法舒地尔抑制Rho激酶通过调节肠道微生物群和代谢产物改善APP/PS1转基因小鼠的认知障碍。

Inhibition of Rho Kinase by Fasudil Ameliorates Cognition Impairment in APP/PS1 Transgenic Mice via Modulation of Gut Microbiota and Metabolites.

作者信息

Yan Yuqing, Gao Ye, Fang Qingli, Zhang Nianping, Kumar Gajendra, Yan Hailong, Song Lijuan, Li Jiehui, Zhang Yuna, Sun Jingxian, Wang Jiawei, Zhao Linhu, Skaggs Keith, Zhang Han-Ting, Ma Cun-Gen

机构信息

Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Institute of Brain Science, Medical School of Shanxi Datong University, Datong, China.

The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Research Center of Neurobiology, Shanxi University of Chinese Medicine, Taiyuan, China.

出版信息

Front Aging Neurosci. 2021 Oct 14;13:755164. doi: 10.3389/fnagi.2021.755164. eCollection 2021.

DOI:10.3389/fnagi.2021.755164

PMID:34721000

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8551711/

Abstract

Fasudil, a Rho kinase inhibitor, exerts therapeutic effects in a mouse model of Alzheimer's disease (AD), a chronic neurodegenerative disease with progressive loss of memory. However, the mechanisms remain unclear. In addition, the gut microbiota and its metabolites have been implicated in AD. We examined the effect of fasudil on learning and memory using the Morris water-maze (MWM) test in APPswe/PSEN1dE9 transgenic (APP/PS1) mice (8 months old) treated (i.p.) with fasudil (25 mg/kg/day; ADF) or saline (ADNS) and in age- and gender-matched wild-type (WT) mice. Fecal metagenomics and metabolites were performed to identify novel biomarkers of AD and elucidate the mechanisms of fasudil induced beneficial effects in AD mice. The MWM test showed significant improvement of spatial memory in APP/PS1 mice treated with fasudil as compared to ADNS. The metagenomic analysis revealed the abundance of the dominant phyla in all the three groups, including (23.7-44%) and (6.4-26.6%), and the increased relative abundance ratio of / in ADNS (59.1%) compared to WT (31.7%). In contrast, the / ratio was decreased to the WT level in ADF (32.8%). Lefse analysis of metagenomics identified as an ADF potential biomarker, while and as ADNS potential biomarkers. Metabolite analysis revealed the increment of various metabolites, including glutamate, hypoxanthine, thymine, hexanoyl-CoA, and leukotriene, which were relative to ADNS or ADF microbiota potential biomarkers and mainly involved in the metabolism of nucleotide, lipids and sugars, and the inflammatory pathway. Memory deficit in APP/PS1 mice was correlated with the gut microbiome and metabolite status. Fasudil reversed the abnormal gut microbiota and subsequently regulated the related metabolisms to normal in the AD mice. It is believed that fasudil can be a novel strategy for the treatment of AD via remodeling of the gut microbiota and metabolites. The novel results also provide valuable references for the use of gut microbiota and metabolites as diagnostic biomarkers and/or therapeutic targets in clinical studies of AD.

摘要

法舒地尔是一种Rho激酶抑制剂，在阿尔茨海默病（AD）小鼠模型中具有治疗作用，AD是一种慢性神经退行性疾病，会导致记忆力逐渐丧失。然而，其作用机制尚不清楚。此外，肠道微生物群及其代谢产物与AD有关。我们使用莫里斯水迷宫（MWM）试验，检测了法舒地尔对经腹腔注射法舒地尔（25 mg/kg/天；ADF）或生理盐水（ADNS）处理的8月龄APPswe/PSEN1dE9转基因（APP/PS1）小鼠以及年龄和性别匹配的野生型（WT）小鼠学习和记忆的影响。进行粪便宏基因组学和代谢产物分析，以确定AD的新型生物标志物，并阐明法舒地尔在AD小鼠中产生有益作用的机制。MWM试验表明，与ADNS相比，经法舒地尔处理的APP/PS1小鼠的空间记忆有显著改善。宏基因组分析揭示了所有三组中优势菌门的丰度，包括厚壁菌门（23.7 - 44%）和拟杆菌门（6.4 - 26.6%），与WT（厚壁菌门/拟杆菌门比例为31.7%）相比，ADNS组中厚壁菌门/拟杆菌门的相对丰度增加（59.1%）。相比之下，ADF组中厚壁菌门/拟杆菌门比例降至WT水平（32.8%）。宏基因组的Lefse分析确定双歧杆菌属为ADF潜在生物标志物，而梭菌属和脱硫弧菌属为ADNS潜在生物标志物。代谢产物分析显示，包括谷氨酸、次黄嘌呤、胸腺嘧啶、己酰辅酶A和白三烯在内的多种代谢产物增加，这些代谢产物与ADNS或ADF微生物群潜在生物标志物相关，主要参与核苷酸、脂质和糖类代谢以及炎症途径。APP/PS1小鼠的记忆缺陷与肠道微生物群和代谢产物状态相关。法舒地尔逆转了AD小鼠肠道微生物群的异常，并随后将相关代谢调节至正常。据信，法舒地尔可通过重塑肠道微生物群和代谢产物成为治疗AD的新策略。这些新结果也为在AD临床研究中使用肠道微生物群和代谢产物作为诊断生物标志物和/或治疗靶点提供了有价值的数据参考。