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Original research
Rapid gut dysbiosis induced by stroke exacerbates brain infarction in turn
  1. Kaiyu Xu1,
  2. Xuxuan Gao1,
  3. Genghong Xia2,
  4. Muxuan Chen1,
  5. Nianyi Zeng1,
  6. Shan Wang1,
  7. Chao You2,
  8. Xiaolin Tian2,
  9. Huiling Di1,
  10. Wenli Tang1,
  11. Pan Li1,
  12. Huidi Wang2,
  13. Xiuli Zeng2,
  14. Chuhong Tan2,
  15. Fanguo Meng3,
  16. Hailong Li4,
  17. Yan He1,
  18. Hongwei Zhou1,5,
  19. Jia Yin1,2
  1. 1 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
  2. 2 Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
  3. 3 Redox Medical Center for Public Health, Soochow University, Suzhou, Jiangsu, China
  4. 4 Institute of Molecular Enzymology, Soochow University Medical College, Suzhou, Jiangsu, China
  5. 5 State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, Guangdong, China
  1. Correspondence to Professor Jia Yin; jiajiayin{at}; Professor Hongwei Zhou; biodegradation{at}; Professor Yan He; bioyanhe{at}


Objective Stroke is a leading cause of death and disability worldwide. Neuroprotective approaches have failed in clinical trials, thus warranting therapeutic innovations with alternative targets. The gut microbiota is an important contributor to many risk factors for stroke. However, the bidirectional interactions between stroke and gut microbiota remain largely unknown.

Design We performed two clinical cohort studies to capture the gut dysbiosis dynamics after stroke and their relationship with stroke prognosis. Then, we used a middle cerebral artery occlusion model to explore gut dysbiosis post-stroke in mice and address the causative relationship between acute ischaemic stroke and gut dysbiosis. Finally, we tested whether aminoguanidine, superoxide dismutase and tungstate can alleviate post-stroke brain infarction by restoring gut dysbiosis.

Results Brain ischaemia rapidly induced intestinal ischaemia and produced excessive nitrate through free radical reactions, resulting in gut dysbiosis with Enterobacteriaceae expansion. Enterobacteriaceae enrichment exacerbated brain infarction by enhancing systemic inflammation and is an independent risk factor for the primary poor outcome of patients with stroke. Administering aminoguanidine or superoxide dismutase to diminish nitrate generation or administering tungstate to inhibit nitrate respiration all resulted in suppressed Enterobacteriaceae overgrowth, reduced systemic inflammation and alleviated brain infarction. These effects were gut microbiome dependent and indicated the translational value of the brain–gut axis in stroke treatment.

Conclusions This study reveals a reciprocal relationship between stroke and gut dysbiosis. Ischaemic stroke rapidly triggers gut microbiome dysbiosis with Enterobacteriaceae overgrowth that in turn exacerbates brain infarction.

  • brain/gut interaction
  • ischaemia-reperfusion
  • intestinal microbiology

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  • KX and XG contributed equally.

  • Contributors KX, YH, JY and HZ designed the study. KX, XG, GX, MC, NZ, CY and XT performed and supervised the human experiments. KX, XG, GX, SW, HD, HW, XZ, CT, FM and HL performed and supervised the animal experiments. KX, YH, PL and WT performed and analyzed all the data. KX, YH and HZ wrote the manuscript. KX, YH, JY and HZ conceived the study, supervised the participants, and revised the manuscript.

  • Funding These studies were supported by the National Natural Science Foundation of China, NSFC81925026 (HZ), NSFC81870936 (JY), NSFC81671171 (JY), NSFC82022044 (YH), NSFC81800746 (YH), NSFC31800415 (KX); Clinical Research Startup Programme of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education, LC2016PY025 (JY); National Key R&D Program of China, 2019YFA0802300 (YH); Science and Technology Program of Guangzhou, China, 201904010091 (YH); and China Postdoctoral Science Foundation, 2018M630967 (KX).

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

  • Data availability statement Data are available in a public, open access repository. Data are available upon reasonable request. The raw data for 16 S rRNA gene sequences for clinical cohorts and animal experiments are available from the European Nucleotide Archive ( at accession number PRJEB38503 and PRJEB38504.

  • 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.

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