Abstract
BackgroundThe 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.ResultsYoung 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.ConclusionThese 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.-tKeEZTwJymg7KW46YXcRKVideo
Highlights
The gut-brain axis and the intestinal microbiota are emerging as key players in health and disease
We report that faecal microbiota transplant (FMT) from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour and locomotor activity remained unaffected
We report that FMT from aged mice led to a decline of spatial learning and memory in young adult recipients via modulation of synaptic plasticity- and neurotransmission-related proteins in the hippocampus, an area of the central nervous system (CNS) known to be heavily affected by the ageing process [17]
Summary
The gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Germ-free (GF) mice are less responsive to exposure of environmental stressors compared to conventionally reared mice, with conventionalization of GF animals impacting significantly on brain development [6] This observation, along with a growing body of evidence, has shown that the gut microbiota plays a major role in in the development and function of the CNS, affecting learning and memory via metabolic, neuroendocrine and immune pathways [7]. The impact of age-associated shifts of microbiota on the CNS was further confirmed by the observation that microglia cells of the hippocampus fimbria of adult mice acquired an ageing-like phenotype after FMT from aged donors These changes occurred in the absence of an overt increase of both plasma and hippocampal levels of inflammatory cytokines and intestinal permeability
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