Profile and potential role of novel metabolite biomarkers, especially indoleacrylic acid, in pathogenesis of neuromyelitis optica spectrum disorders

Jiangping Bian; Jiali Sun; Haoxiao Chang; Yuzhen Wei; Hengri Cong; Mengyuan Yao; Fuyao Xiao; Huabing Wang; Yaobo Zhao; Jianghong Liu; Xinghu Zhang; Linlin Yin

doi:10.3389/fphar.2023.1166085

Profile and potential role of novel metabolite biomarkers, especially indoleacrylic acid, in pathogenesis of neuromyelitis optica spectrum disorders

Front Pharmacol. 2023 May 19:14:1166085. doi: 10.3389/fphar.2023.1166085. eCollection 2023.

Authors

Jiangping Bian^{1

2}, Jiali Sun¹, Haoxiao Chang^{1

2}, Yuzhen Wei¹, Hengri Cong¹, Mengyuan Yao^{1

2}, Fuyao Xiao^{1

2}, Huabing Wang¹, Yaobo Zhao¹, Jianghong Liu^{3

4}, Xinghu Zhang^{1

3}, Linlin Yin^{1

4

4}

Affiliations

¹ Department of Neuroinfection and Neuroimmunology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
² China National Clinical Research Center for Neurological Diseases, Beijing, China.
³ Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.
⁴ Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China.

Abstract

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune central nervous system (CNS) inflammatory and demyelinating disorder that can lead to serious disability and mortality. Humoral fluid biomarkers with specific, convenient, and efficient profiles that could characterize and monitor disease activity or severity are very useful. We aimed to develop a sensitive and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS)/MS-based analytical method for novel biomarkers finding in NMOSD patients and verified its function tentatively. Methods: Serum samples were collected from 47 NMOSD patients, 18 patients with other neurological disorders (ONDs), and 35 healthy controls (HC). Cerebrospinal fluid (CSF) samples were collected from 18 NMOSD and 17 OND patients. Three aromatic amino acids (phenylalanine, tyrosine, and tryptophan) and nine important metabolites that included phenylacetylglutamine (PAGln), indoleacrylic acid (IA), 3-indole acetic acid (IAA), 5-hydroxyindoleacetic acid (HIAA), hippuric acid (HA), I-3-carboxylic acid (I-3-CA), kynurenine (KYN), kynurenic acid (KYNA), and quinine (QUIN) were analyzed by using the liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method. The profile of IA was further analyzed, and its function was verified in an astrocyte injury model stimulated by NMO-IgG, which represents important events in NMOSD pathogenesis. Results: In the serum, tyrosine and some of the tryptophan metabolites IA and I-3-CA decreased, and HIAA increased significantly in NMOSD patients. The CSF levels of phenylalanine and tyrosine showed a significant increase exactly during the relapse stage, and IA in the CSF was also increased markedly during the relapse and remission phases. All conversion ratios had similar profiles with their level fluctuations. In addition, the serum IA levels negatively correlated with glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) levels in the serum of NMOSD patients were measured by using ultra-sensitive single-molecule arrays (Simoa). IA showed an anti-inflammatory effect in an in vitro astrocyte injury model. Conclusion: Our data suggest that essential aromatic amino acid tryptophan metabolites IA in the serum or CSF may serve as a novel promising biomarker to monitor and predict the activity and severity of NMOSD disease. Supplying or enhancing IA function can promote anti-inflammatory responses and may have therapeutic benefits.

Keywords: aromatic amino acids and metabolites; humoral fluids; indoleacrylic acid; liquid chromatography mass spectrometry; neuromyelitis optica spectrum disorders.

Grants and funding

This work was supported by the Beijing Natural Science Foundation (Nos 7212030 and 7212029), the National Natural Science Foundation of China (No. 82271374), and the National Key Research and Development Program of China (No. 2019YFC0121202).