摘要
目的本研究旨在探讨有氧运动对衰老小鼠认知功能的影响,并阐明有氧运动通过调节肠道菌群-代谢物网络改善认知衰退的分子机制,以期为抗衰老策略及针对年龄相关认知功能障碍的个性化运动干预提供理论依据。方法以自然衰老的C57BL/6小鼠为实验模型,采用16S rRNA测序与飞行时间质谱+多反应监测(time of flight+multiple reaction monitoring,TOF+MRM,TM)广靶代谢组学技术,结合行为学评估、组织病理学检测等方法研究分析。共选取18只小鼠,分为3组:青年对照组(YC,4月龄)、老年对照组(OC,21月龄)和老年有氧运动组(OE,21月龄,接受12周中等强度跑台训练),系统性地研究了12周中等强度跑台运动对衰老小鼠肠道菌群结构、代谢产物谱及海马功能的协同调控作用。结果行为学测试显示,12周有氧运动显著改善了衰老小鼠的空间学习和记忆能力,Morris水迷宫测试中逃逸潜伏期缩短,目标区域探索和平台穿越次数增加。组织病理学分析表明,运动缓解了海马区的年龄相关神经元损伤,提高了神经元密度和形态。16S rRNA测序显示,运动增加了肠道菌群的α多样性,丰富了双歧杆菌属、副拟杆菌属和理研菌属等有益菌群。代谢组学分析鉴定了OC和OE组之间的32种差异代谢物,在OE组中94种上调,30种下调。这些代谢物主要涉及能量代谢重编程(如L-高瓜氨酸)、抗氧化防御(如L-左旋肌肽)、神经保护(如石胆酸)和DNA修复(如ADP-核糖)。网络分析进一步揭示了特定细菌和代谢物之间的强正相关性,如副拟杆菌属与ADP-核糖、双歧杆菌属与石胆酸,暗示了肠道菌群-代谢物轴介导的潜在神经保护途径。结论本研究系统性证明了有氧运动可能通过调节肠道菌群-代谢物网络,对衰老小鼠的认知功能产生积极影响。研究结果揭示了3个关键机制:a.有益肠道菌群的增殖增强了代谢重编程,从而促进了DNA修复途径;b.神经炎症抑制因子水平升高,减少了神经退行性变化;c.增强的抗氧化防御系统维持了神经元稳态。这些发现强调了“菌群-代谢物-脑”轴在介导有氧运动认知益处中的关键作用。本研究不仅加深了对衰老过程中肠-脑轴的理解,而且为开发针对年龄相关认知衰退的个性化运动和益生菌干预措施提供了科学依据。未来研究应进一步在非人灵长类动物和人类临床试验中验证这些机制,以确定运动诱导的肠道菌群-代谢物调节在对抗神经退行性疾病中的转化潜力。
Objective This study aimed to explore the effects of aerobic exercise on cognitive function in aging mice and to elucidate the underlying molecular mechanisms by which aerobic exercise ameliorates cognitive decline through the regulation of gut microbiota-metabolite network.By providing novel insights into the interplay between exercise,gut microbiota,and cognitive health,this research seeks to offer a robust theoretical foundation for developing anti-aging strategies and personalized exercise interventions targeting aging-related cognitive dysfunction.Methods Using naturally aged C57BL/6 mice as the experimental model,this study employed a multi-omics approach combining 16S rRNA sequencing and wide-targeted metabolomics analysis.A total of 18 mice were divided into 3 groups:young control(YC,4-month-old),old control(OC,21-month-old),and old+exercise(OE,21-month-old with 12 weeks of moderate-intensity treadmill training)groups.Behavioral assessments,including the Morris water maze(MWM)test,were conducted to evaluate cognitive function.Histopathological examinations of brain tissue sections provided morphological evidence of neuronal changes.Fecal samples were collected for gut microbiota and metabolite profiling via 16S rRNA sequencing and ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry(UPLC-QTOF-MS).Data were analyzed using a combination of statistical and bioinformatics tools to identify differentially abundant microbial taxa and metabolites and to construct interaction networks between them.Results Behavioral tests revealed that 12 weeks of aerobic exercise significantly improved spatial learning and memory capacity of aged mice,as evidenced by reduced escape latency and increased target area exploration and platform crossings in the MWM.Histopathological analysis demonstrated that exercise mitigated aging-related neuronal damage in the hippocampus,enhancing neuronal density and morphology.16S rRNA sequencing indicated that exercise increased gut microbiotaα-diversity and enriched beneficial bacterial genera,including Bifidobacterium,Parabacteroides,and Rikenella.Metabolomics analysis identified 32 differentially regulated metabolites between OC and OE groups,with 94 up-regulated and 30 down-regulated in the OE group when compared with OC group.These metabolites were primarily involved in energy metabolism reprogramming(e.g.,L-homocitrulline),antioxidant defense(e.g.,L-carnosine),neuroprotection(e.g.,lithocholic acid),and DNA repair(e.g.,ADP-ribose).Network analysis further revealed strong positive correlations between specific bacteria and metabolites,such as Parabacteroides with ADP-ribose and Bifidobacterium with lithocholic acid,suggesting potential neuroprotective pathways mediated by the gut microbiota-metabolite axis.Conclusion This study provides comprehensive evidence that aerobic exercise elicits cognitive benefits in aging mice by modulating the gut microbiota-metabolite network.These findings highlight three key mechanisms:(1)the proliferation of beneficial gut bacteria enhances metabolic reprogramming to boost DNA repair pathways;(2)elevated neuroinflammation-inhibiting factors reduce neurodegenerative changes;and(3)enhanced antioxidant defenses maintain neuronal homeostasis.These results underscore the critical role of the“microbiota-metabolite-brain”axis in mediating the cognitive benefits of aerobic exercise.This study not only advances our understanding of the gut-brain axis in aging but also offers a scientific basis for developing personalized exercise and probiotic-based interventions targeting aging-related cognitive decline.Future research should further validate these mechanisms in non-human primates and human clinical trials to establish the translational potential of exercise-induced gut microbiota-metabolite modulation for combating neurodegenerative diseases.
作者
王安烽
吴桐
张虎
梁计陵
陈宁
WANG An-Feng;WU Tong;ZHANG Hu;LIANG Ji-Ling;CHEN Ning(Tianjiu Research and Development Center for Exercise Nutrition and Foods,Hubei Key Laboratory of Exercise Training and Monitoring,College of Sports Medicine,Wuhan Sports University,Wuhan 430079,China;Department of Physical Education,Central South University,Changsha 410083,China)
出处
《生物化学与生物物理进展》
北大核心
2025年第6期1484-1498,共15页
Progress In Biochemistry and Biophysics
基金
国家自然科学基金(31771318)
“十四五”湖北省教育厅高等院校优势特色学科群“运动与脑科学”专项
武汉体育学院东湖领军人才启动项目资助~~
关键词
有氧运动
衰老
认知功能
肠-脑轴
多组学整合分析
aerobic exercise
aging
cognitive function
gut-brain axis
multi-omics integration analysis
作者简介
通讯联系人:陈宁,Tel:027-67846140,E-mail:nchen510@gmail.com。
