A systematic review of metabolomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID)

Abstract

Background: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/ SEID) is a complex illness that has an unknown aetiology. It has been proposed that metabolomics may contribute to the illness pathogenesis of CFS/ME/SEID. In metabolomics, the systematic identification of measurable changes in small molecule metabolite products have been identified in cases of both monogenic and heterogenic diseases. Therefore, the aim of this systematic review was to evaluate if there is any evidence of metabolomics contributing to the pathogenesis of CFS/ME/SEID. Methods: PubMed, Scopus, EBSCOHost (Medline) and EMBASE were searched using medical subject headings terms for Chronic Fatigue Syndrome, metabolomics and metabolome to source papers published from 1994 to 2020. Inclusion and exclusion criteria were used to identify studies reporting on metabolites measured in blood and urine samples from CFS/ME/SEID patients compared with healthy controls. The Joanna Briggs Institute Checklist was used to complete a quality assessment for all the studies included in this review. Results: 11 observational case control studies met the inclusion criteria for this review. The primary outcome of metabolite measurement in blood samples of CFS/ME/SEID patients was reported in ten studies. The secondary outcome of urine metabolites was measured in three of the included studies. No studies were excluded from this review based on a low-quality assessment score, however there was inconsistency in the scientific research design of the included studies. Metabolites associated with the amino acid pathway were the most commonly impaired with significant results in seven out of the 10 studies. However, no specific metabolite was consistently impaired across all of the studies. Urine metabolite results were also inconsistent. Conclusion: The findings of this systematic review reports that a lack of consistency with scientific research design provides little evidence for metabolomics to be clearly defined as a contributing factor to the pathogenesis of CFS/ ME/SEID. Further research using the same CFS/ME/SEID diagnostic criteria, metabolite analysis method and control of the confounding factors that influence metabolite levels are required.

Potential causal factors of CFS/ME: a concise and systematic scoping review of factors researched

“…Our scoping review included 1161 studies, and although our scope was larger than the 2008 review, there is a clear increase in research in the field. However, our findings echo the conclusions of numerous recent reviews [ 3 , 12 , 15 , 16 , 23 , 27 , 29 ], namely, that our confidence in the evidence is too low to draw conclusions about causal factors. This is due to the preponderance of relatively weak study designs.…”

“…The vastness of the research field on etiological factors reflects the variety of causal hypotheses [ 19 ], and in the past two years alone, numerous systematic reviews have been published examining distinct causal factors such as immunological [ 12 , 16 , 29 ], metabolic [ 15 , 23 ], circulatory [ 27 ], and epigenetic factors [ 3 ]. In 2016, the Research Council of Norway selected the CFS/ME field as the pilot field for a research priority setting partnership strategy, in which patients, next of kin, and related organizations prioritized research questions for commissioned research [ 14 ].…”

Glatiramer Acetate Treatment in Multiple Sclerosis-Associated Fatigue—Beneficial Effects on Self-Assessment Scales But Not on Molecular Markers

“…The pathomechanisms of fatigue in MS are incompletely understood [ 1 , 5 ]. Suggestions are (i) immunological mechanisms such as overexpression of pro-inflammatory cytokines, (ii) metabolic dysregulation, (iii) diffuse axonal damage, (iv) fatigability due to reduced plasticity of the MS brain, or (v) neuropsychological influences [ 6 , 7 , 8 ]. Functional MRI studies revealed different areas of cortical activation in fatigued MS patients as compared to non-fatigued patients, indicating different functional patterns in both groups [ 9 , 10 ].…”

A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease

“…Impaired NK cell cytotoxicity is the most consistently described feature in ME/CFS/SEID [42]. Mitochondrial dysfunction may therefore be a consequence, rather than a primary causative factor, in ME/CFS/SEID [44].…”

“…It has been described that these differences make ME/CFS/SEID patients chemically distinguishable from respective HC participants [13]. This is only a small representation of available metabolite studies, a detailed investigation on metabolomic dysregulation in ME/CFS/SEID patients compared to healthy controls has been conducted by Huth et al [44].…”