Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

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 alpha-ketoglutarate 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.