Gut metabolites identified in cerebrospinal fluid of genetic interferonopathy support gut–brain endothelial dysfunction

IF 3.4 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology Pub Date : 2026-02-19 DOI:10.1002/cti2.70074

Russell C Dale, Madysen Elbourne, Markus J Hofer, Shrujna Patel, Shekeeb Mohammad, Velda X Han, Josephine Yu, Shanlin Fu, Arlene D'Silva, Michelle A Farrar, Sushil Bandodkar, Jingya J Yan

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Abstract

Objective

Aicardi–Goutières syndrome (AGS) is a rare genetic interferonopathy because of aberrant DNA or RNA metabolism with secondary host anti-viral (interferon) activation. This metabolomics study aimed to improve the biological understanding of AGS and explore potential biomarkers.

Methods

We performed untargeted cerebrospinal fluid (CSF) metabolomics using a UPLC-Q-Exactive-HFx Mass Spectrometry of 10 genetically confirmed AGS patients (8 males, mean 4.8 years, range 0.2–16.5) and age-sex matched controls. Metabolites were then quantified and validated using UHPLC-QqQ-MS/MS in CSF and serum.

Results

We identified expected elevated inflammatory metabolites (neopterin and kynurenine) and unexpected elevated gut microbe metabolites in CSF samples: Indole, p-Cresol, γ-Butyrobetaine and N-Butyryl-L-homoserine lactone (all P_FDR < 0.05). Using a targeted assay, we confirmed elevation of these metabolites in CSF, and also in the serum of patients with AGS (all P < 0.01).

Conclusion

Our findings suggest gut microbe metabolite leakage traversing the gut–blood–brain barrier in AGS, potentially because of endothelial dysfunction.

Abstract Image

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遗传干扰素病脑脊液中发现的肠道代谢物支持肠-脑内皮功能障碍。

目的：aicardii - gouti综合征（AGS）是一种罕见的遗传性干扰素病，其病因是DNA或RNA代谢异常，伴有继发性宿主抗病毒（干扰素）激活。这项代谢组学研究旨在提高对AGS的生物学认识，并探索潜在的生物标志物。方法：我们使用uplc - q - ex- hfx质谱法对10例遗传确诊的AGS患者（8名男性，平均4.8岁，范围0.2-16.5）和年龄性别匹配的对照组进行了非靶向脑脊液（CSF）代谢组学分析。然后使用uhplc - qq -MS/MS对CSF和血清中的代谢物进行定量和验证。结果：我们在脑脊液样本中发现了预期的升高的炎症代谢物（新蝶呤和犬尿氨酸）和意想不到的升高的肠道微生物代谢物：吲哚、对甲酚、γ-丁基β碱和n -丁基- l-高丝氨酸内酯（均为P FDR P）。结论：我们的研究结果表明，AGS中肠道微生物代谢物渗漏穿过肠-血脑屏障，可能是由于内皮功能障碍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical & Translational Immunology Medicine-Immunology and Allergy

CiteScore

12.00

自引率

1.70%

发文量

审稿时长

13 weeks

期刊介绍： Clinical & Translational Immunology is an open access, fully peer-reviewed journal devoted to publishing cutting-edge advances in biomedical research for scientists and physicians. The Journal covers fields including cancer biology, cardiovascular research, gene therapy, immunology, vaccine development and disease pathogenesis and therapy at the earliest phases of investigation.