Fecal Microbiota Transplantation from Old Mice to Young Mice Impairs Cognitive Function

The microbiome of the gut changes with age, and this is presently thought to have a meaningful influence over the course of aging. It is perhaps in the same ballpark as the effects of exercise on the pace of aging and risk of age-related disease, and certainly overlaps with the effects of diet, particularly that of calorie restriction.

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In general, aging is accompanied by a reduction in beneficial microbial species that produce metabolites known to improve cell and tissue function, such as butyrate, propionate, and indoles. Equally, harmful inflammatory microbial species grow in numbers, and contribute to the chronic inflammation that characterizes aging, disrupting tissue maintenance and accelerating the progression towards age-related disease.

Today's open access paper is a representative example of a broad range of present work that attempts to quantify the degree to which age-related changes in the gut microbiome are harmful. There are two ways to go about this, involving fecal microbiota transplantation from either (a) old to young animals and looking for harms, or (b) from young to old animals and looking for benefits. The former is the case here, and researchers quite credibly show that an old microbiome impairs cognitive function in young mice.

What is to be done about the aging of the gut microbiome? The most plausible path forward is to adapt the existing use of fecal microbiota transplantation in human medicine in order to transplant material from young donors into older individuals. In medical conditions in which the intestine is overtaken by harmful pathogens, this treatment can be a lasting cure: the balance of species in the gut is permanently changed in these cases. Lasting reversal of the impaired state of an old microbiome also appears possible via transplantation from a young individual, based on work conducted in short-lived species such as killifish. It is a promising approach, but is not at present receiving the level of interest required for clinical development to move ahead.

Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients

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.

Source: Fight Aging!