How Gut Bacteria Could Trigger Memory Loss as We Age

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How Gut Bacteria Could Trigger Memory Loss as We Age

Memory loss and aging go hand-in-hand for most of us, but scientists are getting closer to understanding why. A new study, conducted by researchers at the Arc Institute in Palo Alto, California, and published in Nature, found that a prime suspect may be living in our gut.

“The biggest question that came out of this experiment is: How does the brain know about what’s going on [in the microbiome]?” said Christoph Thaiss, PhD, core investigator at Arc Institute and an assistant professor of pathology at Stanford University, Stanford, California. 

Thaiss focuses his research on how environmental factors, as well as age, predispose individuals to various diseases over the course of their life. When he teamed up with first author Timothy Cox, MD/PhD student at the University of Pennsylvania, Philadelphia, he’d set his sights on the aging gut microbiome. 

The Perfect Test Subjects

“It was previously known that the microbiome changes with age in the same way that we, the host, change with age,” explained Cox. “And so the question was, are there any consequences of that?”

To answer, the researchers took a group of old and young mice and had them live together. When mice cohabitate, “their microbiomes kind of average out because the mice are coprophagic,” said Cox. 

In other words, they eat each other’s poop.

The researchers were surprised by what they observed. After just a month, the young mice that were “otherwise totally healthy” showed signs of severe memory impairment.

Cox had extensive experience conducting memory tests on mice from his previous research on Alzheimer’s disease. “The main test that we use is something called novel object recognition. This takes advantage of the fact that mice are naturally curious and they like to explore new things,” said Cox.

Researchers show mice two identical objects, and the mice get to explore those objects so they learn what they are. Then they remove those objects. An hour later, they put the familiar object back in the cage “along with a new object called the novel object,” said Cox.

Normal mice remember that they’ve seen the familiar object and will spend 2-3 times more time exploring the novel object because it’s new and interesting to them. “Old mice, mice with Alzheimer’s disease, or those that have cognitive impairment forget that they’ve seen the first object before,” said Cox. “When they get exposed to the two objects for the testing phase, instead of spending more time with the new object, they spend equal time with both objects.”

A Surprising Result

The research team was not expecting to see any memory impairment in the young mice, let alone severe memory impairment. “But when we tested the young mice that were living with old mice, they were basically identical to the old mice in terms of performance. They did really poorly on the standard test,” said Cox.

The team was in such disbelief, in fact, that they had multiple people repeat the test to see if they could get the same outcome. “The more experiments we did, the more we got the same thing, and so we became more and more confident in it,” said Cox.

While the research team was surprised by the results, David Hafler, MD, professor of immunobiology and former chairman of the Department of Neurology at Yale School of Medicine, New Haven, Connecticut, was not. “I wasn’t surprised, but I was really very delighted to see more evidence of the gut-brain [connection],” he said (he was not involved in the study).

How This Gut-Brain Connection Works

To find a possible culprit in the gut, the team used germ-free mice. They transplanted the microbiomes of healthy, young mice and old mice and observed the exact same effects: The germ-free mice that received the old microbiomes displayed learning and memory impairment. “This gave us really strong evidence that this was a microbiome phenotype because it was reproduced with a fecal transplant,” said Cox. 

After testing several, they narrowed the search down to a bacterium called Parabacteroides goldsteinii, though Thaiss believes “there are other species that change with age, and there might be other species that have cognitive impact.”

The main function of P goldsteinii is its production of medium-chain fatty acids (MCFAs). High levels of MCFAs accumulate with age and activate gut-resident myeloid immune cells to produce inflammatory signaling molecules. This study allowed researchers to dive into the gut-brain connection, tracing the effects of MCFAs through intestinal immune cells into sensory neurons and up the vagus nerve into the hippocampus of the brain, where memories are formed. The result: “The function of vagal afferent neurons is impaired, the interoceptive signal received by the brain is weakened, and hippocampal function declines,” they write.

“It all fits in with these bigger narratives,” said Hafler. “This is all in mice, and our work has been in both mice and humans, but I think it’s really exciting and suggests the importance of these pathways. I think it just adds to the story of the increasing importance of the gut-brain connection. It’s just becoming increasingly clear.”

Next Steps

A deeper understanding of the gut’s role in cognitive decline could have implications beyond memory impairment. “We did several methods of vagal nerve stimulation. We’re able to restore memory in mice,” said Cox. “Vagal nerve stimulation is already FDA-approved for epilepsy and depression, but it’s now being looked at for many different diseases, including rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. In the future, we might be able to apply that to cognitive decline.”

“Ultimately, the goal is to do something about cognitive decline in humans,” said Thaiss. “How can we understand and manipulate this communication [between the gut and the brain]? How much of this pathway is active and involved in regulating cognitive decline in humans? These are the two main questions that have come out of this study that I think are going to keep us and others in the field busy for a while.”

David Hafler declared having no competing interests. Disclosure information for all study authors is available in the original study publication.