Insights into metabolite diagnostic biomarkers for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, by Emi Yamano, Yasuyoshi Watanabe and Yosky Kataoka in Int. J. Mol. Sci. 2021, 22(7), 3423; [] 26 March 2021
(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures 2.0)


Review abstract:

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.

Table 2. Summary of major biochemical pathways with significant metabolites across patients with ME/CFS:

Table 2. Summary of major biochemical pathways with significant metabolites across patients with ME/CFS.




4. Conclusions
Common metabolic fluctuations were observed in fatigued animal models and human patients with ME/CFS and these findings could contribute to the elucidation of the pathophysiology of ME/CFS. Biomarker research, to distinguish between patients with ME/CFS and healthy individuals, is still evolving.

In previous studies, reactive oxygen metabolite-derived compounds (d-ROMs) [54] in the blood, exosomes and inclusion proteins/micro RNAs [5], monocyte number, and lipoprotein profiles have been reported to be informative markers for discriminating patients with ME/CFS from healthy controls [55]. Furthermore, inflammation and immune system activation have been suggested by many previous studies to be the root causes of ME/CFS, and the results from many such studies have shown elevation of cytokines and lymphokines in plasma [56].

Using positron emission tomography (PET), neuroinflammation was detected in wide-spread brain regions of patients with ME/CFS, which was associated with the severity of the specific neuro-psychologic symptoms [57].

We believe that in future, it will be possible to establish highly precise objective diagnostic biomarkers for ME/CFS, exhibiting diverse pathologies through the implementation of research that would integrate metabolomic markers reflecting the specific metabolism underlying the pathophysiology of fatigue with highly precise in vivo biomarkers.

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