Scientists have plenty of ideas about why aging impairs memory. Reductions in blood flow in the brain, shrinking brain volume, and malfunctioning neural repair systems have all been blamed. Now, new research in mice points to another possible culprit: microbes in the gut.
In a study published today in Nature, scientists show how a bacterium that is particularly common in older animals can drive memory loss. This microbe makes compounds that impair signaling along neurons connecting the gut with the brain, dampening activity in brain regions associated with learning and memory, the team found.
“This is a tour de force,” says Haijiang Cai, a neuroscientist at the University of Arizona who studies gut-brain communication and was not involved in the work. “They define the pathway all the way from aging and bacteria … to cognitive function—it’s really impressive.” However, he and others emphasize it remains to be seen whether a similar mechanism exists in humans—and if so, how important it is compared with other drivers of cognitive decline.
Research on the so-called gut-brain axis has exploded in recent decades. Multiple studies have identified differences in microbiome composition between healthy people and those with cognitive disorders such as Alzheimer’s disease. This kind of research can’t establish cause and effect, though, and the literature is rife with conflicting results.
Some groups have used animal experiments to probe the microbe-memory link. In the new study, Stanford University researchers Christoph Thaiss and Maayan Levy tinkered with the microbiomes of young mice—either by housing them with older animals or feeding them these animals’ poop—and then gave them memory tests. For example, one such test rates animals higher if they spend more time exploring new objects than those they’ve seen before.
Young mice given old-mouse microbiomes performed worse on memory tests than untreated mice, and giving them antibiotics appeared to restore performance, suggesting microbes from the old mice were responsible. Old mice given antibiotics were also less forgetful, according to the study.
Of the many gut bacterial species that became more abundant in the mice with age, the researchers were especially interested in one called Parabacteroides goldsteinii. Feeding P. goldsteinii alone to animals that had had their normal microbiomes wiped out caused a drop in memory compared with controls; giving microbiome-free animals one of several other bacterial species did not.
In further experiments, Thaiss and colleagues pieced together how P. goldsteinii might cause memory problems: The bacterium releases molecules known as medium-chain fatty acids. Mice fed these molecules had dampened activity along the vagus nerve, a bundle of neurons that communicates sensations such as stomach fullness to the brain. These animals also showed reduced activity in the hippocampus, a brain region associated with learning and memory.
The fatty acids activate a receptor called GPR84, found on inflammation-promoting cells. The team suspected it was this inflammation that impaired the vagus nerve. Indeed, using drugs or other techniques to block GPR84 receptors or reduce the number of inflammatory cells seemed to protect young mice from the cognitive effects of old-mouse microbiomes. Compounds that stimulate the vagus nerve directly—including glucagonlike peptide-1 (GLP-1) (which binds to the same receptors as ubiquitous weight-loss drugs such as Wegovy) and capsaicin, the molecule that gives chili peppers their kick—boosted memory performance in older animals.
“It’s an incredible amount of work,” says University of Oxford cell biologist David Greaves, adding that several of the paper’s themes, including the connection between inflammation and aging-related decline, dovetail with existing research.
Sean Gibbons, a microbiome researcher at the Institute for Systems Biology, adds that his group has identified a connection between healthy aging and declines in microbes related to Parabacteroides—though the broader literature is inconsistent on Parabacteroides specifically. It’s hard to judge the significance of P. goldsteinii or this novel pathway compared with other aging-related changes, Gibbons adds. “There’s probably 60 other different mechanisms at play at the same time.”
Cai says he’d like to see more data on how exactly the vagus nerve activates the mouse hippocampus. He finds the result that nerve stimulants such as capsaicin restore cognitive function particularly surprising. “Does that mean that older people, if they eat more spicy food or take … GLP-1 agonists, they can improve cognitive function?” Cai is doubtful—and studies of these compounds’ effects on cognitive decline have produced mixed results.
Thaiss, who also runs a lab at the Arc Institute, emphasizes it’s too soon to say whether methods used in this study can be applied to people. Several groups are exploring the effect of electrical stimulation of the vagus nerve on cognition, but that technique is “basically a sledgehammer approach that electrically stimulates the entire nerve bundle,” he says. To have specific control of brain function, “we really need something that allows us to manipulate the activity of individual neurons.”
Thaiss suspects other bacteria and gut molecules may similarly influence the brain, and wonders what other brain functions might be affected. His team is now studying P. goldsteinii in humans to see whether its abundance is linked to cognitive function in older age. “Some people live to 100 years and are cognitively extremely sharp, while others start forgetting things in their 50s and 60s,” Thaiss says. Perhaps different signals coming from the gut could help explain some of that variation.