Xinglou Chengqi Decoction improves neurological function in experimental stroke mice as evidenced by gut microbiota analysis and network pharmacology
Xinglou Chengqi Decoction improves neurological function in experimental stroke mice as evidenced by gut microbiota analysis and network pharmacology
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肠道菌群分析和网络药理学证明星蒌承气汤可改善实验性中风小鼠的神经功能
DOI：
10.1016/s1875-5364(21)60079-1
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发表时间：
2021-12-24
影响因子：
4.6
通讯作者：
Ma Da-Yong
中科院分区：
文献类型：
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作者：
Gao Qiang;Han Zhen-Yun;Ma Da-Yong
本研究旨在基于肠道菌群分析和网络药理学，探讨醒楼承气汤（XCD）的脑保护机制。建立小鼠短暂性大脑中动脉闭塞（MCAO）模型，进行行为学评价、TTC和TUNEL染色。此外，为了研究肠道微生物群对中风后神经功能的影响，C57BL/6小鼠在缺血性中风（IS）前14天接受抗生素鸡尾酒治疗，以消耗肠道微生物群。采用高通量16S rDNA基因测序、代谢组学技术和流动多因子技术分别分析细菌群落、SCFAs和炎症因子。最后，作为补充，运用网络药理学和分子对接等手段，全面探索XCD治疗IS的多组分、多靶点、多通道机制，涉及ADME筛选、靶点鉴定、网络分析、功能注释、途径富集分析等。我们发现XCD能有效改善神经功能，缓解脑梗死，减少神经元凋亡。此外，XCD促进IL-10等抗炎因子的释放，下调tnf - α、IL-17A、IL-22等促炎因子。此外，XCD显著提高了短链脂肪酸（SCFAs）水平，尤其是丁酸。这种机制可能与产生scfa的细菌（如Verrucomicrobia和Akkermansia）以及调节炎症的细菌（如Paraprevotella、Roseburia、Streptophyta和Enterococcu）的调节有关。最后，在网络药理分析中，筛选出XCD中的51个活性化合物和44个IS与XCD的交叉靶点。作为验证，XCD中的组件与关键目标很好地对接。显然，生物过程主要参与调控氧化石墨烯富集过程中的凋亡过程、炎症反应、脂肪酸反应、内皮屏障的建立等。XCD可以改善实验性中风小鼠的神经功能，部分原因是对肠道微生物群的调节。同时，网络药理学和分子对接揭示出XCD治疗IS具有“多组分、多靶点、多通道”的特点。
The current study was designed to explore the brain protection mechanism of Xinglou Chengqi Decoction (XCD) based on gut microbiota analysis and network pharmacology. A transient middle cerebral artery occlusion (MCAO) model of mice was established, followed by behavioral evaluation, TTC and TUNEL staining. Additionally, to investigate the effects of gut microbiota on neurological function after stroke, C57BL/6 mice were treated with anti-biotic cocktails 14 days prior to ischemic stroke (IS) to deplete the gut microbiota. High-throughput 16S rDNA gene sequencing, metabonomics technique, and flow multifactor technology were used to analyze bacterial communities, SCFAs and inflammatory cytokines respectively. Finally, as a supplement, network pharmacology and molecular docking were applied to fully explore the multicomponent-multitarget-multichannel mechanism of XCD in treating IS, implicated in ADME screening, target identification, network analysis, functional annotation, and pathway enrichment analysis. We found that XCD effectively improved neurological function, relieved cerebral infarction and decreased the neuronal apoptosis. Moreover, XCD promoted the release of anti-inflammatory factor like IL-10, while down-regulating pro-inflammatory factors such as TNF-alpha, IL-17A, and IL-22. Furthermore, XCD significantly increased the levels of short chain fatty acids (SCFAs), especially butyric acid. The mechanism might be related to the regulation of SCFAs-producing bacteria like Verrucomicrobia and Akkermansia, and bacteria that regulate inflammation like Paraprevotella, Roseburia, Streptophyta and Enterococcu. Finally, in the network pharmacological analysis, 51 active compounds in XCD and 44 intersection targets of IS and XCD were selected. As a validation, components in XCD docked well with key targets. It was obviously that biological processes were mainly involved in the regulation of apoptotic process, inflammatory response, response to fatty acid, and regulation of establishment of endothelial barrier in GO enrichment. XCD can improve neurological function in experimental stroke mice, partly due to the regulation of gut microbiota. Besises, XCD has the characteristic of "multi-component, multi-target and multi-channel" in the treatment of IS revealed by network pharmacology and molecular docking.