Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
Doctors with M.E. Honorary Fellows, Dr. Lucinda Bateman, Professor Anthony Komaroff and Professor Ian Lipkin continue investigations into ME with co-authorship of newly published research that gives further support to findings of altered metabolomic profiles in ME/CFS patients.
The levels of metabolites altered in these profiles highlight the interconnected nature of ME/CFS pathophysiology, and enable identification of two potentially significant abnormalities that may shed light on causes behind fatigue and cognitive dysfunction.
“Here we report confirmation of decreased levels of phospholipids, including phosphatidylcholine and sphingolipids, and provide evidence for dysregulation of the Kennedy pathway and the tricarboxylic acid cycle.”
“Our findings provide potential insights into the pathobiology of clinical features of ME/CFS by providing a mechanistic framework for understanding compromised energy production, loss of integrity of cellular and mitochondrial membranes, inflammation, impaired cognition, dysregulated autonomic function, impediments to repair of tissue injury, and redox imbalance.”
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance and gastrointestinal problems. The pathogenesis is not fully understood. Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls. In ME/CFS cases, the regression, Bayesian and enrichment analyses all revealed abnormal levels of several membrane lipids indicating dysregulation of the Kennedy pathway: decreased plasma levels of plasmalogens, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, and phospholipid ethers. Enrichment analyses revealed decreased levels of cholines, ceramides and carnitines, and increased levels of long chain triglycerides, dicarboxylic acids, hydroxy-eicosapentaenoic acid, and the tricarboxylic acid cycle intermediates alphaketoglutarate and succinate. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873). Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight specific abnormalities that may provide insights into the pathogenesis of ME/CFS.
Citation
Che, X., Brydges, CR., Yu, Y., Price, A., Joshi, S., Roy, A., Lee, B., Barupal, DK., Cheng, A., Palmer, DM., Levine, S., Peterson, DL., Vernon, SD., Bateman, L., Hornig, M, Montoya, JG., Komaroff, AL., Fiehn, O., Lipkin, WI. Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Published online June 22, 2021. https://doi.org/10.1101/2021.06.14.21258895
Dr. Lucinda Bateman
Honorary Fellow
Founder and Chief Medical Officer, Bateman Horne Center of Excellence for ME/CFS and Fibromyalgia, Utah, co-author, International Consensus Criteria, Expert Witness, US Institute of Medicine
Prof. Anthony Komaroff
Honorary Fellow
Distinguished Professor, Harvard Medical School, Physician at Brigham and Women’s Hospital, Boston
Prof. Ian Lipkin
Honorary Fellow
Director, NIAID/NINDS Center for Solutions for ME/CFS, Columbia University, Professors of Epidemiology, Neurology
and Pathology & Cell Biology, Columbia University Medical Center, Director, Center for Infection and Immunity, Mailman School of Public Health