The circulating metabolome is a product of interactions between the genome, epigenome, exposome and microbiome. The metabolome may be altered in people with multiple sclerosis (MS); however, existing metabolomics studies were relatively small or characterized a limited number of metabolites. Herein, we performed a multi-site study profiling the circulating metabolome to obtain relative abundances for 269 metabolites in a large cohort of MS patients and healthy controls. After adjusting for batch effects and extensive quality control, we created an overall metabolic dysfunction score, defined apriori sets of metabolites using known metabolic pathways, and derived novel networks of correlated metabolites using a weighted correlation network analysis (WGCNA). We assessed whether metabolic dysfunction, individual metabolites, metabolic pathways or WGCNA-identified module scores differed between people with MS versus healthy controls (HC) after adjusting for age, sex and race using generalized estimating equations (participants could provide multiple samples). In a subset of patients, information on disability status was also available. Similar models assessed the association between metabolites and metabolite sets with measures of disability. In people with MS, we identified striking abnormalities in a WGCNA-defined module enriched in aromatic amino acid (AAA) metabolites (FDR-adjusted p-value=2.77E-18) that are also strongly associated with disability (FDR-adjusted p-value for AAA module=1.01E-4). Consistent results were obtained using apriori-defined metabolite sets or in analyses of individual metabolites. The identified abnormalities likely relate to imbalances in gut microbial metabolism of AAAs resulting in reduced production of immunomodulatory metabolites and increased production of metabotoxins (indole acetate, phenylacetylglutamine, p-cresol sulfate, p-cresol glucuronide). Single cell RNA sequencing data analysis demonstrated altered AAA metabolism in CSF and blood derived monocyte cell populations, while treatment of human peripheral blood mononuclear cells with AAA-derived metabotoxins resulted in increased production of tumor necrosis factor-α. We identify novel metabolic alterations in people with MS potentially contributing to disease pathophysiology.

中文翻译：

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多发性硬化症代谢变化的多组学评估可确定芳香族氨基酸代谢的变化。

循环代谢组是基因组，表观基因组，外显子和微生物组之间相互作用的产物。多发性硬化症（MS）患者的代谢组可能会改变；然而，现有的代谢组学研究相对较小或以有限数量的代谢产物为特征。本文中，我们进行了一项多点研究，对循环代谢组进行了分析，以获取大量MS患者和健康对照人群中269种代谢产物的相对丰度。在调整批次效应和广泛的质量控制后，我们创建了一个整体代谢功能障碍评分，使用已知的代谢途径定义了先验的代谢物组，并使用加权相关网络分析（WGCNA）得出了相关代谢物的新型网络。我们评估了代谢功能障碍，个体代谢产物，MS患者和健康对照者（HC）的代谢途径或WGCNA识别的模块评分在使用广义估计方程调整了年龄，性别和种族之后（参与者可以提供多个样本）而有所不同。在一部分患者中，也可获得有关残疾状况的信息。相似的模型评估了代谢物和代谢物组之间的关联以及残疾程度。在MS患者中，我们在WGCNA定义的模块中发现了惊人的异常，该模块中富含芳香族氨基酸（AAA）代谢物（FDR调整后的p值= 2.77E-18），也与残疾（FDR调整后的p- AAA模块的值= 1.01E-4）。使用先验定义的代谢物组或对单个代谢物进行分析可获得一致的结果。所发现的异常可能与AAAs的肠道微生物代谢失衡有关，导致免疫调节代谢产物的产生减少，而metabooxins（乙酸吲哚，苯乙酰基谷氨酰胺，对甲酚硫酸盐，对甲酚葡萄糖醛酸）的产生增加。单细胞RNA测序数据分析表明，CSF和血液来源的单核细胞群体中的AAA代谢发生了变化，而用AAA衍生的metabotoxins处理人外周血单核细胞导致肿瘤坏死因子-α的产生增加。我们发现MS患者中可能导致疾病病理生理的新型代谢改变。对甲酚硫酸盐，对甲酚葡萄糖醛酸）。单细胞RNA测序数据分析表明，CSF和血液来源的单核细胞群体中的AAA代谢发生了变化，而用AAA衍生的metabotoxins处理人外周血单核细胞导致肿瘤坏死因子-α的产生增加。我们发现MS患者中可能导致疾病病理生理的新型代谢改变。对甲酚硫酸盐，对甲酚葡萄糖醛酸）。单细胞RNA测序数据分析表明，CSF和血液来源的单核细胞群体中的AAA代谢发生了变化，而用AAA衍生的metabotoxins处理人外周血单核细胞导致肿瘤坏死因子-α的产生增加。我们发现MS患者中可能导致疾病病理生理的新型代谢改变。