Benakis Corinne, Poon Carrie, Lane Diane, Brea David, Sita Giulia, Moore Jamie, Murphy Michelle, Racchumi Gianfranco, Iadecola Costantino, Anrather Josef
From the Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York.
Stroke. 2020 Jun;51(6):1844-1854. doi: 10.1161/STROKEAHA.120.029262. Epub 2020 May 14.
Background and Purpose- Commensal gut bacteria have a profound impact on stroke pathophysiology. Here, we investigated whether modification of the microbiota influences acute and long-term outcome in mice subjected to stroke. Methods- C57BL/6 male mice received a cocktail of antibiotics or single antibiotic. After 4 weeks, fecal bacterial density of the 16S rRNA gene was quantitated by qPCR, and phylogenetic classification was obtained by 16S rRNA gene sequencing. Infarct volume and hemispheric volume loss were measured 3 days and 5 weeks after middle cerebral artery occlusion, respectively. Neurological deficits were tested by the Tape Test and the open field test. Results- Mice treated with a cocktail of antibiotics displayed a significant reduction of the infarct volume in the acute phase of stroke. The neuroprotective effect was abolished in mice recolonized with a wild-type microbiota. Single antibiotic treatment with either ampicillin or vancomycin, but not neomycin, was sufficient to reduce the infarct volume and improved motorsensory function 3 days after stroke. This neuroprotective effect was correlated with a specific microbial population rather than the total bacterial density. In particular, random forest analysis trained for the severity of the brain damage revealed that Bacteroidetes S24.7 and the enzymatic pathway for aromatic metabolism discriminate between large versus small infarct size. Additionally, the microbiota signature in the ampicillin-treated mice was associated with a reduced gut inflammation, long-term favorable outcome shown by an amelioration of the stereotypic behavior, and a reduction of brain tissue loss in comparison to control and was predictive of a regulation of short-chain fatty acids and tryptophan pathways. Conclusions- The findings highlight the importance of the intestinal microbiota in short- and long-term outcomes of ischemic stroke and raises the possibility that targeted modification of the microbiome associated with specific microbial enzymatic pathways may provide a preventive strategy in patients at high risk for stroke. Visual Overview- An online visual overview is available for this article.
背景与目的——共生肠道细菌对中风病理生理学具有深远影响。在此，我们研究了微生物群的改变是否会影响中风小鼠的急性和长期预后。方法——C57BL/6雄性小鼠接受抗生素鸡尾酒或单一抗生素治疗。4周后，通过qPCR定量16S rRNA基因的粪便细菌密度，并通过16S rRNA基因测序获得系统发育分类。分别在大脑中动脉闭塞后3天和5周测量梗死体积和半球体积损失。通过胶带试验和旷场试验测试神经功能缺损。结果——接受抗生素鸡尾酒治疗的小鼠在中风急性期梗死体积显著减小。在用野生型微生物群重新定殖的小鼠中，神经保护作用被消除。单独使用氨苄青霉素或万古霉素而非新霉素治疗足以减小梗死体积并改善中风后3天的运动感觉功能。这种神经保护作用与特定的微生物群体而非总细菌密度相关。特别是，针对脑损伤严重程度进行训练的随机森林分析表明，拟杆菌属S24.7和芳香族代谢的酶促途径可区分大梗死灶与小梗死灶的大小。此外，与对照组相比，氨苄青霉素治疗小鼠的微生物群特征与肠道炎症减轻、刻板行为改善所显示的长期良好预后以及脑组织损失减少相关，并可预测短链脂肪酸和色氨酸途径的调节。结论——这些发现突出了肠道微生物群在缺血性中风短期和长期预后中的重要性，并提出与特定微生物酶促途径相关的微生物组靶向修饰可能为中风高危患者提供预防策略的可能性。可视化概述——本文提供在线可视化概述。
