Fecal microbiota transplantation and short-chain fatty acids protected against cognitive dysfunction in a rat model of chronic cerebral hypoperfusion.
Fecal microbiota transplantation and short-chain fatty acids protected against cognitive dysfunction in a rat model of chronic cerebral hypoperfusion.
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DOI：
10.1111/cns.14089
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发表时间：
2023-06
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
在解释肠道微生物生态失调和微生物代谢物短链脂肪酸（SCFAs）在慢性脑缺血发病机制中的明确作用和机制尚未探索。在这项研究中，我们研究了慢性脑灌注不足（CCH）诱导的肠道微生物群和SCFAs的代谢谱，以及粪便微生物群移植（FMT）和SCFAs治疗对CCH诱导的海马神经元损伤的影响和机制。采用双侧颈总动脉闭塞（BCCAo）建立CCH模型。采用16S核糖体RNA测序和气相色谱-质谱联用技术评估小鼠粪便和海马的肠道微生物群和SCFAs谱。对海马组织进行RNA测序分析。通过免疫印迹、免疫沉淀、免疫荧光和酶联免疫吸附试验验证了潜在的分子通路和差异基因。通过Morris水迷宫测试评估认知功能。透射电镜观察线粒体和突触的超微结构。慢性脑灌流不足导致粪便乙酸和丙酸减少，海马乙酸减少，FMT和SCFAs通过改变粪便微生物群落结构和组成而逆转。此外，在海马中，FMT和SCFAs的补充通过抑制小胶质细胞和星形胶质细胞的激活以及将小胶质细胞表型从M1转换为M2来发挥抗神经炎症作用。此外，FMT和SCFAs治疗减轻了神经元丢失和小胶质细胞介导的突触丢失，维持了突触囊泡融合和释放的正常过程，从而提高了突触的可塑性。此外，FMT和SCFAs的补充通过线粒体代谢重编程阻止了氧化磷酸化功能障碍。FMT和SCFAs治疗的上述作用导致CCH诱导的认知障碍受到抑制。我们的研究结果强调，FMT和SCFAs补充将是一种可行的肠道微生物群策略，以减轻慢性脑缺血诱导的神经元损伤。粪便微生物群移植（FMT）和短链脂肪酸（SCFAs）补充通过将小胶质细胞表型从M1转换为M2发挥抗神经炎症作用。此外，FMT和SCFAs治疗减轻了神经元丢失和小胶质细胞介导的突触丢失，维持了突触囊泡融合和释放的正常过程，从而提高了突触的可塑性。此外，FMT和SCFAs的补充通过线粒体代谢重编程阻止了氧化磷酸化功能障碍。
Clear roles and mechanisms in explaining gut microbial dysbiosis and microbial metabolites short‐chain fatty acids (SCFAs) alterations in chronic cerebral ischemic pathogenesis have yet to be explored. In this study, we investigated chronic cerebral hypoperfusion (CCH)‐induced gut microbiota and metabolic profiles of SCFAs as well as the effects and mechanisms of fecal microbiota transplantation (FMT) and SCFAs treatment on CCH‐induced hippocampal neuronal injury. Bilateral common carotid artery occlusion (BCCAo) was used to establish the CCH model. Gut microbiota and SCFAs profiles in feces and hippocampus were evaluated by 16S ribosomal RNA sequencing and gas chromatography–mass spectrometry. RNA sequencing analysis was performed in hippocampal tissues. The potential molecular pathways and differential genes were verified through western blot, immunoprecipitation, immunofluorescence, and ELISA. Cognitive function was assessed via the Morris water maze test. Ultrastructures of mitochondria and synapses were tested through a transmission electron microscope. Chronic cerebral hypoperfusion induced decreased fecal acetic and propionic acid and reduced hippocampal acetic acid, which were reversed after FMT and SCFAs administration by changing fecal microbial community structure and compositions. Furthermore, in the hippocampus, FMT and SCFAs replenishment exerted anti‐neuroinflammatory effects through inhibiting microglial and astrocytic activation as well as switching microglial phenotype from M1 toward M2. Moreover, FMT and SCFAs treatment alleviated neuronal loss and microglia‐mediated synaptic loss and maintained the normal process of synaptic vesicle fusion and release, resulting in the improvement of synaptic plasticity. In addition, FMT and SCFAs supplement prevented oxidative phosphorylation dysfunction via mitochondrial metabolic reprogramming. The above effects of FMT and SCFAs treatment led to the inhibition of CCH‐induced cognitive impairment. Our findings highlight FMT and SCFAs replenishment would be the feasible gut microbiota‐based strategy to mitigate chronic cerebral ischemia‐induced neuronal injury. Fecal microbiota transplantation (FMT) and short‐chain fatty acids (SCFAs) replenishment exerted anti‐neuroinflammatory effects through switching microglial phenotype from M1 toward M2. Furthermore, FMT and SCFAs treatment alleviated neuronal loss and microglia‐mediated synaptic loss and maintained the normal process of synaptic vesicle fusion and release, resulting in the improvement of synaptic plasticity. In addition, FMT and SCFAs supplement prevented oxidative phosphorylation dysfunction via mitochondrial metabolic reprogramming.
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白藜芦醇预处理在脑缺血性耐受性的长期窗口内诱导基因组和代谢适应，从而导致生物能效率。
影响因子：
5.1
作者：
Khoury N;Xu J;Stegelmann SD;Jackson CW;Koronowski KB;Dave KR;Young JI;Perez-Pinzon MA
通讯作者：
Perez-Pinzon MA
影响因子：
5.2
作者：
Lee KE;Kim JK;Kim DH
通讯作者：
Kim DH
影响因子：
5.6
作者：
Chu, Yan-Biao;Li, Jun;Zhang, Shi
通讯作者：
Zhang, Shi
影响因子：
11
作者：
Boehme, Marcus;van de Wouw, Marcel;Cryan, John F.
通讯作者：
Cryan, John F.
影响因子：
5
作者：
Huang F;Liu X;Xu S;Hu S;Wang S;Shi D;Wang K;Wang Z;Lin Q;Li S;Zhao S;Jin K;Wang C;Chen L;Wang F
通讯作者：
Wang F