Abstract
Multiple sclerosis (MS) is an autoimmune disease that leads to the demyelination of nerve axons. An increasing number of studies suggest that patients with MS exhibit altered metabolic profiles, which might contribute to the course of MS. However, the alteration of metabolic profiles in Chinese patients with MS and their potential roles in regulating the immune system remain elusive. In this study, we performed a global untargeted metabolomics approach in plasma samples from 22 MS-affected Chinese patients and 21 healthy subjects. A total of 42 differentially abundant metabolites (DAMs) belonging to amino acids, lipids, and carbohydrates were identified in the plasma of MS patients and compared with those in healthy controls. We observed an evident reduction in the levels of amino acids, such as L-tyrosine, L-isoleucine, and L-tryptophan, whereas there was a great increase in the levels of L-glutamic acid and L-valine in MS-affected patients. The levels of lipid and carbohydrate metabolites, such as sphingosine 1-phosphate and myo-inositol, were also reduced in patients with MS. In addition, the concentrations of proinflammatory cytokines, such as IL-17 and TNF-α, were significantly increased, whereas those of several anti-inflammatory cytokines and chemokines, such as IL-1ra, IL-7, and MIP-1α, were distinctly reduced in the plasma of MS patients compared with those in healthy subjects. Interestingly, some DAMs, such as L-tryptophan and sphingosine 1-phosphate, showed an evident negative correlation with changes in the level of TNF-α and IL-17, while tightly positively correlating with altered concentrations of anti-inflammatory cytokines and chemokines, such as MIP-1α and RANTES. Our results revealed that altered metabolomic profiles might contribute to the pathogenesis and course of MS disease by modulating immuno-inflammatory responses in the peripheral system, which is essential for eliciting autoimmune responses in the central nervous system, thus resulting in the progression of MS. This study provides potential clues for developing therapeutic strategies for MS in the near future.
Highlights
Multiple sclerosis (MS), an immunoinflammatory disease, is caused by the chronic demyelination of nerve axons and, disrupts the function of the central nervous system (CNS), eventually leading to severe disability, such as autonomic dysfunction, paralysis, disability of motor control, and cognitive impairment of the brain [1,2,3]
We found that upregulated metabolites, such as palmitic acid, isocitric acid, methyl jasmonate, sorbitol, and spermidine, positively correlated with proinflammatory cytokines, such as IL-17 and Tumor necrosis factor-a (TNF-a), while they negatively correlated with various chemokines, such as IL-8, IL-12, and PDGF-bb (Figure 6)
Multiple studies have demonstrated that amino acid metabolites, such as tryptophan, play an indispensable role in regulating immune homeostasis in MS [79,80,81,82,83] and in an experimental autoimmune encephalomyelitis (EAE) model [91,92,93]
Summary
Multiple sclerosis (MS), an immunoinflammatory disease, is caused by the chronic demyelination of nerve axons and, disrupts the function of the central nervous system (CNS), eventually leading to severe disability, such as autonomic dysfunction, paralysis, disability of motor control, and cognitive impairment of the brain [1,2,3]. According to the latest open-source data of MS global epidemiology derived from the Atlas of MS (www.atlasofms.org), which is compiled and updated by the Multiple Sclerosis International Federation (MSIF), it is estimated that 2.8 million people are affected by MS worldwide. To date, no comprehensive statistical data on MS epidemiology have been reported in China, even though multiple regional studies have revealed the incidence of MS in the Chinese population [5,6,7,8,9]. Studies have verified that multiple genetic variants confer an MS risk through the regulation of immune responses [15,16,17]
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