Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids

Abstract

The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma of 52 female subjects, equally sampled between controls and ME/CFS patients, which delivered data for about 1750 blood compounds spanning 20 super-pathways, subdivided into 113 sub-pathways. Statistical analysis combined with pathway enrichment analysis points to a few disrupted metabolic pathways containing many unexplored compounds. The most intriguing finding concerns acyl cholines, belonging to the fatty acid metabolism sub-pathway of lipids, for which all compounds are consistently reduced in two distinct ME/CFS patient cohorts. We compiled the extremely limited knowledge about these compounds and regard them as promising in the quest to explain many of the ME/CFS symptoms. Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort. We also report on lower dipeptides and elevated sphingolipids abundance in patients compared to controls. Disturbances in the metabolism of many of these molecules can be linked to the profound organ system symptoms endured by ME/CFS patients.

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

“…From the database searches, seven papers were identified and a further three studies were found in citation screening of the eligible papers. One additional paper was identified in a final search conducted on 2 February 2020 [21]. All of the results in this review were observational case control studies that compared metabolite levels in plasma, serum or urine samples in CFS/ME/SEID patients to HC.…”

“…In four studies, CFS/ ME/SEID patients met the diagnostic criteria for 1994 Fukuda [21][22][23][24], three studies met the CCC [18,25,26], two studies met 1994 Fukuda and Oxford [27,28], one study met 1994 Fukuda and CCC [29] and one study met 1994 Fukuda, CCC and IOM [30]. Four of the studies included only female participants [21][22][23]26]. Seven studies measured metabolites in plasma samples and three studies measured metabolites in serum and urine samples using varying forms of extraction techniques and mass spectrometry.…”

“…Seven studies measured metabolites in plasma samples and three studies measured metabolites in serum and urine samples using varying forms of extraction techniques and mass spectrometry. Two studies used the same Nuclear Magnetic Resonance Spectrometry analysis method and two studies used the same Metabolon Mass Spectrometry method [18,21,22,26]. In seven of the studies, metabolite analysis were untargeted, three of the studies were targeted and one study performed both a targeted and untargeted assessment (Table 1).…”

“…Outcomes were assessed in a standard, valid and reliable way with appropriate statistical analysis for comparisons between CFS/ME/SEID patients and HC in 100 per cent of studies. Identification criteria for CFS/ME/SEID patients and HC was used in 90 per cent of the included studies [18,21,22,[24][25][26][27][28][29][30]. One study did not detail any inclusion or exclusion criteria for the HC [23].…”

Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Not Due to Anti-mitochondrial Antibodies

“…The results were supported by increased mRNA expression of pyruvate dehydrogenase kinases that are inhibitory to PDC (21). Recent studies also show that many fatty acids may generate acetyl-CoA that fuel the TCA-cycle independently of PDC (44). Similar observations on altered energy metabolism may occur in different types of cellular stress such as starvation (45).…”