Microbiome Depletion in Aged Mice Reverses Aspects of the Aging of the Brain
The composition of the gut microbiome changes with age. Microbial species capable of provoking inflammation, by infiltrating tissues or via production of harmful metabolites, grow in number. This occurs at the expense of populations that produce beneficial metabolites, such as butyrate, known to promote function in a number of different tissues. The reasons for this shift of composition are not fully understood, especially since meaningful change starts to occur relatively early in adult life. Immune dysfunction likely plays a significant role, however, as the immune system is responsible for gardening the gut microbiome, keeping harmful species to a minimum.
Rejuvenation of the aged gut microbiome via fecal microbiota transplantation from a young donor has been shown to improve health and extend life in animal studies. To what degree are these benefits a restoration of youthful microbial metabolite production versus a removal of inflammatory species, however? Today's open access paper provides evidence to suggest that it is mostly a matter of reducing the production of harmful metabolites. The researchers did not rejuvenate the aged microbiome in old mice, but instead used high dose antibiotic treatment to greatly reduce all microbial populations in the gut. This allowed the assessment of health and physiology in an environment in which the production of harmful microbial metabolites was also greatly reduced.
The result reported in the paper is a significant improvement in aspects of brain health. Removing the gut microbiome in this way is not a viable approach to therapy for the population at large, but the results reported here suggest that benefits will arise from any approach that successfully reverses the increase in numbers of harmful microbes that is characteristic of the aged gut microbiome. Restoring the youthful population sizes of helpful microbes is good, but likely less important to the benefits demonstrated in animal studies of gut microbiome rejuvenation via fecal microbiota transplantation.
Microbiome depletion rejuvenates the aging brain
Aging is associated with cognitive decline and increased vulnerability to neurodegeneration driven by an array of molecular and cellular changes like impaired vascular integrity, demyelination, reduced neurogenesis, and chronic inflammation. Recent studies implicate the gut microbiome as a modulator of brain aging, but the underlying mechanisms remain elusive. Here, we show that depleting the gut microbiome by administering antibiotics to aged mice induces widespread molecular and structural rejuvenation in the brain.
Our transcriptomic analyses by single-nucleus RNA sequencing revealed pronounced transcriptional shifts across multiple brain cell types. We confirmed that antibiotic treatment improves vascular density, promotes myelination, enhances neurogenesis, and reduces microglial reactivity. Functionally, microbiome-depleted mice showed improved hippocampal memory performance. Analyses of brain and plasma cytokine levels showed a decrease in several pro-inflammatory factors post-treatment and identified candidate factors, including the chemokine eotaxin-1. Inhibiting eotaxin-1 alone can reverse several aspects of brain aging.
Our findings demonstrate that age-associated microbial inflammation contributes to brain aging and that its attenuation can restore youthful features at the molecular, cellular, and functional levels. Targeting the gut microbiome or its circulating mediators may therefore represent a non-invasive approach to promote brain health and cognitive resilience in aging.