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
- 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 (https://www.ebi.ac.uk/ena/) at accession number PRJEB38503 and PRJEB38504.
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