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While the gut microbiota has been implicated as an important regulator of host immunity, brain health and healthy aging, and age-related changes in the gut microbiome have been linked to cognitive decline and frailty in elderly populations (discussed in detail in The Gut Immune Connection), there is limited evidence for a causal role of the gut microbiota in brain health during the aging process, or for an understanding of the molecular mechanisms involved in it.

“…transplantation of the fecal microbiome from young animals was successful in altering the microbial community structure of the microbiome from older animals.”

In a recent study published in the prestigious journal Nature Aging by lead author Marcus Boehme from the University College Cork, Cork Ireland, the investigators did a comprehensive study in mice to determine if the gut microbiome plays a role in age-related biological, and behavioral changes, and tried to identify the underlying mechanisms. As such experiments are nearly impossible to perform in human subjects, the investigators transplanted fecal microbiota from either young (age 3–4 months) or old (age 19–20 months) donor mice into aged recipient mice (age 19–20 months). While they found clear differences between young and aged mice in the diversity of microbes before the fecal microbial transplant (FMT), they detected no differences between the number of microbial groups gained or lost between the groups following FMT. However, following FMT, the baseline differences in diversity were no longer significant, e.g. old and young gut microbiota looked the same. his “equalization” involved twenty genera which transitioned in the old mouse microbiome towards young mouse abundance following FMT, including the genus Enterococcus. These findings confirmed that the transplantation of the fecal microbiome from young animals was successful in altering the community structure of the microbiome from older animals.

“…the successful transplantation of the microbiota from young donors not only changed several gut microbiota, but it reversed aging-associated differences in peripheral and brain immunity…”

Remarkably, the successful transplantation of the microbiota from young donors not only changed several gut microbiota, but it reversed aging-associated differences in peripheral and brain immunity, as well as the expression of metabolites and signaling molecules in the hippocampus, a key brain region involved in memory, of aging recipient mice. Structural and functional changes in the hippocampus has previously been identified in human patients with Alzheimer’s disease. As previously demonstrated, aging induced significant differences in hippocampal metabolites, and 35 metabolites of such age-related molecules were restored towards pre-aged levels by FMT from young mouse donors.

Specific aspects of gut-associated, circulating and hippocampal immunity were restored following FMT from young into aged mice, suggesting that this intervention drove restorations in immune functions. Alterations in these immune functions may underlie improvements in age-associated cognitive deficits which coincided with the improvements in behavior. The authors hypothesized that FMT- induced gut microbiota-derived signaling molecules may play a role in the alteration in hippocampal physiology through indirect or direct mechanisms, as several of the metabolites they identify are able to cross the blood–brain barrier.

“…microbiota derived from young donor mice attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host.”

To identify the mechanisms underlying hippocampal changes following FMT, the authors characterized microglial cells, the brain’s resident immune cells, in the hippocampus. Microglia are essential for regulating cellular aspects of cognition, supporting neuroplasticity and responding to various signals, including inflammatory cytokines. Higher populations of activated microglia, distinguished by enlarged somas, are prominent in neuroinflammatory and neurodegenerative conditions. Aged mice showed substantial enlargement in microglia cell size, consistent with the observed metabolic and immunological changes. This morphological abnormality was reversed by FMT from young donors without other changes in microglia complexity and morphology. At a functional level, the microbiota derived from young donor mice attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host.

Based on their fascinating results, the authors concluded that the microbiome may be a potential therapeutic target to promote healthy aging, opening up a new way to the development of new anti-aging medications. At the same time, the need for future studies was emphasized to elucidate how specific gut microbes drive these changes in “rejuvenating” the aging gut brain axis.

“Many factors have been implicated to explain the “lost in translation” phenomenon…”

However, before jumping to the premature conclusion that the findings of this study may be translatable to patients suffering from Alzheimer’s disease and early cognitive decline any time soon, it is important to remember that there are many stellar preclinical scientific publications demonstrating the ability to change emotional, social and cognitive behavioral traits by transplanting fecal material into germ free mice, the majority of which have failed attempts to translate them into clinical meaningful treatments for human populations. Many factors have been implicated to explain this “lost in translation” phenomenon, including (but not limited to) the dramatic brain differences between mice and men, the much greater genetic and phenotypic heterogeneity in humans and the problem of colonization resistance of the gut microbiome, which generally does not allow transplanted gut microbes to permanently settle inside the gut microbial ecosystem of another host.

While it is possible that science will ultimately identify microbial neuroactive metabolites that will slow and possibly even reverse the aging process of the brain, at the moment, the much more realistic and evidence-based approach to achieve the same goal is with lifestyle changes, in particular by focusing on microbiome-friendly anti-inflammatory diets. Evidence for such beneficial diet-related interventions has been discussed in previous editions of the MGC blog, and is summarized in The Gut Immune Connection. While rejuvenating microbiome transplants are a fascinating idea, and the impressive scientific evidence laid out in this publication supports their feasibility, their potential usefulness remains limited to mice!