An Aged Gut Microbiome Impairs Hippocampal Function via the Vagus Nerve

The gut microbiome changes with age, in part because the immune system falters in its task of removing harmful microbes. Microbial populations responsible for producing beneficial metabolites decline in number, while populations that provoke chronic inflammation and other harms grow in number. Researchers are only just beginning to catalog the long list of harmful outcomes produced by an aged gut microbiome. The open access paper here is an example of this research, using mice to demonstrate a connection between the gut microbiome and hippocampal function in the brain, essential to memory.

Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment remain yet highly debated. Here we showed that fecal microbiota transplantation (FMT) from aged, but not young, animal donors in young mice is sufficient to trigger profound hippocampal alterations including astrogliosis, decreased adult neurogenesis, decreased novelty-induced neuronal activation and impairment in hippocampus-dependent memory. Furthermore, similar alterations were reported when mice were subjected to an FMT from aged human donors.

To decipher the mechanisms involved in mediating these microbiota-induced effects on brain function, we mapped the vagus nerve (VN)-related neuronal activity patterns and report that aged-mice FM transplanted animals showed a reduction in neuronal activity in the ascending VN output brain structure, whether under basal condition or after VN stimulation. Targeted pharmacogenetic manipulation of VN-ascending neurons demonstrated that the decrease in vagal activity is detrimental to hippocampal functions. In contrast, increasing vagal ascending activity alleviated the adverse effects of aged mice FMT on hippocampal functions, and had a detrimental effect on memory in aged mice. Thus, pharmacogenetic VN stimulation is a potential therapeutic strategy to lessen microbiota-dependent age-associated impairments in hippocampal functions.


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