Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile and vascular dysfunction

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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder with undefined mechanisms, no diagnostic tools and treatments. To investigate concurrent system dysfunctions, we recruited age- and sex-matched ME/CFS patients and healthy controls for a multi-modal analysis of energy metabolism, immune profiles and plasma proteomics. Immune cells from ME/CFS patients show elevated adenosine monophosphate (AMP) and adenosine diphosphate (ADP) with a reduced ATP/ADP ratio, indicating decreased ATP generation and cellular energy stress. Immune profiling reveals skewing towards less mature effector subsets of CD4⁺, CD8⁺ and gd T cells, with reduced CD1c⁺CD141^- conventional DC type 2 and CD56^lowCD16⁺ terminal natural killer cells. Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients. Classification and Regression Tree modelling identifies variables with strong predictive potential for ME/CFS. Together, this study provides insights into the somatic symptoms and underlying biology of ME/CFS.