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

Arnaud Germain, Dinesh K Barupal, Susan M Levine, Maureen R Hanson, Arnaud Germain, Dinesh K Barupal, Susan M Levine, Maureen R Hanson

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.

Keywords: ME/CFS; acyl cholines; dipeptides; lipids; metabolomics; steroids.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Box plot distribution of logged values for the metabolites that are part of the acyl choline pathway. Controls (CTRL) are shown in red and patients (myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)) in blue. The yellow diamond represents the mean. (a) Arachidonoyl-choline, (b) Dihomolinoleoyl-choline, (c) Docosahexaenoyl-choline, (d) Linoleoyl-choline, (e) Oleoyl-choline, (f) Palmitoyl-choline, (g) Stearoyl-choline.
Figure 2
Figure 2
Box plot distribution of concentrations for the metabolites in Table 3. Controls (CTRL) are shown in red and patients (ME/CFS) in blue. The yellow diamond represents the mean. (a) CER(18:0), (b) CER(18:1), (c) CER(20:0).
Figure 3
Figure 3
Display of the fold change (controls/patients) of the median, averaged for each of the 94 sub-pathways. Roman numbers at the bottom of the figure are assigned as follow for each of the nine super-pathways: I = amino acids, II = carbohydrates, III = cofactors and vitamins, IV = energy, V = lipids, VI = nucleotides, VII = partially characterized molecules, VIII = peptides, and IX = xenobiotics. Labelled sub-pathways are discussed in the manuscript; brown ones are over-abundant in controls compared to patients while purple ones are the opposite. The number associated with each sub-pathway reflects the number of metabolites included. Omitted from the graph are eight drug sub-pathways as well as the tobacco metabolites, all classified as xenobiotics.

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