The sight of a delectable plate of lasagna or the aroma of a holiday ham are sure to get hungry bellies rumbling in anticipation of a feast to come. But although we’ve all experienced the sensation of “eating” with our eyes and noses before food meets mouth, much less is known about the information superhighway, known as the vagus nerve, that sends signals in the opposite direction — from your gut straight to your brain.

These signals relay more than just what you’ve eaten and when you are full. A new study in mice from researchers at Stanford Medicine and the Palo Alto, California-based Arc Institute has identified a critical link between the bacteria that live in your gut and the cognitive decline that often occurs with aging.

The mouse study showed that the composition of the naturally occurring bacterial population that lives in the gut, known as the gut microbiome, changes with age — favoring some species of bacteria over others. These changes are registered by immune cells in the gastrointestinal tract, which spark an inflammatory response that hampers the ability of the vagus nerve to signal to the hippocampus — the part of the brain responsible for memory formation and spatial navigation. Stimulating the activity of the vagus nerve in older animals turned old, forgetful mice into whisker-sharp whizzes able to remember novel objects and escape from mazes as nimbly as their younger counterparts. 

“The degree of reversibility of age-related cognitive decline in the animals just by altering gut-brain communication was a surprise,” Thaiss said. “We tend to think of memory decline as a brain-intrinsic process. But this study indicates that we can enhance memory formation and brain activity by changing the composition of the gastrointestinal tract — a kind of remote control for the brain.”

Thaiss, who is also a core investigator at Palo Alto-based Arc Institute, is a senior author of the study, which was published March 11 in Nature. Maayan Levy, PhD, an assistant professor of pathology and Arc Institute innovation investigator, is the other senior author. Timothy Cox, a graduate student at the University of Pennsylvania, is the lead author of the research.

“Our study emphasizes that processes in the brain can be modulated through peripheral intervention,” Levy said. “Since the gastrointestinal tract is easily accessible orally, modulating the abundance of gut microbiome metabolites is a very appealing strategy to control brain function.” 

The call is coming from inside the body

The idea that hundreds of species of bacteria are nestled comfortably in our intestines used to be surprising. But the gut microbiome is experiencing a kind of media heyday as people realize that its function is critical to not just how we digest our food, but also to our overall health. A little more than a decade ago, researchers showed that tinkering with rodents’ gut microbiomes affected the animals’ social and cognitive behaviors. Thaiss and Levy wondered whether a similar process could be responsible for the memory loss and cognitive troubles often associated with aging.

Signals from inside the body to the brain — like those that travel from the intestines to the brain via the vagus nerve — are part of what’s called interoception. In contrast, signals from outside the body, conveyed primarily by the five senses of taste, touch, smell, vision and hearing, are called exteroception.

“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.

Thaiss added, “Basically, we’ve identified a three-step pathway toward cognitive decline that starts with gastrointestinal aging and the subsequent microbial and metabolic changes that occur. The myeloid cells in the GI tract sense these changes, and their inflammatory response impairs the connection between the gut and the brain via the vagus nerve. This is a direct driver of memory decline. And if we restore the activity of the vagus nerve, we can restore an old animal’s memory function to that of a young animal.”

The researchers are now investigating whether a similar gut microbiome and brain activity pathway exists in humans, and whether it also contributes to age-related cognitive decline. Importantly, vagus nerve stimulation is approved by the Food and Drug Administration as a treatment for depression or epilepsy and to aid stroke recovery. The researchers are also interested in developing ways to non-invasively monitor, and perhaps even control, the activity of peripheral neurons to affect memory formation and cognition.

“Our hope is that ultimately these findings can be translated into the clinic to combat age-related cognitive decline in people,” Thaiss said. 

Researchers from Monell Chemical Senses Center in Philadelphia; the University of California, Irvine; University College Cork, Ireland; Calico Life Sciences LLC; and the Children’s Hospital of Philadelphia contributed to the work.

The study was funded by the Arc Institute, the National Institutes of Health (grants NIH DK019525, T32AG000255, F30AG081097, T32HG000046, F30AG080958, DP2-AG-067511, DP2-AG-067492, DP1-DK-140021, R01-NS-134976 and R01-DK-129691), the Burroughs Wellcome Fund, the American Cancer Society, the Pew Scholar Award, the Searle Scholar Program, the Edward Mallinckrodt Jr. Foundation, the W.W. Smith Charitable Trust, the Blavatnik Family Fellowship, the Prevent Cancer Foundation, the Polybio Research Foundation, the V Foundation, the Kathryn W. Davis Aging Brain Scholar Program, the McKnight Brain Research Foundation, the Kenneth Rainin Foundation, the IDSA Foundation and the Human Frontier Science Program.