Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown etiology or effective treatments. Post-exertional malaise (PEM) is a key symptom that distinguishes ME/CFS patients. Investigating changes in the urine metabolome between ME/CFS patients and healthy subjects following exertion may help us understand PEM. The aim of this pilot study was to comprehensively characterize the urine metabolomes of eight female healthy sedentary control subjects and ten female ME/CFS patients in response to a maximal cardiopulmonary exercise test (CPET). Each subject provided urine samples at baseline and 24 h post-exercise. A total of 1403 metabolites were detected via LC-MS/MS by Metabolon® including amino acids, carbohydrates, lipids, nucleotides, cofactors and vitamins, xenobiotics, and unknown compounds. Using a linear mixed effects model, pathway enrichment analysis, topology analysis, and correlations between urine and plasma metabolite levels, significant differences were discovered between controls and ME/CFS patients in many lipid (steroids, acyl carnitines and acyl glycines) and amino acid subpathways (cysteine, methionine, SAM, and taurine; leucine, isoleucine, and valine; polyamine; tryptophan; and urea cycle, arginine and proline). Our most unanticipated discovery is the lack of changes in the urine metabolome of ME/CFS patients during recovery while significant changes are induced in controls after CPET, potentially demonstrating the lack of adaptation to a severe stress in ME/CFS patients.

ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature

“…Positive studies: (103,104,384,390) Positive studies: no studies of metabolite levels in blood reported. Multiple reports of brain hypometabolism on imaging (see Table 4).…”

Ginsenoside Rg1 can reverse fatigue behavior in CFS rats by regulating EGFR and affecting Taurine and Mannose 6-phosphate metabolism

“…Previous results showed that the differential metabolites identified here were also associated with CFS in different contexts and animal models, which attests the validity of our work. Among these metabolites, Taurine plays a specifically important role ( Germain et al, 2017 ; Glass et al, 2023 ). Germain et al found that CFS patients had low Taurine content, which was mainly affected by lipid metabolism and amino acids ( Germain et al, 2017 ).…”

Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise

“…To date, few studies on EVs in ME/CFS have been published (Almenar-Pérez et al, 2020;Bonilla et al, 2022;Castro-Marrero et al, 2018;Eguchi et al, 2020;Giloteaux et al, 2023Giloteaux et al, , 2020González-Cebrián et al, 2022;Tsilioni et al, 2022). In 2018, Castro-Marrero and colleagues were the first to analyse EVs isolated from ME/CFS patients and they found a higher EV concentration and smaller sized EVs in 10 ME/CFS patients in comparison to five healthy controls (Castro-Marrero et al, 2018).…”

“…The intensity and duration of PEM is usually unpredictable, making it challenging for individuals with ME/CFS to plan activities or engage in regular daily tasks (IOM, 2015 ; Stussman et al., 2020 ). Research suggests that PEM may involve dysregulation of the immune system, impaired energy metabolism, and abnormal responses to exertion at the cellular level (Germain et al., 2022 ; Glass et al., 2023 ; Van Booven et al., 2023 ).…”