Abstract
BACKGROUND: In recent years, evidence has indicated a metabolic shift towards increased demand for lipids in various lymphoid cell populations from people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We previously screened the mitochondrial function and gene expression of B cell-derived lymphoblastoid cell lines (LCLs) generated from the blood of people with ME/CFS to characterise a model for hypothesis discovery and testing, observing elevated expression of gene products facilitating amino acid and fatty acid degradation for energy. METHOD: In this follow-up study we have expanded this characterisation by profiling the polar metabolomes and non-polar lipidomes of an all-female cohort of 17 healthy control and 15 ME/CFS LCLs, and we integrated this new data with the previously generated proteomic and transcriptomic data. RESULTS: In the polar metabolome we detected no significantly altered individual features, while integrated multi-omic analysis by MetaboAnalyst indicated 15 dysregulated pathways. Next, in the non-polar lipidome, we identified that PC(O-38:4) had significantly reduced levels in ME/CFS LCLs and was almost entirely discriminative of ME/CFS status. Among all detected classes of lipids we found that triradylglycerolipids ("triglycerides"), diradylglycerolipids and fatty acids were the most significantly affected and were elevated, and that most lipids exhibited average levels higher than in healthy controls. BioPAN pathway analysis of the lipidomic data predicted a more-active gene product that we confirmed to be significantly elevated in both our proteomic and transcriptomic data, this being phosphatidylserine synthase 1 (PTDSS1), plus 7 other gene products that were concordantly altered in expression in the transcriptomic data. We also found that ME/CFS LCLs exhibited a significant tendency towards more saturated lipid content. CONCLUSIONS: LCLs generated from circulating B cells from people with ME/CFS show accumulation of lipids, skewed lipid profiles and altered activity of related metabolic enzymes such as PTDSS1. These findings will inform future hypothesis-driven studies of primary lymphoid cell populations from people with ME/CFS to dissect specific immunometabolic mechanisms that may be involved in the syndrome, particularly relating to intersections between lipid abnormalities and potential effects on immune cell effector functions.