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益生菌干预慢性社会挫败应激抑郁小鼠的研究
Alternative TitleThe effect of probiotic on depressed mice subjected to chronic social defeat stress
胡前英
Contributor赵 媚
2021-06
Abstract抑郁症是一种以持久心境低落、兴趣降低和快感缺乏为核心症状的复杂精神疾病。解析肠道微生物与抑郁症之间的关系为利用益生菌辅助治疗抑郁症提供理论基础。益生菌可通过脑-肠轴对抑郁症发挥积极的干预作用,但其中的分子机制并不清楚,且由于临床研究的局限性,故本研究选用慢性社会挫败应激小鼠抑郁症模型作为研究对象,用益生菌对其进行干预,从行为学测定、肠道菌群以及炎症系统三方面解析益生菌对抑郁小鼠行为表型和生理功能的影响机制。 益生菌资源是本研究的基础,通过分离、纯化和鉴定,本研究共计获得分属于5个不同属和9个不同种的益生菌,其中分离获得的一株植物乳酸杆菌生长状态优势明显,且已有相关报道关于其与抑郁症相关精神疾病具有辅助治疗作用,因此我们在后续研究中选其作为干预实验的益生菌株。 为模拟当下社会压力应激引起人们 的各种抑郁症状本研究选用慢性社会挫败应激小鼠抑郁症模型作为干预对象 。通过慢性社会挫败应激抑郁症模型 造模后,利用相关行为学测试评估小鼠的行为学变化,结果表明应 激后的小鼠与对照组小鼠相比,表现出显著的社会交往回避行为 ,以及社会交往兴趣显著下降 ,并表现出显著的绝望行为 ,说明造模成功。 使用该小鼠抑郁症 模型,采取构建抑郁症模型与干预同时进行的方案,探讨植物乳酸杆菌 对慢性社会挫败应激抑郁小鼠的干预作用及其机制。结果表明,灌胃植物乳酸杆菌进行干预能显著改善慢性社会挫败应激后抑郁小鼠的行为表型,抑郁小鼠的社会交往回避行为下降, 社会交往兴趣 显著提高,并且抑郁小鼠的绝望行为有显著的改善。 为探讨植物乳酸杆菌 能够缓解抑郁小鼠行为表型的原因,我们从肠道菌群以及炎症系统两个方面进行探索。通过对小鼠粪便宏基因组进行测序和相关生物信息学分析,结果表明与对照组相比,慢性社会挫败应激能造成抑郁小鼠肠道菌群发生显著的改变 ,包括抑郁小鼠肠道菌群多样性增加,组内多样性减少,主要菌群组成结构发生变化,其中6个属分类水平上菌属以及 10个种分类水平上菌株发生显著的改变而植物乳酸杆菌干预能一定程度上恢复这些由慢性社会挫败应激所导致的菌群紊乱提示我们植物乳酸杆菌的干预可通过调节肠道微生态衡来缓解抑郁小鼠的相关抑郁样行为表型。并通过 RT-qPCR测定相关炎症因子的表达水平变化发现,植物乳酸杆菌能显著降低由慢性社会挫败应激所引起抑郁小鼠炎症因子IL-1β、IL-2以及 TNF-α的高表达水平 。 通过上述益生菌的分离鉴定以及植物乳酸杆菌干预慢性社会挫败应激小鼠抑郁症模型的研究,从行为表型到肠道菌群以及炎症系统的关联性研究, 揭示植物乳酸杆菌对于抑郁症治疗的可能机制 ,为进一步推广利用益生菌辅助治疗抑郁症等精神疾病奠定理论基础, 同时也初步窥探益生菌是如何影响抑郁状态下肠道微生态环境和炎症系统 ,为脑-肠轴与精神疾病相关研究提供实例。
Other AbstractDepression is a complex mental disorder with persistent depression, decreased in-terest, and anhedonia as the main core symptoms. Demonstrating the relationship be-tween intestinal microbiota and depression provides a theoretical basis for the use of probiotics to assist in the treatment of depression. Probiotics can play a positive role in the therapy of depression through the brain-gut axis, but the molecular mechanism re-mains unclear. Due to the limitations of clinical research, this study selects a chronic social defeat stress mice depression model as the study subject with treatment of probi-otic, analyzing the mechanism of probiotics' influence on the behavioral phenotype and physiological function of depressed mice from three aspects: behavioral measurement, intestinal microbiota and inflammatory system. Probiotic resource is the basis of this research. Through separation, purification and identification from probiotic powder, a total of 5 different genera and 9 different species are obtained as probiotics. Among them, a strain named Lactobacillus planta-rum has obvious advantages in growth status, and there are related reports about its adjuvant therapeutic effect on depression-related mental illness, so we selected it as a probiotic strain for intervention experiments in follow-up studies. In order to simulate the various depressive symptoms of people caused by social stress, this study selected the chronic social defeat mice depression model as the inter-vention subject. After the chronic social defeat stress model was established, the behav-ioral phenotype of the mice was evaluated using relevant behavioral tests. The results showed that the mice subjected to the social defeat stress showed significant social avoidance behaviors and significant desperate behavior, meanwhile, those stressed mice strikingly decreased social interest compared with the control mice indicating that the construction of depression model was successful. Then we adopted a plan of constructing the chronic social defeat mice depression model and conducting treatment of probiotic at the same time, to explore the interven-tion effect of Lactobacillus plantarum on depression and its mechanism. The results showed that the intervention by gavage of Lactobacillus plantarum could significantly improve the behavioral phenotype of depression-like mice. The social avoidance be-havior of depressed mice decreased, and their social interest was significantly increased. In addition, desperate behavior of depressed mice improved significantly owing to the treatment of probiotic. In order to explore the reasons why Lactobacillus plantarum could alleviate the behavioral phenotypes of depressed mice, we explored the intestinal microbiota and the inflammatory system. Through sequencing mouse fecal metagenomics and operating bioinformatics analysis, we found that compared with the control group, chronic social defeat stress could cause significant changes in the gut microbiota of depressed mice, including the diversity of intestinal flora increased, the diversity within the group de-creased, and the composition of the main microbiome changed. Thoes changes in bac-terial genera included 6 genera and 10 species.The treatment of Lactobacillus planta-rum could restore these bacteria imbalance caused by chronic social defeat to a certain extent, which implied that the intervention of Lactobacillus plantarum could alleviate the behavioral phenotypes of depressed mice by adjusting the intestinal ecosystem. The changes in the expression levels of related inflammatory cytokine were measured by RT-qPCR. The results found that Lactobacillus plantarum could significantly reduce the expression of highly activated inflammatory cytokine IL-1β, IL-2 and TNF-α in depressed mice indicating that Lactobacillus plantarum could alleviate the related phe notype of depressed mice by reducing inflammation activation. Overall, we applied Lactobacillus plantarum to chronic social defeat stress mice depression model after the isolation and identification of the above-mentioned probiot-ics. We conducted the investigation among the behavioral phenotype, intestinal micro-biota and the inflammatory system in depressed mice. It revealed that Lactobacillus plantarum had a favorable effect on depression. The possible mechanism of treatment lays a theoretical foundation for the further promotion of the use of probiotics to assist in the treatment of depression and other mental illnesses. At the same time, this study also initially explores how probiotics affect the gut ecosystem and inflammation system, providing a case of the field of brain-gut axis study involving mental disorder.
Keyword抑郁症 益生菌 肠道菌 炎症 因子
Subtype硕士
Language中文
Degree Name理学硕士
Degree Discipline健康心理学
Degree Grantor中国科学院心理研究所
Place of Conferral中国科学院心理研究所
Document Type学位论文
Identifierhttp://ir.psych.ac.cn/handle/311026/39561
Collection健康与遗传心理学研究室
Recommended Citation
GB/T 7714
胡前英. 益生菌干预慢性社会挫败应激抑郁小鼠的研究[D]. 中国科学院心理研究所. 中国科学院心理研究所,2021.
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