Zheng Mingxuan, Ye Huaiyu, Yang Xiaoying, Shen Lijun, Dang Xuemei, Liu Xiaoli, Gong Yuying, Wu Qingyuan, Wang Li, Ge Xing, Fang Xiaoli, Hou Benchi, Zhang Peng, Tang Renxian, Zheng Kuiyang, Huang Xu-Feng, Yu Yinghua
Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110033, China.
Brain Behav Immun. 2024 Jan;115:565-587. doi: 10.1016/j.bbi.2023.11.016. Epub 2023 Nov 17.
Obesity is a risk factor for cognitive dysfunction and neurodegenerative disease, including Alzheimer's disease (AD). The gut microbiota-brain axis is altered in obesity and linked to cognitive impairment and neurodegenerative disorders. Here, we targeted obesity-induced cognitive impairment by testing the impact of the probiotic Clostridium butyricum, which has previously shown beneficial effects on gut homeostasis and brain function. Firstly, we characterized and analyzed the gut microbial profiles of participants with obesity and the correlation between gut microbiota and cognitive scores. Then, using an obese mouse model induced by a Western-style diet (high-fat and fiber-deficient diet), the effects of Clostridium butyricum on the microbiota-gut-brain axis and hippocampal cognitive function were evaluated. Finally, fecal microbiota transplantation was performed to assess the functional link between Clostridium butyricum remodeling gut microbiota and hippocampal synaptic protein and cognitive behaviors. Our results showed that participants with obesity had gut microbiota dysbiosis characterized by an increase in phylum Proteobacteria and a decrease in Clostridium butyricum, which were closely associated with cognitive decline. In diet-induced obese mice, oral Clostridium butyricum supplementation significantly alleviated cognitive impairment, attenuated the deficit of hippocampal neurite outgrowth and synaptic ultrastructure, improved hippocampal transcriptome related to synapses and dendrites; a comparison of the effects of Clostridium butyricum in mice against human AD datasets revealed that many of the genes changes in AD were reversed by Clostridium butyricum; concurrently, Clostridium butyricum also prevented gut microbiota dysbiosis, colonic barrier impairment and inflammation, and attenuated endotoxemia. Importantly, fecal microbiota transplantation from donor-obese mice with Clostridium butyricum supplementation facilitated cognitive variables and colonic integrity compared with from donor obese mice, highlighting that Clostridium butyricum's impact on cognitive function is largely due to its ability to remodel gut microbiota. Our findings provide the first insights into the neuroprotective effects of Clostridium butyricum on obesity-associated cognitive impairments and neurodegeneration via the gut microbiota-gut-brain axis.
肥胖是认知功能障碍和神经退行性疾病（包括阿尔茨海默病（AD））的一个风险因素。肥胖会改变肠道微生物群-脑轴，并与认知障碍和神经退行性疾病有关。在此，我们通过测试丁酸梭菌益生菌的影响来针对肥胖诱导的认知障碍，该益生菌先前已显示出对肠道稳态和脑功能具有有益作用。首先，我们对肥胖参与者的肠道微生物谱进行了表征和分析，并分析了肠道微生物群与认知分数之间的相关性。然后，使用西式饮食（高脂肪和低纤维饮食）诱导的肥胖小鼠模型，评估了丁酸梭菌对微生物群-肠道-脑轴和海马认知功能的影响。最后，进行粪便微生物群移植以评估丁酸梭菌重塑肠道微生物群与海马突触蛋白和认知行为之间的功能联系。我们的结果表明，肥胖参与者存在肠道微生物群失调，其特征是变形菌门增加，丁酸梭菌减少，这与认知能力下降密切相关。在饮食诱导的肥胖小鼠中，口服补充丁酸梭菌可显著减轻认知障碍，减轻海马神经突生长和突触超微结构的缺陷，改善与突触和树突相关的海马转录组；将小鼠中丁酸梭菌的作用与人类AD数据集进行比较发现，AD中许多基因变化被丁酸梭菌逆转；同时，丁酸梭菌还可预防肠道微生物群失调、结肠屏障损伤和炎症，并减轻内毒素血症。重要的是，与来自供体肥胖小鼠的粪便微生物群移植相比，来自补充丁酸梭菌的供体肥胖小鼠的粪便微生物群移植促进了认知变量和结肠完整性，突出表明丁酸梭菌对认知功能的影响很大程度上归因于其重塑肠道微生物群的能力。我们的研究结果首次揭示了丁酸梭菌通过肠道微生物群-肠道-脑轴对肥胖相关认知障碍和神经退行性变的神经保护作用。
