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Urinary and Plasma Metabolomics Identify the Distinct Metabolic Profile of Disease State in Chronic Mouse Model of Multiple Sclerosis

Journal of Neuroimmune Pharmacology volume 14, pages 241–250 (2019)Cite this article

Abstract

Identification of non-invasive biomarkers of disease progression in multiple sclerosis (MS) is critically needed for monitoring the disease progression and for effective therapeutic interventions. Urine is an attractive source for non-invasive biomarkers because it is easily obtained in the clinic. In search of a urine metabolite signature of progression in chronic experimental autoimmune encephalomyelitis (EAE), we profiled urine at the chronic stage of the disease (day 45 post immunization) by global untargeted metabolomics. Using a combination of high-throughput liquid-and-gas chromatography with mass spectrometry, we found 105 metabolites (P < 0.05) significantly altered at the chronic stage, indicating a robust alteration in the urine metabolite profile during disease. Assessment of altered metabolites against the Kyoto Encyclopedia of Genes and Genomes revealed distinct non-overlapping metabolic pathways and revealed phenylalanine-tyrosine and associated metabolism being the most impacted. Combined with previously performed plasma profiling, eight common metabolites were significantly altered in both of the biofluids. Metaboanalyst analysis of these common metabolites revealed that phenylalanine metabolism and Valine, leucine, and isoleucine biosynthetic pathways are central metabolic pathways in both bio-fluids and could be analyzed further, either for the discovery of therapeutics or biomarker development. Overall, our study suggests that urine and plasma metabolomics may contribute to the identification of a distinct metabolic fingerprint of EAE disease discriminating from the healthy control which may aid in the development of an objective non-invasive monitoring method for progressive autoimmune diseases like MS.

Untargeted urinary metabolomics of a chronic mouse model of multiple sclerosis identified Phenylalanine, tyrosine & tryptophan metabolism as the significantly altered metabolic pathway. Eight common metabolites were identified when we combined urinary and plasma metabolic signature, which revealed a perturbation of Phenylalanine metabolism and valine, leucine & isoleucine metabolic pathways, involved in CNS dysfunction during diseases. The identified eight metabolic signature of urine and plasma may be of clinical relevance as potential biomarkers and guide towards the identification of specific metabolic pathways as novel drug targets.

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Acknowledgements

The study was supported in part by funds from the Henry Ford Health System internal funding (A20020) and a research grant from the National Multiple Sclerosis Society (RG 4311A4/4) to SG.

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Affiliations

  1. Department of Neurology, Henry Ford Health System, E&R Building, Room 4051, Detroit, MI, 48202, USA

    J. Singh, M. Cerghet, H. Suhail & Shailendra Giri

  2. Center for Bioinformatics, Henry Ford Health System, Detroit, MI, 48202, USA

    L. M. Poisson & I. Datta

  3. Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, 48202, USA

    L. M. Poisson & I. Datta

  4. Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, 40-752, Katowice, Poland

    K. Labuzek

  5. Division of Gynecology Oncology, Department of Women’s Health Services, Henry Ford Health System, Detroit, MI, 48202, USA

    R. Rattan

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  1. J. Singh
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  2. M. Cerghet
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  3. L. M. Poisson
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Correspondence to Shailendra Giri.

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Singh, J., Cerghet, M., Poisson, L.M. et al. Urinary and Plasma Metabolomics Identify the Distinct Metabolic Profile of Disease State in Chronic Mouse Model of Multiple Sclerosis. J Neuroimmune Pharmacol 14, 241–250 (2019). https://doi.org/10.1007/s11481-018-9815-4

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  • DOI: https://doi.org/10.1007/s11481-018-9815-4

Keywords

  • Metabolomics
  • EAE
  • Multiple sclerosis
  • Metabolomics
  • Urine
  • Biomarkers
  • GC-MS/LC-MS
  • Metabolic pathways