Rapid gut dysbiosis induced by stroke exacerbates brain infarction in turn

Abstract

ObjectiveStroke 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.DesignWe 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.ResultsBrain 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.ConclusionsThis 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.

Dysbiosis of Gut Microbiota Is an Independent Risk Factor of Stroke-Associated Pneumonia: A Chinese Pilot Study

“…In terms of the composition of the gut microbiota, we were able to determine the bacterial taxa that most likely explain the differences between the SAP and non-SAP groups by applying the LEfSe algorithm, which has been validated for high-dimensional microbiome data sets. Some disease-promoting pathogens, such as Enterococcus ( Xia et al., 2019 ; Tan et al., 2020 ; Xu et al., 2021 ), overgrew in SAP subjects and were related to worse clinical outcomes in these patients. The integration of data regarding the most relevant taxa that characterized each patient group allowed us to calculate the MDI, which was significantly elevated in patients with SAP, especially in those with severe pneumonia, and related to systemic inflammation and immunosuppression, two important variables of SAP ( Hoffmann et al., 2017 ).…”

“…Furthermore, clinical data concerning the association between the gut microbiota and SAP in China remain limited. We previously reported that disruption of the gut microbiota and its metabolites, including trimethylamine-N-oxide and SCFAs, are associated with stroke injury and outcome in AIS patients ( Xia et al., 2019 ; Tan et al., 2020 ; Xu et al., 2021 ). We further identified that an expansion of Enterobacteriaceae in the gut is an independent risk factor for poor functional outcome in AIS patients ( Xu et al., 2021 ).…”

“…We previously reported that disruption of the gut microbiota and its metabolites, including trimethylamine-N-oxide and SCFAs, are associated with stroke injury and outcome in AIS patients ( Xia et al., 2019 ; Tan et al., 2020 ; Xu et al., 2021 ). We further identified that an expansion of Enterobacteriaceae in the gut is an independent risk factor for poor functional outcome in AIS patients ( Xu et al., 2021 ). In the present study, we conducted two independent cohorts to investigate whether the gut microbiota composition correlates with and predicts SAP in patients with AIS.…”

The Microbiota-Gut-Brain Axis in Health and Disease and Its Implications for Translational Research

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“…Observation of a clinical cohort of patients with ischemic stroke revealed a fast induction of intestinal ischemia and an excessive production of nitrate resulting in gut dysbiosis with expansion of Enterobacteriaceae (Xu et al, 2021). Overgrowth of Enterobacteriaceae magnifies brain infarction by enhancing systemic inflammation and is a potential risk biomarker for a poor primary outcome of patients.…”