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

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Gut microbiota
Original research
Integrated metagenomic and metabolomic analysis reveals distinctive stage-specific gut-microbiome-derived metabolites in intracranial aneurysms
  1. Haitao Sun1,2,3,
  2. Kaijian Sun1,
  3. Hao Tian1,
  4. Xiheng Chen4,
  5. Shixing Su1,
  6. Yi Tu1,
  7. Shilan Chen1,2,
  8. Jiaxuan Wang2,
  9. Meichang Peng1,2,
  10. Meiqin Zeng1,2,
  11. Xin Li2,
  12. Yunhao Luo2,
  13. Yugu Xie2,
  14. Xin Feng1,
  15. Zhuang Li2,
  16. Xin Zhang1,
  17. Xifeng Li1,
  18. Yanchao Liu1,
  19. Wei Ye5,
  20. Zhengrui Chen5,
  21. Zhaohua Zhu6,
  22. Youxiang Li4,
  23. Fangbo Xia2,
  24. Hongwei Zhou2,
  25. Chuanzhi Duan1
  1. 1 Neurosurgery Centre, Department of Cerebrovascular Surgery, Engineering Technology Research Centre of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, The National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
  2. 2 Microbiome Medicine Centre, Clinical Biobank Centre, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
  3. 3 Key Laboratory of Mental Health of the Ministry of Education, Guangdong–Hong Kong–Macao Greater Bay Area Centre for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, Guangdong, China
  4. 4 Beijing Neurosurgical Institute, Beijing Engineering Research Center for Interventional Neuroradiology, Department of Neurosurgery, Beijing TianTan Hospital, Capital Medical University, Beijing, China
  5. 5 The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
  6. 6 Clinical Research Centre, Orthopedic Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
  1. Correspondence to Professor Chuanzhi Duan; doctor_duan{at}126.com; Professor Hongwei Zhou; hzhou{at}smu.edu.cn; Dr Fangbo Xia; xiafb08{at}163.com; Dr Haitao Sun; 2009sht{at}smu.edu.cn

Abstract

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.

  • BRAIN/GUT INTERACTION
  • INTESTINAL MICROBIOLOGY

Data availability statement

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.

https://doi.org/10.1136/gutjnl-2024-332245

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    Data availability statement

    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.

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    Footnotes

    • HS, KS and HT contributed equally.

    • Correction notice This article has been corrected since it published Online First. The supplementary files have been replaced.

    • Contributors HS is responsible for the overall content as guarantor. HS and CD jointly conceptualised and organised the study. HS, KS and HT designed experiments and prepared the manuscript. FX, HZ, ZL and ZZ provided expertise and participated in the design of the experiments. FX mainly completed targeted metabolomic analysis. HS, FX, KS, HT and JW interpreted the data; HT and MP mainly completed animal experiments. SC, HT, FX, MP and YT assisted in drafting the manuscript. XC, SS, MZ, XL, YLu, YX, XF, XZ, XL and YLiu collected the patient samples, and WY and ZC collected clinical information. HZ, CD and ZL revised the manuscript. All authors read and approved the final manuscript.

    • Funding This work was supported by the National Natural Science Foundation of China (81974178, 81974177), Guangdong Basic and Applied Basic Research Foundation (2023A1515030045) and the Presidential Foundation of Zhujiang Hospital of Southern Medical University (No. yzjj2022ms4), Guangzhou Key Research Programme on Brain Science (202206060001).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.