As people age, memory decline often affects daily life. Now, a study in mice shows that age-related changes in gut bacteria impair memory by triggering inflammation that disrupts gut-to-brain signaling, and restoring this pathway can reverse cognitive decline.

The findings, published in Nature, suggest that targeting gut bacteria, their metabolites, or gut-to-brain signaling could offer new strategies to prevent or treat age-related memory decline. 

Memories are formed in the hippocampus, using networks of neurons called “engrams,” but the brain’s ability to create these networks decreases with age for reasons not fully understood. Recent research suggests the gut microbiota plays a key role in brain function and memory, but exactly how gut signals reach the brain and influence cognition remains unclear.

Timothy Cox at the University of Pennsylvania in Philadelphia and his colleagues investigated how age-related changes in gut bacteria affect memory in mice.

Memory loss

The researchers transferred microbes from older mice to younger ones, either by housing them together or by transplanting gut bacteria. Young mice exposed to the microbiota of older mice developed memory problems, both in short-term recognition tasks and longer-term spatial learning. 

When mice were raised without any microbes or treated with antibiotics, the memory decline did not occur, and antibiotics could even reverse memory problems after they had developed.

As mice got older, a gut microbe called Parabacteroides goldsteinii increased and caused memory problems when transferred to young mice. Mice naturally carrying higher levels of this bacterium also had poorer memory, the researchers found.

Intervention targets

Further experiments showed that P. goldsteinii produces medium-chain fatty acids (MCFAs), which can travel through the gut and impair brain function without entering the brain itself. Young mice exposed to MCFAs developed memory problems, the team found.

MCFAs activate a receptor on specific immune cells called myeloid cells. When triggered, these cells release inflammatory molecules. In turn, inflammation disrupts gut-to-brain signaling through the vagus nerve, reducing the activity of the hippocampus and impairing memory. However, removing myeloid cells or reactivating vagal neurons restored cognition in mice. 

“Our results provide several targets for peripheral intervention and suggest that inflammation-induced interoceptive dysfunction might be a generalizable principle underlying age-associated cognitive decline,” the authors say.