Rapid gut dysbiosis induced by stroke exacerbates brain infarction in turn
Rapid gut dysbiosis induced by stroke exacerbates brain infarction in turn
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DOI：
10.1136/gutjnl-2020-323263
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发表时间：
2021-08-01
期刊：
影响因子：
24.5
通讯作者：
Yin, Jia
中科院分区：
文献类型：
--
作者：
Xu, Kaiyu;Gao, Xuxuan;Yin, Jia
目的脑卒中是世界范围内导致死亡和残疾的主要原因。神经保护方法在临床试验中失败了，从而阻碍了具有替代靶点的治疗创新。肠道微生物群是导致中风的许多危险因素的重要因素。然而，中风和肠道微生物群之间的双向相互作用在很大程度上仍然未知。设计：我们进行了两项临床队列研究，以捕获卒中后肠道生态失调动力学及其与卒中预后的关系。然后，我们使用大脑中动脉闭塞模型来探索小鼠脑卒中后肠道生态失调，并解决急性缺血性脑卒中和肠道生态失调之间的因果关系。最后，我们测试了氨基胍、超氧化物歧化酶和钨酸盐是否可以通过恢复肠道生态失调来减轻中风后脑梗死。结果脑缺血迅速引起肠道缺血，通过自由基反应产生过量硝酸盐，导致肠道菌群失调，肠杆菌科细菌大量扩增。肠杆菌科细菌富集通过增强全身炎症而加重脑梗死，是卒中患者原发性不良结局的独立危险因素。施用氨基胍或超氧化物歧化酶以减少硝酸盐的产生或施用钨酸盐以抑制硝酸盐呼吸都导致抑制肠杆菌科的过度生长，减少全身炎症和减轻脑梗死。这些作用是肠道微生物组依赖性的，表明脑-肠轴在中风治疗中的转化价值。结论本研究揭示了脑卒中与肠道生态失调之间的相互关系。缺血性卒中迅速引发肠道微生物群失调，肠杆菌科过度生长，进而加重脑梗死。
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.