Blood-based untargeted metabolomics in Relapsing-Remitting Multiple Sclerosis revealed testable therapeutic target

Abstract

Abstract Relapsing-remitting (RRMS), a most common form of MS, is characterized by acute attacks alternated by partial or complete recovery periods. The major focus of our research is to identify the therapeutic target using metabolomics. Metabolomics is a fast emerging field which can provide a direct “functional readout of the physiological state” of an organism. Identification of blood-based metabolic pathway(s) in relapsing-remitting form of MS (RRMS) which could be used for therapy. Using untargeted ultra-performance liquid and gas mass spectrometry, we measured serum metabolites from 33 RRMS patients, and 14 healthy subjects (HS). A total of 621 known metabolites were detected and 60 metabolites were significantly altered in the serum of RRMS compared to HS. Bioinformatics analysis revealed four metabolic pathways altered in RRMS including glycerophospholipid, citrate cycle, sphingolipids, and pyruvate metabolism. PBMCs isolated from RRMS patients exhibited higher glycolysis suggesting altered metabolic state of immune cells. EAE mice treated with glycolytic inhibitor 2-deoxyglucose (2-DG; once daily), resulted in a significantly delayed (P<0.001) the disease progression. 2DG inhibited (P<0.01) interleukin 17 production by reducing glycolysis (P<0.01) in monocytes of treated EAE group. Using untargeted metabolomic and Seahorse bioanalyzer approaches, we document that RRMS patients showed altered metabolic state “metabotype”. Targeting glycolysis, upstream of metabolic pathways altered in RRMS, using pharmacological inhibitor ameliorated the disease progression and pathology in a preclinical model of MS.