The gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Shifts in intestinal microbiota composition affect a variety of systems; however, evidence of their direct impact on cognitive functions is still lacking. We tested whether faecal microbiota transplant (FMT) from aged donor mice into young adult recipients altered the hippocampus, an area of the central nervous system (CNS) known to be affected by the ageing process and related functions. Young adult mice were transplanted with the microbiota from either aged or age-matched donor mice. Following transplantation, characterization of the microbiotas and metabolomics profiles along with a battery of cognitive and behavioural tests were performed. Label-free quantitative proteomics was employed to monitor protein expression in the hippocampus of the recipients. We report that FMT from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour and locomotor activity remained unaffected. This was paralleled by altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus. Also, a strong reduction of bacteria associated with short-chain fatty acids (SCFAs) production (Lachnospiraceae, Faecalibaculum, and Ruminococcaceae) and disorders of the CNS (Prevotellaceae and Ruminococcaceae) was observed. Finally, the detrimental effect of FMT from aged donors on the CNS was confirmed by the observation that microglia cells of the hippocampus fimbria, acquired an ageing-like phenotype; on the contrary, gut permeability and levels of systemic and local (hippocampus) cytokines were not affected. These results demonstrate that age-associated shifts of the microbiota have an impact on protein expression and key functions of the CNS. Furthermore, these results highlight the paramount importance of the gut-brain axis in ageing and provide a strong rationale to devise therapies aiming to restore a young-like microbiota to improve cognitive functions and the declining quality of life in the elderly.

中文翻译：

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来自老年供体小鼠的粪便微生物群移植通过调节年轻受体的海马突触可塑性和神经传递相关蛋白来影响空间学习和记忆

肠脑轴和肠道微生物群正在成为健康和疾病的关键参与者。肠道微生物群组成的变化会影响多种系统；然而，仍然缺乏它们对认知功能的直接影响的证据。我们测试了从老年供体小鼠到年轻成年受体的粪便微生物群移植 (FMT) 是否改变了海马体，海马体是已知受衰老过程和相关功能影响的中枢神经系统 (CNS) 区域。年轻的成年小鼠被移植了来自老年或年龄匹配的供体小鼠的微生物群。移植后，进行了微生物群和代谢组学特征的表征以及一系列认知和行为测试。无标记定量蛋白质组学用于监测受体海马中的蛋白质表达。我们报告说，来自老年捐赠者的 FMT 导致年轻成年受者的空间学习和记忆受损，而焦虑、探索行为和运动活动不受影响。这与海马中涉及突触可塑性和神经传递的蛋白质的表达改变平行。此外，观察到与短链脂肪酸 (SCFAs) 产生（毛螺菌科、粪杆菌科和瘤胃球菌科）和中枢神经系统疾病（普雷沃菌科和瘤胃球菌科）相关的细菌大量减少。最后，观察到海马菌毛的小胶质细胞获得了类似衰老的表型，证实了来自老年供体的 FMT 对 CNS 的有害影响；相反，肠道通透性以及全身和局部（海马）细胞因子的水平没有受到影响。这些结果表明，与年龄相关的微生物群变化对中枢神经系统的蛋白质表达和关键功能有影响。此外，这些结果强调了肠-脑轴在衰老中的重要性，并为设计旨在恢复类似年轻人的微生物群以改善认知功能和老年人生活质量下降的疗法提供了强有力的理论依据。