The community of bacteria living in the intestines could be one of the drivers of memory loss in old age, at least in mice. As rodents age, shifts in their gut microbes weaken the signaling pathway connecting the gut to the brain, a study published in the journal Nature finds.
“Age-related memory loss is not just shaped by brain-intrinsic factors, but factors outside of the brain play a role too, such as signals coming from the gastrointestinal tract,” the study co-author, Christoph Thaiss at Stanford University in California, told Refractor.
Aging is often accompanied by a decline in cognitive function that varies from person to person. Previous studies have suggested that the gut microbiome influences cognition, but how these microbes contribute to age-associated cognitive decline has remained unclear.
To understand the exact communication pathway between the brain and the gut, Thaiss and his colleagues exposed young mice (two months old) to old mice (18 months old) by placing them in a single cage together. After living in close proximity for one month, the gut microbiomes of all the mice resembled those of an old-like state.
Also, within a month, the young mice developed memory problems as evidenced by two signs.
Everything old is new again
First, young mice naturally spend more time with a new toy than an old one, whereas aged mice essentially forget the old toy and treat both as new. However, the young mice that had adopted the aged-microbiome profile in this study struggled to recognize objects they had seen before. Secondly, the same group took longer to locate a safe escape hole in a maze. Meanwhile, a control group of young mice housed with other young mice stayed sharp.
The team suspected that shifting gut bacteria might have caused this cognitive impairment. Sure enough, after comparing the gut bacteria of young and old mice, the team zeroed in on Parabacteroides goldsteinii as a candidate species to study in further detail, says Thaiss.
P. goldsteinii produces medium-chain fatty acids, a byproduct of its metabolism, which trigger a receptor called GPR84 on immune cells in the gut. These, in turn, release inflammatory molecules. These molecules disrupt sensory signaling from the gut to the brain, especially communication through the vagus nerve, resulting in impaired memory formation, says Janosch Heller at Dublin City University, who was not involved in the study.
“Age-associated expansion of P. goldsteinii was shown to be transmissible to young mice, sufficient to induce memory impairment,” he adds.
The researchers also showed that treating young mice who had the aged microbiome with antibiotics – which effectively cleared their guts of microbial colonization – restored their memory. “It was remarkable to see the degree of reversibility of memory loss in aged animals,” Thaiss told us.
However, “the experiments were conducted in mice, so we still need to see if the precise details of this new microbiome-gut-brain axis circuit for memory and learning translate from bench to bedside,” says Gerard Clarke at University College Cork, who wasn’t involved in this work.
That said, the findings do point toward potential treatments for age-related memory loss.
The researchers were able to reverse memory loss in aged mice using several approaches beyond antibiotics, including targeted viruses that attack the problematic gut bacteria, drugs that block the inflammatory pathway, and compounds that stimulate the gut-brain connection directly. While these experiments were indeed conducted in mice, the authors are optimistic that similar strategies could one day be developed to slow or reverse memory decline in humans.
You can hear more from Thaiss about the finer details of the study in the following video from Stanford spinout, the Arc Institute, under which the Thaiss Lab operates.
