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

Zahoor, Insha; Suhail, Hamid; Datta, Indrani; Ahmed, Mohammad Ejaz; Poisson, Laila M; Waters, Jeffrey; Bin, Rui; Singh, Jaspreet; Cerghet, Mirela; Kumar, Ashok; Hoda, Md Nasrul; Rattan, Ramandeep; Mangalam, Ashutosh K; Giri, Shailendra

Metabolic aberrations impact the pathogenesis of multiple sclerosis (MS) and possibly can provide clues for new treatment strategies. Using untargeted metabolomics, we measured serum metabolites from 35 relapsing-remitting patients and 14 healthy age-matched controls. Out of 632 known metabolites detected, 60 were significantly altered in relapsing-remitting MS (RRMS). Bioinformatics analysis identified an altered “metabotype” in RRMS patients, represented by 4 changed metabolic pathways of glycerophospholipid, citrate cycle, sphingolipid, and pyruvate metabolism. Interestingly, the common upstream metabolic pathway feeding these 4 pathways is the glycolysis pathway. Real-time bioenergetic analysis of the patient derived peripheral blood mononuclear cells, showed enhanced glycolysis, supporting the altered metabolic state of immune cells. Experimental autoimmune encephalomyelitis mice treated with the glycolytic inhibitor, 2-deoxy-D-glucose ameliorated the disease progression and inhibited the disease pathology significantly by promoting the anti-inflammatory phenotype of monocytes/macrophage in the central nervous system. Our study suggests that targeting glycolysis offers a potential target for MS.