1784903829490,"version":"3.55.0"},"reference-count":57,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T00:00:00Z","timestamp":1616716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["25460399, 20K09524, 18H02724"],"award-info":[{"award-number":["25460399, 20K09524, 18H02724"]}]},{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"publisher","award":["20ak0101059h0005"],"award-info":[{"award-number":["20ak0101059h0005"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with\/without infectious or neuropsychiatric symptoms, and with a minimum duration of 6 consecutive months. Its pathogenesis is not fully understood. There are no firmly established diagnostic biomarkers or treatment, due to incomplete understanding of the etiology of ME\/CFS and diagnostic uncertainty. Establishing a biomarker for the objective diagnosis is urgently needed to treat a lot of patients. Recently, research on ME\/CFS using metabolome analysis methods has been increasing. Here, we overview recent findings concerning the metabolic features in patients with ME\/CFS and the animal models which contribute to the development of diagnostic biomarkers for ME\/CFS and its treatment. In addition, we discuss future perspectives of studies on ME\/CFS.<\/jats:p>","DOI":"10.3390\/ijms22073423","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T13:17:53Z","timestamp":1616764673000},"page":"3423","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Insights into Metabolite Diagnostic Biomarkers for Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome"],"prefix":"10.3390","volume":"22","author":[{"given":"Emi","family":"Yamano","sequence":"first","affiliation":[{"name":"Laboratory for Pathophysiological and Health Science, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyoshi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Laboratory for Pathophysiological and Health Science, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosky","family":"Kataoka","sequence":"additional","affiliation":[{"name":"Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan"},{"name":"Multi-Modal Microstructure Analysis Unit, RIKEN\u2014JEOL Collaboration Center, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s12576-015-0399-y","article-title":"Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder","volume":"65","author":"Tanaka","year":"2015","journal-title":"J. Physiol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1016\/S0140-6736(04)15794-2","article-title":"Fatigue in neurological disorders","volume":"363","author":"Chaudhuri","year":"2004","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1111\/j.1365-2796.2011.02428.x","article-title":"Myalgic encephalomyelitis: International Consensus Criteria","volume":"270","author":"Carruthers","year":"2011","journal-title":"J. Intern. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"953","DOI":"10.7326\/0003-4819-121-12-199412150-00009","article-title":"The chronic fatigue syndrome: A comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group","volume":"121","author":"Fukuda","year":"1994","journal-title":"Ann. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.bbi.2019.11.015","article-title":"Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis\/chronic fatigue syndrome","volume":"84","author":"Eguchi","year":"2020","journal-title":"Brain. Behav. Immun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jcv.2006.08.013","article-title":"Chronic fatigue syndrome","volume":"37","author":"Devanur","year":"2006","journal-title":"J. Clin. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s11011-019-0388-6","article-title":"Myalgic encephalomyelitis or chronic fatigue syndrome: How could the illness develop?","volume":"34","author":"Morris","year":"2019","journal-title":"Metab. Brain Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/S0140-6736(06)68073-2","article-title":"Chronic fatigue syndrome","volume":"367","author":"Prins","year":"2006","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1136\/jnnp.56.6.679","article-title":"Skeletal muscle bioenergetics in the chronic fatigue syndrome","volume":"56","author":"Barnes","year":"1993","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"SC11","DOI":"10.12659\/MSM.881699","article-title":"Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS)","volume":"17","author":"Maes","year":"2011","journal-title":"Med. Sci. Monit."},{"key":"ref_11","first-page":"1","article-title":"Chronic fatigue syndrome and mitochondrial dysfunction","volume":"2","author":"Myhill","year":"2009","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Dierckx, R.A.J.O., Otte, A., de Vries, E.F.J., van Waarde, A., and Sommer, I.E. (2021). PET\/SPECT\/MRI\/fMRI Studies in the Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome. PET and SPECT in Psychiatry, Springer.","DOI":"10.1007\/978-3-030-57231-0"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1300\/J092v11n01_02","article-title":"Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols","volume":"11","author":"Carruthers","year":"2003","journal-title":"J. Chronic Fatigue Syndr."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Reeves, W.C., Wagner, D., Nisenbaum, R., Jones, J.F., Gurbaxani, B., Solomon, L., Papanicolaou, D.A., Unger, E.R., Vernon, S.D., and Heim, C. (2005). Chronic fatigue syndrome\u2014A clinically empirical approach to its definition and study. BMC Med., 3.","DOI":"10.1186\/1741-7015-3-19"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"h2087","DOI":"10.1136\/bmj.h2087","article-title":"The long wait for a breakthrough in chronic fatigue syndrome","volume":"350","author":"Lloyd","year":"2015","journal-title":"BMJ"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/B978-0-12-801401-1.00005-0","article-title":"Metabolism in chronic fatigue syndrome","volume":"66","author":"Armstrong","year":"2014","journal-title":"Adv. Clin. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/s12967-020-02356-2","article-title":"A systematic review of metabolomic dysregulation in Chronic Fatigue Syndrome\/Myalgic Encephalomyelitis\/Systemic Exertion Intolerance Disease (CFS\/ME\/SEID)","volume":"18","author":"Huth","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1042\/BST20170503","article-title":"Metabolic abnormalities in chronic fatigue syndrome\/myalgic encephalomyelitis: A mini-review","volume":"46","author":"Tomas","year":"2018","journal-title":"Biochem. Soc. Trans."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nrm.2016.25","article-title":"Metabolomics: Beyond biomarkers and towards mechanisms","volume":"17","author":"Caroline","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nrmicro1177","article-title":"Metabolic footprinting and systems biology: The medium is the message","volume":"3","author":"Kell","year":"2005","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/nrm1451","article-title":"Mertabolic profiling: From diagnostics to systems biology","volume":"5","author":"Fernie","year":"2004","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10105","DOI":"10.1038\/s41598-017-10172-w","article-title":"Targeted metabolome profiling by dual-probe microdialysis sampling and treatment using Gardenia jasminoides for rats with type 2 diabetes","volume":"7","author":"Wang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8830","DOI":"10.1038\/s41598-017-09311-0","article-title":"Disease-syndrome combination modeling: Metabolomic strategy for the pathogenesis of chronic kidney disease","volume":"7","author":"Li","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.bbr.2018.03.020","article-title":"Identification of metabolite biomarkers for L-DOPA-induced dyskinesia in a rat model of Parkinson\u2019s disease by metabolomic technology","volume":"347","author":"Wang","year":"2018","journal-title":"Behav. Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.neulet.2003.08.051","article-title":"Establishment and assessment of a rat modelof fatigue","volume":"352","author":"Tanaka","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1111\/j.1471-4159.2009.06057.x","article-title":"Chronic stress elicits prolonged activation of alpha-MSH secretion and subsequent degeneration of melanotroph","volume":"109","author":"Ogawa","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.nut.2008.11.021","article-title":"Changes in plasma and tissue amino acid levels in an animal model of complex fatigue","volume":"25","author":"Jin","year":"2009","journal-title":"Nutrition"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kume, S., Yamato, M., Tamura, Y., Jin, G., Nakano, M., Miyashige, Y., Eguchi, A., Ogata, Y., Goda, N., and Iwai, K. (2015). Potential biomarkers of fatigue identified by plasma metabolome analysis in rats. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120106"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1039\/b914751a","article-title":"Metabonomics study of urine and plasma in depression and excess fatigue rats by ultra fast liquid chromatography coupled with ion trap-time of flight mass spectrometry","volume":"6","author":"Zhang","year":"2010","journal-title":"Mol. Biosyst."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10056","DOI":"10.1038\/s41598-018-28477-9","article-title":"Insights into myalgicencephalomyelitis\/chronic fatigue syndrome phenotypes through comprehensive metabolomics","volume":"8","author":"Barupal","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1097\/01.psy.0000116249.60477.e9","article-title":"Exploratory open label, randomized study of acetyl-and propionylcarnitine in chronic fatigue syndrome","volume":"66","author":"Vermeulen","year":"2004","journal-title":"Psychosom. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8182020","DOI":"10.1155\/2017\/8182020","article-title":"Detection of Urine Metabolites in a Rat Model of Chronic Fatigue Syndrome before and after Exercise","volume":"2017","author":"Shao","year":"2017","journal-title":"Biomed Res. Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"34990","DOI":"10.1038\/srep34990","article-title":"Index markers of chronic fatigue syndrome with dysfunction of TCAand urea cycles","volume":"6","author":"Yamano","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_34","first-page":"E5472","article-title":"Metabolic features of chronic fatigue syndrome","volume":"113","author":"Naviaux","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.3389\/fneur.2018.01033","article-title":"Neuroinflammation and Cytokines in Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (ME\/CFS): A Critical Review of Research Methods","volume":"9","author":"VanElzakker","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1002\/nbm.1512","article-title":"Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: Comparison with major depressive disorder","volume":"23","author":"Murrough","year":"2010","journal-title":"NMR Biomed."},{"key":"ref_37","first-page":"15","article-title":"Elevations of Ventricular Lactate Levels Occur in Both Chronic Fatigue Syndrome and Fibromyalgia","volume":"5","author":"Natelson","year":"2017","journal-title":"Fatigue"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1002\/nbm.2772","article-title":"Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology","volume":"25","author":"Shungu","year":"2012","journal-title":"NMR Biomed."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1021\/acschemneuro.6b00056","article-title":"In vivo Imaging of Human Neuroinflammation","volume":"7","author":"Albrecht","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"ref_40","first-page":"349","article-title":"A prominent lactate peak as a potential key magnetic resonance spectroscopy (MRS) feature of progressive multifocal leukoencephalopathy (PML): Spectrum pattern observed in three patients","volume":"17","author":"Bjelan","year":"2017","journal-title":"Bosn. J. Basic Med. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1097\/00001756-200302100-00013","article-title":"Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome","volume":"14","author":"Chaudhuri","year":"2003","journal-title":"Neuroreport"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1034\/j.1600-0447.2002.01300.x","article-title":"Relative increase in choline in the occipital cortex in chronic fatigue syndrome","volume":"106","author":"Puri","year":"2002","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.crad.2008.07.002","article-title":"Magnetic resonance spectroscopy of the brain: Review of metabolites and clinical applications","volume":"64","author":"Soares","year":"2009","journal-title":"Clin. Radiol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"McGregor, N.R., Armstrong, C.W., Lewis, D.P., and Gooley, P.R. (2019). Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME\/CFS Cases. Diagnostics, 9.","DOI":"10.3390\/diagnostics9030070"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1007\/s11306-015-0816-5","article-title":"Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients","volume":"11","author":"Armstrong","year":"2015","journal-title":"Metabolomics"},{"key":"ref_46","first-page":"208","article-title":"Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (ME\/CFS)","volume":"5","author":"Booth","year":"2012","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1039\/C6MB00600K","article-title":"Metabolic profiling of a myalgic encephalomyelitis\/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism","volume":"13","author":"Germain","year":"2017","journal-title":"Mol. Biosyst."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Missailidis, D., Annesley, S.J., Allan, C.Y., Sanislav, O., Lidbury, B.A., Lewis, D.P., and Fisher, P.R. (2020). An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME\/CFS Patients. Int. J. Mol. Sci., 21.","DOI":"10.20944\/preprints201909.0043.v3"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.beem.2012.05.003","article-title":"Cellular and molecular mechanisms of mitochondrial function","volume":"26","author":"Osellame","year":"2012","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e89376","DOI":"10.1172\/jci.insight.89376","article-title":"Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy\/chronic fatigue syndrome","volume":"1","author":"Fluge","year":"2016","journal-title":"JCI Insight"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Germain, A., Ruppert, D., Levine, S.M., and Hanson, M.R. (2018). Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites, 8.","DOI":"10.3390\/metabo8040090"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Germain, A., Barupal, D.K., Levine, S.M., and Hanson, M.R. (2020). Comprehensive Circulatory Metabolomics in ME\/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids. Metabolites, 10.","DOI":"10.3390\/metabo10010034"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"104578","DOI":"10.1016\/j.psyneuen.2019.104578","article-title":"The role of low-grade inflammation in ME\/CFS (Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome)\u2014Associations with symptoms","volume":"113","author":"Jonsjo","year":"2020","journal-title":"Psychoneuroendocrinology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.biopsycho.2016.05.005","article-title":"A potential biomarker for fatigue: Oxidative stress and anti-oxidative activity","volume":"118","author":"Fukuda","year":"2016","journal-title":"Biol. Psychol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"19933","DOI":"10.1038\/s41598-020-77105-y","article-title":"Deep phenotyping of myalgic encephalomyelitis\/chronic fatigue syndrome in Japanese population","volume":"10","author":"Kitami","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.bbi.2012.06.006","article-title":"Biomarkers for chronic fatigue","volume":"26","author":"Klimas","year":"2012","journal-title":"Brain. Behav. Immun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"945","DOI":"10.2967\/jnumed.113.131045","article-title":"Neuroinflammation in Patients with Chronic Fatigue Syndrome\/Myalgic Encephalomyelitis: An (1)(1)C-(R)-PK11195 PET Study","volume":"55","author":"Nakatomi","year":"2014","journal-title":"J. Nucl. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/7\/3423\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:41:29Z","timestamp":1760161289000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/7\/3423"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,26]]},"references-count":57,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22073423"],"URL":"https:\/\/doi.org\/10.3390\/ijms22073423","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,26]]}}}