Blood-based targeted metabolipidomics reveals altered omega fatty acid-derived lipid mediators in relapsing-remitting multiple sclerosis patients

Unresolved and uncontrolled inflammation is considered a hallmark of pathogenesis in chronic inflammatory diseases like multiple sclerosis (MS), suggesting a defective resolution process. Inflammatory resolution is an active process partially mediated by endogenous metabolites of dietary polyunsaturated fatty acids (PUFA), collectively termed specialized pro-resolving lipid mediators (SPMs). Altered levels of resolution mediators have been reported in several inflammatory diseases and may partly explain impaired inflammatory resolution. Performing LC-MS/MS-based targeted lipid mediator profiling, we observed distinct changes in fatty acid metabolites in serum from 30 relapsing-remitting MS (RRMS) patients relative to 30 matched healthy subjects (HS). Robust linear regression revealed 12 altered lipid mediators after adjusting for confounders (p <0.05). Of these, 15d-PGJ2, PGE3, and LTB5 were increased in MS while PGF2a, 8,9-DiHETrE, 5,6-DiHETrE, 20-HETE, 15-HETE, 12-HETE, 12-HEPE, 14-HDoHE, and DHEA were decreased in MS compared to HS. In addition, 12,13-DiHOME and 12,13-DiHODE were positively correlated with expanded disability status scale values (EDSS). Using Partial Least Squares, we identified several lipid mediators with high VIP scores (VIP > 1: 32% - 52%) of which POEA, PGE3, DHEA, LTB5, and 12-HETE were top predictors for distinguishing between RRMS and HS (AUC =0.75) based on the XGBoost Classifier algorithm. Collectively, these findings suggest an imbalance between inflammation and resolution. Altogether, lipid mediators appear to have potential as diagnostic and prognostic biomarkers for RRMS.