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. Conclusion Our investigation highlights the potential of gut-microbiome-derived tryptophan metabolites as biomarkers for distinguishing RIA from UIA patients. The findings suggest a novel pathogenic role for gut-microbiome-derived IS in elastin degradation in the IA wall leading to the rupture of IA. All data relevant to the study are included in the article or uploaded as online supplemental information. All data relevant to the study are available in the manuscript including its online supplementary files, or from the corresponding authors upon reasonable request.

中文翻译：

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综合宏基因组和代谢组分析揭示了颅内动脉瘤中独特的阶段特异性肠道微生物组衍生代谢物


目的 我们的研究旨在探讨肠道微生物群及其代谢物对颅内动脉瘤（IA）进展的影响以及源自肠道微生物组的精确相关代谢生物标志物。设计我们从两个不同的地理区域招募了 358 名未破裂 IA (UIA) 患者和 161 名破裂 IA (RIA) 患者，对血浆代谢组学和粪便宏基因组学进行综合分析。采用机器学习算法来开发分类器模型，随后在独立队列中进行验证。建立 IA 小鼠模型是为了验证所鉴定的特定代谢物的潜在作用。结果在不同的 IA 阶段观察到肠道微生物群及其相关代谢物的分类和功能特征的明显变化。值得注意的是，RIA 血浆中色氨酸代谢物，特别是硫酸吲哚酚 (IS) 显着升高。同时，在 RIA 的肠道微生物组中观察到色氨酸酶表达和产生吲哚的微生物群上调。利用肠道微生物组衍生的色氨酸代谢物的模型在验证队列中区分 RIA 和 UIA 患者方面表现出显着的功效 (AUC=0.97)。抗生素消除肠道微生物群可降低血浆 IS 浓度，减少小鼠 IA 形成和破裂，并下调动脉瘤壁中基质金属蛋白酶 9 的表达，同时减少弹性蛋白降解。补充 IS 可以逆转肠道微生物群耗竭的影响。结论 我们的研究强调了肠道微生物组衍生的色氨酸代谢物作为区分 RIA 和 UIA 患者生物标志物的潜力。研究结果表明，肠道微生物组衍生的 IS 在 IA 壁弹性蛋白降解中发挥新的致病作用，导致 IA 破裂。 与研究相关的所有数据都包含在文章中或作为在线补充信息上传。与研究相关的所有数据都可以在手稿中获得，包括其在线补充文件，或者根据合理要求从通讯作者处获得。