Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating long-term multisystem disorder with a central and inexplicably persistent fatigue symptom that is unable to be relieved by rest. Energy metabolism and oxidative stress have been recent focal points of ME/CFS research and in this study we were able to elucidate metabolic pathways that were indicative of their dysfunction. Blood and urine samples were collected from 34 females with ME/CFS (34.9 ± 1.8 SE years old) and 25 non-ME/CFS female participants (33.0 ± 1.6 SE years old). All samples underwent metabolic profiling via 1D 1 H Nuclear Magnetic Resonance spectroscopy and quantitated metabolites were assessed for significance. Blood glucose was elevated while blood lactate, urine pyruvate, and urine alanine were reduced indicating an inhibition of glycolysis that may potentially reduce the provision of adequate acetyl-CoA for the citric acid cycle. We propose that amino acids are being increasingly used to provide an adequate carbohydrate source for the citric acid cycle. We suggest that this is via glutamate forming 2-oxoglutarate through an enzyme that deaminates it and subsequently elevates blood aspartate. Dysfunctional energy metabolism appears to have impacted creatinine and its elevation in urine suggests that it may be used as an alternative for anaerobic ATP production within muscle. A decrease in blood hypoxanthine and an increase in urine allantoin further suggest the elevation of ROS in ME/CFS patients. These findings bring new information to the research of energy metabolism, chronic immune activation and oxidative stress issues within ME/CFS.

Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Furthermore, the translocation of these enteric lactic acid products into the bloodstream could contribute to the elevated lactate reported in the cerebrospinal fluid of ME/CFS patients [138][139][140] and in the blood of a subgroup of patients [141]. This contrasts with reports of reduced blood lactate as measured by H-NMR metabolomics [39], which suggests that lactic acidosis may only affect a subgroup of patients. If IBS comorbidity accompanied by gut dysbiosis and hyperpermeability is indeed a subtype of ME/CFS, translocation of lactic acid produced by abnormally enriched Gram positive enteric bacteria in the affected individuals, rather than excessive production by host metabolism could explain this inconsistency.…”

“…A subsequent study utilizing MS conversely reported an elevation in ornithine concentration with a decrease in citrulline, but this also suggests urea cycle dysregulation [6]. Subsequent work undertaken by the authors of the first study proposed that impaired glycolytic formation of pyruvate could be providing less downstream, oxidized pyruvate derivatives to be used as substrate for the tricarboxylic acid (TCA) cycle [39]. Work by others suggested that instead of a reduction in the glycolytic pyruvate supply, a deficiency in pyruvate dehydrogenase (PDH) function may form a bottleneck for the provision of TCA cycle substrate [40].…”

Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance

“…Finally, multiple gene sets regulated by INMEST involved cellular energy metabolism, which is curious given that fatigue is the cardinal symptom of ME and linked to alterations in cellular metabolism (39). The GO: Negative regulation of cellular carbohydrate metabolism is affected by INMEST with genes like GCK encoding the glucose sensor Glucokinase, which shifts cellular metabolism based on the availability of glucose (40) and was found in this cohort to be repressed in ME-patients after INMEST treatment ( Fig.…”

The Effects of Acetate-Free Citrate-Containing Dialysate on Calcium Metabolism and Fatigue in Patients on Maintenance Hemodialysis

“…Indeed, Michael et al reported that citrate-containing A(-)D also might contribute to improving fatigue in hemodialysis patients [22]. Comprehensive metabolomic analyses of plasma from chronic fatigue syndrome have demonstrated that citrate was preferentially decreased, which suggested deficiencies in adenosine triphosphate production secondary to dysregulation of the flow from pyruvate to citrate via acetyl CoA and that dysfunctional energy metabolism through the citric acid cycle is a fatigue phenotype [23]. We previously reported that fatigue can be an important predictor for cardiovascular events in hemodialysis patients independent of their nutritional or inflammatory status [6].…”