Assessing Rejuvenation in Mice Produced by Fecal Microbiota Transplantation

Today's open access paper reports on an effort to measure the effects of microbial rejuvenation on tissue function in mice. Fecal microbiota transplantation can reverse the aging of the gut microbiome, at least when carried out in animal studies, and as measured by the detrimental shift in microbial populations that takes place with age. Transplanting microbes from a young gut into an old gut reverses many of the alterations in relative abundance of specific microbial species, and has been shown to improve health and extend life span in some species.

In an old mouse, or human, there are fewer microbes producing beneficial metabolites, and more inflammatory microbes that provoke the immune system. This contributes to declining tissue function and increased chronic inflammation. Interestingly, this shift may be largely due to the aging of the immune system, and a progressive failure to sufficiently garden the gut microbiome, but there may be other contributing causes as well. How large an effect on function is produced by the aging of the gut microbiome versus other issues in aging? The fastest way to answer that question is to restore a youthful gut microbiome and assess the results.

Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain

Altered intestinal microbiota composition in later life is associated with inflammaging, declining tissue function, and increased susceptibility to age-associated chronic diseases, including neurodegenerative dementias. Here, we tested the hypothesis that manipulating the intestinal microbiota influences the development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina.

Using fecal microbiota transplantation (FMT), we exchanged the intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice. Whole metagenomic shotgun sequencing and metabolomics were used to develop a custom analysis workflow, to analyze the changes in gut microbiota composition and metabolic potential. Effects of age and microbiota transfer on the gut barrier, retina, and brain were assessed using protein assays, immunohistology, and behavioral testing.

We show that microbiota composition profiles and key species enriched in young or aged mice are successfully transferred by FMT between young and aged mice and that FMT modulates resulting metabolic pathway profiles. The transfer of aged donor microbiota into young mice accelerates age-associated central nervous system (CNS) inflammation, retinal inflammation, and cytokine signaling and promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability. Conversely, these detrimental effects can be reversed by the transfer of young donor microbiota.

These findings demonstrate that the aging gut microbiota drives detrimental changes in the gut-brain and gut-retina axes suggesting that microbial modulation may be of therapeutic benefit in preventing inflammation-related tissue decline in later life.