NMR-Based Metabolomics Separates the Distinct Stages of Disease in a Chronic Relapsing Model of Multiple Sclerosis
NMR-Based Metabolomics Separates the Distinct Stages of Disease in a Chronic Relapsing Model of Multiple Sclerosis
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DOI：
10.1007/s11481-015-9622-0
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发表时间：
2015-09-01
影响因子：
6.2
通讯作者：
Anthony, Daniel C.
中科院分区：
文献类型：
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作者：
Dickens, Alex M.;Larkin, James R.;Anthony, Daniel C.
复发性实验性变应性脑脊髓炎（Cr-EAE）常用于探索MS新疗法的发病机制和疗效，但Cr-EAE的代谢组是否与人类多发性硬化症（MS）具有可比性尚不清楚。对于多发性硬化症，可以通过结合磁共振波谱和偏最小二乘判别分析（PLS-DA）的血液代谢组学来诊断和分期。在这里，我们试图发现这种方法是否可以用于区分Cr-EAE的顺序疾病状态，以及相同的代谢物是否具有歧视性。在不同的时间点从临床相关的ms模型中获取尿液和血浆样本，使用PLS-DA模型对尿液样本进行建模提供了一些预测模型，但不能区分所有疾病状态。然而，血浆样品的PLS-DA建模能够区分临床无症状动物（第10、28天）和疾病活跃动物（第14、38天）。我们还能够在第14天和第38天将Cr-EAE小鼠与未成熟小鼠和仅接受完全弗氏佐剂治疗的对照小鼠区分开来。支撑这些模型的关键代谢物包括脂肪酸、葡萄糖和牛磺酸。在人体研究中，脂肪酸和葡萄糖这两种代谢物也是区分复发缓解型MS和继发性进展型MS的关键代谢物。这些结果证明了这种代谢组学方法区分不同疾病状态的敏感性。此外，在人类和小鼠模型中，代谢物的一些变化（但不是全部）是保守的，这可能对未来的药物开发有用。
Relapsing experimental allergic encephalomyelitis (Cr-EAE) is commonly used to explore the pathogenesis and efficacy of new therapies for MS, but it is unclear whether the metabolome of Cr-EAE is comparable to human multiple sclerosis (MS). For MS, the diagnosis and staging can be achieved by metabolomics on blood using a combination of magnetic resonance spectroscopy and partial least squares discriminant analysis (PLS-DA). Here, we sought to discover whether this approach could be used to differentiate between sequential disease states in Cr-EAE and whether the same metabolites would be discriminatory. Urine and plasma samples were obtained at different time-points from a clinically relevant model of MS. Using PLS-DA modelling for the urine samples furnished some predictive models, but could not discriminate between all disease states. However, PLS-DA modelling of the plasma samples was able to distinguish between animals with clinically silent disease (day 10, 28) and animals with active disease (day 14, 38). We were also able to distinguish Cr-EAE mice from naive mice at all-time points and control mice, treated with complete Freund's adjuvant alone, at day 14 and 38. Key metabolites that underpin these models included fatty acids, glucose and taurine. Two of these metabolites, fatty acids and glucose, were also key metabolites in separating relapsing-remitting MS from secondary-progressive MS in the human study. These results demonstrate the sensitivity of this metabolomics approach for distinguishing between different disease states. Furthermore, some, but not all, of the changes in metabolites were conserved in humans and the mouse model, which could be useful for future drug development.