Integrated metagenomic and metabolomic analysis reveals distinctive stage-specific gut-microbiome-derived metabolites in intracranial aneurysms

作者：Haitao Sun, Kaijian Sun, Hao Tian, Xiheng Chen, Shixing Su, Yi Tu, Shilan Chen, Jiaxuan Wang, Meichang Peng, Meiqin Zeng, Xin Li, Yunhao Luo, Yugu Xie, Xin Feng, Zhuang Li, Xin Zhang, Xifeng Li, Yanchao Liu, Wei Ye, Zhengrui Chen, Zhaohua Zhu, Youxiang Li, Fangbo Xia, Hongwei Zhou, Chuanzhi Duan · 发表于：Gut · 年份：2024 · DOI：10.1136/gutjnl-2024-332245 · 被引用次数：23 · 研究领域：Gut microbiota and health、Intracranial Aneurysms: Treatment and Complications、Neuroinflammation and Neurodegeneration Mechanisms

OBJECTIVE: Our study aimed to explore the influence of gut microbiota and their metabolites on intracranial aneurysms (IA) progression and pinpoint-related metabolic biomarkers derived from the gut microbiome. DESIGN: We recruited 358 patients with unruptured IA (UIA) and 161 with ruptured IA (RIA) from two distinct geographical regions for conducting an integrated analysis of plasma metabolomics and faecal metagenomics. Machine learning algorithms were employed to develop a classifier model, subsequently validated in an independent cohort. Mouse models of IA were established to verify the potential role of the specific metabolite identified. RESULTS: Distinct shifts in taxonomic and functional profiles of gut microbiota and their related metabolites were observed in different IA stages. Notably, tryptophan metabolites, particularly indoxyl sulfate (IS), were significantly higher in plasma of RIA. Meanwhile, upregulated tryptophanase expression and indole-producing microbiota were observed in gut microbiome of RIA. A model harnessing gut-microbiome-derived tryptophan metabolites demonstrated remarkable efficacy in distinguishing RIA from UIA patients in the validation cohort (AUC=0.97). Gut microbiota depletion by antibiotics decreased plasma IS concentration, reduced IA formation and rupture in mice, and downregulated matrix metalloproteinase-9 expression in aneurysmal walls with elastin degradation reduction. Supplement of IS reversed the effect of gut microbiota depletion....