Intestinal dysbiosis causes spatial memory impairment in alcohol-exposed male mice by inducing neuroinflammation

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology Pub Date : 2024-10-28 DOI:10.1016/j.expneurol.2024.115028

Xinlei Zhang , Lulu Wang , Chen Xu , Heng Wang , An Yan , Qingmeng Zheng , Ke Wang , Xiaomeng Qiao

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Abstract

Alcohol abuse damages the brain and triggers cognitive impairment. Intestinal dysbiosis has recently been shown to be involved in psychiatric disorders, which suggests the possibility of intestine-to-brain interactions in the development of alcohol abuse. In this study, chronic intermittent alcohol exposure (CIAE) model was established in C57BL/6 male mice and the spatial memory were detected by Barnes maze (n = 16/group). The fecal microbiota and its metabolites were detected by 16S rDNA sequencing and non-target liquid chromatograph mass spectrometer (LC-MS) (n = 8/group). Effects of alcohol on intestinal barrier and blood-brain barrier (BBB) permeability were detected by Evens blue leakage assay (n = 4/group), and the activation state of microglia and TLR4 expression were conducted by immunofluorescence co-localization (n = 4/group). The morphological changes of microglia were analyzed with Image J Analyze Skeleton software, and the protein levels of TLR4 and inflammatory factors were detected by Western Blot (n = 8/group). Results indicated that alcohol alters the components of fecal microbiota and metabolites, and damages the intestinal barrier and BBB, leading to spatial memory impairment in mice. By giving mice specific prebiotics (n = 16/group), we pointed out that increased endotoxin coming from Gram negative bacteria such as lipopolysaccharides (LPS) cross the BBB to activate microglia and inflammatory pathways in the prefrontal cortical (PFC) and hippocampus (HIP), releasing inflammatory factors and resulting in neuroinflammation. Thus, the fecal microbiota seems to be a potential target in the management of alcoholic brain disease.

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肠道菌群失调通过诱发神经炎症导致酒精暴露雄性小鼠空间记忆受损

酗酒会损害大脑并引发认知障碍。最近有研究表明，肠道菌群失调与精神疾病有关，这表明在酒精滥用的发展过程中可能存在肠道与大脑之间的相互作用。本研究以C57BL/6雄性小鼠为研究对象，建立了慢性间歇性酒精暴露（CIAE）模型，并通过巴恩斯迷宫检测了小鼠的空间记忆能力（n = 16/组）。通过 16S rDNA 测序和非目标液相色谱质谱仪（LC-MS）检测粪便微生物群及其代谢物（n = 8/组）。用伊文思蓝渗漏试验检测酒精对肠道屏障和血脑屏障（BBB）通透性的影响（4人/组），用免疫荧光共定位法检测小胶质细胞的活化状态和TLR4的表达（4人/组）。用 Image J Analyze Skeleton 软件分析小胶质细胞的形态学变化，用 Western Blot 检测 TLR4 和炎症因子的蛋白水平（n = 8/组）。结果表明，酒精会改变粪便微生物群的成分和代谢产物，破坏肠道屏障和 BBB，导致小鼠空间记忆受损。通过给小鼠服用特定的益生元（n = 16/组），我们指出，来自革兰氏阴性细菌的内毒素增加，如脂多糖（LPS）穿过BBB，激活前额叶皮质（PFC）和海马（HIP）的小胶质细胞和炎症通路，释放炎症因子，导致神经炎症。因此，粪便微生物群似乎是治疗酒精性脑病的一个潜在靶点。

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来源期刊

Experimental Neurology 医学-神经科学

CiteScore

10.10

自引率

3.80%

发文量

258

审稿时长

42 days

期刊介绍： Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.