Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease characterized by unexplained physical fatigue, cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. People with ME/CFS often report a prodrome consistent with infections. Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of plasma from 106 ME/CFS cases and 91 frequency-matched healthy controls. Subjects in the ME/CFS group had significantly decreased levels of plasmalogens and phospholipid ethers (p < 0.001), phosphatidylcholines (p < 0.001) and sphingomyelins (p < 0.001), and elevated levels of dicarboxylic acids (p = 0.013). Using machine learning algorithms, we were able to differentiate ME/CFS or subgroups of ME/CFS from controls with area under the receiver operating characteristic curve (AUC) values up to 0.873. Our findings provide the first metabolomic evidence of peroxisomal dysfunction, and are consistent with dysregulation of lipid remodeling and the tricarboxylic acid cycle. These findings, if validated in other cohorts, could provide new insights into the pathogenesis of ME/CFS and highlight the potential use of the plasma metabolome as a source of biomarkers for the disease.

Developing a blood cell-based diagnostic test for myalgic encephalomyelitis/chronic fatigue syndrome using peripheral blood mononuclear cells

“…By quantifying levels of intracellular metabolites via PBMCs' Raman spectra, we observed metabolic differences the ME/CFS and two control cohorts. Most of the metabolic changes that have been reported in previous ME/CFS studies of plasma are consistent with direct and indirect effects of energy strain (31)(32)(33)(34)(35) and abnormal lipid metabolism (34)(35)(36)(37)(38). Our findings agree with the altered utilization of amino acids in patients with ME/CFS, including AAAs of tryptophan, tyrosine, and phenylalanine.…”

Developing a Blood Cell‐Based Diagnostic Test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Peripheral Blood Mononuclear Cells

“…Most of the metabolic changes that have been reported in previous ME/CFS studies of plasma are consistent with direct and indirect effects of energy strain [32][33][34][35][36] and abnormal lipid metabolism. [35][36][37][38][39] Our findings agree with the altered utilization of amino acids in patients with ME/CFS, including AAAs of tryptophan, tyrosine, and phenylalanine. This was also shown in the MS group compared to healthy controls.…”

A multicenter virome analysis of blood, feces, and saliva in myalgic encephalomyelitis/chronic fatigue syndrome

“…Our analyses included plasma, peripheral blood mononuclear cells (PBMC), stool, and saliva from ME/CFS cases and healthy controls, representing two separate case-control cohorts (Table 1 disease status, bacteriome, and metabolome analyses can be found elsewhere. 7,8 For the detection of viruses, we employed multiplex MassTag and nested polymerase chain reaction (PCR) assays, unbiased high-throughput sequencing and capture sequencing (VirCapSeq). We and others have previously reported detection thresholds for these platforms as follows: MassTag PCR, 100-1000 copies 9 ; nested PCR, 5-10 copies 10 ; unbiased high-throughput sequencing, 1000-10 000 copies 11 ; VirCapSeq, 10-100 copies.…”

“…Subjects were recruited from five sites in the United States and matched where feasible (71% of cohort 1, 86% of cohort 2) for site of collection, age, sex, and other demographic indices. Additional information on cohort 2 characteristics, including disease status, bacteriome, and metabolome analyses can be found elsewhere 7,8 . For the detection of viruses, we employed multiplex MassTag and nested polymerase chain reaction (PCR) assays, unbiased high‐throughput sequencing and capture sequencing (VirCapSeq).…”