Enhancing gut-brain communication reversed cognitive decline, improved memory formation in aging mice

“Exteroception is basically how we perceive the outside,” Thaiss said. “We have a lot of detailed knowledge about how this works. But we know much less about how the brain senses what is going on inside the body. We don’t know how many internal senses there are, or even all of what they are sensing. It’s clear that our exteroception capabilities decline with age — we grow to need eyeglasses and hearing aids, for example. And this study shows that aging also affects interoception.”

To test their theory that the gut microbiome plays a role in the “senior moments” many of us experience, the researchers housed young (2-month-old) mice together with old (18-month-old) mice. Living (and pooping) in close proximity exposed the young mice to the gut microbiomes of the old mice and vice versa. After one month, the researchers examined the compositions of the microbiomes of the old and young animals.

They found that the shared digs caused the microbiomes of the young mice to more closely resemble that of the older animals. When they compared the abilities of the mice to recognize a novel object, or to find the exit in a maze, the young mice with “old” microbiomes performed significantly more poorly than their peers — showing less curiosity about the unfamiliar object and bumbling about the maze in ways similar to that of old animals.

When the researchers compared young mice and old mice raised in a germ-free environment since birth (meaning neither group had gut bacteria), the young mice maintained their ability to form memories. But when they transplanted young, germ-free mice with microbiomes from old mice, the young mice again performed like older animals in the memory and cognition tests. Interestingly, the germ-free old mice did not experience a loss of memory and cognition as they aged, performing as well as 2-month-old animals.

Strikingly, treating young mice with “old” microbiomes (and, therefore, faltering cognitive abilities) with broad-spectrum antibiotics for two weeks restored the animals’ cognitive abilities, causing them to avidly investigate unfamiliar objects and scamper through the maze as well as their control peers.

“The object recognition test is like cognitive recognition tests in humans, where you are shown a series of images, then have to remember which ones you’ve seen before after some time passes,” Thaiss said. “And the maze test is like people trying to recall where they parked their car at a large shopping center. What these tasks have in common, in mice and in people, is that they are very strongly dependent on activity in the hippocampus, because that is where memories are encoded.”

What’s different in their guts?

Digging deeper, the researchers identified specific changes that occur in the composition of the gut microbiome of mice as they age. In particular, the relative abundance of a bacteria called Parabacteroides goldsteinii increases in old mice and is directly associated with cognitive decline in the animals. They showed that colonizing the guts of young mice with this bacterial species inhibited their performance on the object recognition and maze escape tasks, and that this deficit correlated with a reduction of activity in the hippocampus.

When they treated old mice with a molecule that activates the vagus nerve, however, the cognitive performance of the animals was indistinguishable from that of young animals.

Further experiments showed that the increasing prevalence of the Parabacteroides goldsteinii bacteria correlated with an increasing amount of metabolites called medium-chain fatty acids, and that these metabolites cause a group of immune cells in the gut called myeloid cells to initiate an inflammatory response. This inflammation inhibits the activity of the vagus nerve, the activity of the hippocampus and the ability to form lasting memories.