title: Profile of Circulatory Metabolites in a Relapsing-remitting Animal Model of Multiple Sclerosis using Global Metabolomics.
abstract: Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS. Although, MS is well characterized in terms of the role played by immune cells, cytokines and CNS pathology, nothing is known about the metabolic alterations that occur during the disease process in circulation. Recently, metabolic aberrations have been defined in various disease processes either as contributing to the disease, as potential biomarkers, or as therapeutic targets. Thus in an attempt to define the metabolic alterations that may be associated with MS disease progression, we profiled the plasma metabolites at the chronic phase of disease utilizing relapsing remitting-experimental autoimmune encephalomyelitis (RR-EAE) model in SJL mice. At the chronic phase of the disease (day 45), untargeted global metabolomic profiling of plasma collected from EAE diseased SJL and healthy mice was performed, using a combination of high-throughput liquid-and-gas chromatography with mass spectrometry. A total of 282 metabolites were identified, with significant changes observed in 44 metabolites (32 up-regulated and 12 down-regulated), that mapped to lipid, amino acid, nucleotide and xenobiotic metabolism and distinguished EAE from healthy group (p<0.05, false discovery rate (FDR)<0.23). Mapping the differential metabolite signature to their respective biochemical pathways using the Kyoto Encyclopedia of Genes and Genomics (KEGG) database, we found six major pathways that were significantly altered (containing concerted alterations) or impacted (containing alteration in key junctions). These included bile acid biosynthesis, taurine metabolism, tryptophan and histidine metabolism, linoleic acid and D-arginine metabolism pathways. Overall, this study identified a 44 metabolite signature drawn from various metabolic pathways which correlated well with severity of the EAE disease, suggesting that these metabolic changes could be exploited as (1) biomarkers for EAE/MS progression and (2) to design new treatment paradigms where metabolic interventions could be combined with present and experimental therapeutics to achieve better treatment of MS.
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA ; Department ofNeurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Ak
authors.initials: A
authors.lastname: Mangalam
authors.forename: Lm
authors.initials: L
authors.lastname: Poisson
authors.forename: E
authors.initials: E
authors.lastname: Nemutlu
authors.forename: I
authors.initials: I
authors.lastname: Datta
authors.forename: A
authors.initials: A
authors.lastname: Denic
authors.forename: P
authors.initials: P
authors.lastname: Dzeja
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez
authors.forename: R
authors.initials: R
authors.lastname: Rattan
authors.forename: S
authors.initials: S
authors.lastname: Giri
keywords: Biomarker; Experimental autoimmune encephalitis; Metabolic pathways; Metabolite signature; Metabolomics; Multiple sclerosis; Plasma