Can Fecal Transplant Reverse Signs of Brain Aging?

Transplanting fecal microbiota may reverse age-related declines in immunity, behavior, and cognition, a new animal study suggests.

After investigators conducted fecal microbiota transplantation (FMT) from young donor mice into aged recipient mice, they found that the gut microbiomes of the elderly mice began to resemble those of the younger ones. In addition, the hippocampi of the elderly mice became more physically and chemically similar to that of the young mice.

After FMT, the elderly mice also performed more proficiently on tasks such as mazes and were better able to remember the maze layout on subsequent attempts.

"Our results reveal that the microbiome may be a suitable therapeutic target to promote healthy aging," co-investigator Timothy Dinan, MD, PhD, professor of psychiatry and principal investigator at the APC Microbiome Institute, University College Cork, Ireland, told Medscape Medical News.

They also show that "fecal transplantation from a young to an old animal has a rejuvenating impact," Dinan added.

The findings were published online August 9 in Nature Aging.

Restored Immune Cells

"Studies in humans and other animals have shown a relationship between the cognitive decline associated with aging and changes in the gut microbiota," Dinan noted.

However, "to date, studies have found an association but provided little evidence to indicate that the gut microbiota is involved in regulating cognitive function," he said.

The gut microbiota is a "key regulator of host immunity, especially in aging," the authors write. They add that the immune system "influences hippocampal-associated cognitive behavior." The immune system thus may be an "important link between alterations in the gut microbiota and potential effects on the brain in aging."

To investigate these issues, the researchers performed several FMTs in young (3 to 4 months) and old (19 to 20 months) mice, including the following:

Fecal microbiota from naive young mice into aged mice (aged yFMT)
Fecal microbiota from naive old mice into aged mice (controls) (aged oFMT)
Fecal microbiota from naive young mice into other naive young mice (young yFMT)

Results showed that yFMT modulated age-induced peripheral and hippocampal immunity.

In addition, aging triggered "a substantial increase" in early activated CD8+ T-cells in gut-associated mesenteric lymph nodes, which was reversed by yFMT. However, memory CD8+ T-cells (CD44) were unaffected.

Because of the relationship between gut microbiota, neuroinflammatory processes, and brain plasticity, the researchers examined hippocampal microglia, the brain's "resident microphages."

Hippocampal microglia regulate cellular aspects of cognition and support neuroplasticity. Higher populations of activated microglia are "prominent" in neurodegenerative conditions.

The investigators found that aged oFMT mice showed "substantial enlargement" in microglia cell soma size, which was reversed by yFMT, and that yFMT restored genes linked to the microglia sensome that had been altered by the aging process.

"These data highlight that yFMT is capable of restoring distinct age-associated changes in microglia activation, a hallmark of cognitive decline," the researchers write.

There were also significant differences between aged and young mice in hippocampal metabolism. However, 35 metabolites that play a critical role in cognition and neuroplasticity and were altered in aging were restored to pre-aged levels by yFMT. These included numerous amino acids, retinol (vitamin A), GABA, and N-glycolylneuraminate.

In particular, the investigators found that yFMT "remodels the microbiome to restore aspects of the aged hippocampal metabolome, with glutamine as a potential driver," they write.

"Rejuvenating Impact"

"Alterations in the gut microbiome have been widely linked to changes in behavior, including hippocampal-dependent cognition, which declines during the aging process," the investigators explain. This was the motive behind examining whether yFMT might rescue aging-induced hippocampus-associated behavioral abnormalities in aged mice in cognitive tasks.

Results showed that impaired learning and increased latency on entering a target quadrant in a maze trial was attenuated in aged mice that received FMT from a young donor, "indicating that yFMT may improve aging-associated impairments in long-term spatial memory," the researchers write.

"Notably, there were no differences in locomotor activity between groups," they add.

Moreover, yFMT restored age-associated memory impairments in aged mice on a training task as well as two environmental interactions: novel object recognition and three-chamber social interaction tests.

Although there was no age effect on anxiety-like behavior in aged mice, yFMT "dramatically increased" time spent in the open arms of the elevated plus maze, which "could indicate a potential anxiety-alleviating therapeutic effect of yFMT in an aged host," the investigators suggest.

"When aged mice have a transplant from young mice, it brings about major changes in the biology of the aging brain," Dinan noted.

For example, significant changes in the hippocampus were observed. This brain region plays a fundamental role in memory processes and stress responses.

"Immune function in the brain is also found to revert to an earlier stage in development following transplantation," said Dinan.

Translational Relevance

Commenting on the findings for Medscape Medical News, Jane Foster, PhD, professor, Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada, called the study "excellent" and noted that it demonstrated "a proof-of-concept that microbiota-targeted therapies may have potential to repair damage and possibly facilitate healthy aging."

Foster, who was not involved with the research, said it is well established that the microbiome "educates and regulates the immune system." However, it is "novel to demonstrate a beneficial action on the immune system in aged mice," she added.

Although the results are encouraging, they will "need to be considered in clinical populations," Foster noted.

Also commenting for Medscape Medical News, Emeran Mayer, MD, distinguished research professor of medicine, UCLA G. Oppenheimer Center for Neurobiology of Stress and Resilience and UCLA Brain Gut Microbiome Center, called this a "very comprehensive and diligently executed study by one of the leading groups on brain-gut microbiome interactions in the world, addressing an important subject with potentially big translational relevance."

However, "before jumping to the premature conclusion that the findings may be translatable to patients suffering from Alzheimer's disease and early cognitive decline, 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 were not translatable into human populations," said Mayer, who was not involved with the current study.

"Most importantly, we already know that dietary interventions, with a largely plant-based diet, affecting composition and function of the gut microbiota can have a profound effect on cognitive decline in humans," he said.

It has also been previously shown "that an important component of this diet-induced benefit is related to an increase in anti-inflammatory short-chain fatty acids," Mayer noted.

In an accompanying editorial, Rochellys Diaz Heijtz, PhD, associate professor and group leader in the Department of Neuroscience at the Karolinska Institute, and colleagues call the results "encouraging" as a "potential therapeutic approach for the treatment of aging-associated cognitive decline and anxiety disorders, which could move rapidly to clinical testing."

Dinan reported that, although fecal microbiota "may offer an opportunity to prevent or ameliorate the cognitive decline seen with aging," his group plans to "study consortia of bacteria to achieve a similar goal."

This type of approach "will not only be safer but, for most patients, an acceptable form of therapy," he said.

The study was supported by research grants from Science Foundation Ireland. Dinan has reported being a speaker at meetings for Servier, Lundbeck, Janssen, and AstraZeneca, and receiving research funding from Cremo and Nutricia. Disclosures for the other authors are listed in the article. The editorialists and Foster have reported no relevant financial relationships. Mayer has reported being a scientific advisory board member for Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.

Nature Aging. Published online August 9, 2021. Abstract, Editorial

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