As organisms age, changes in the bacteria that live within the digestive system can directly cause the memory loss that commonly accompanies aging. Researchers have discovered that by reversing these microbial changes and stimulating the nerves that connect the gut to the brain, they can completely restore memory function in aging mice. These results were recently published in the journal nature.
Timothy O. Cox, a graduate researcher at the University of Pennsylvania, led the research team. Pathology researchers Christophe A. Theis and Marjan Levy of Stanford Medicine and the Ark Research Institute served as senior authors on the paper. The research team wanted to understand the biological mechanisms that determine how memory changes over the lifespan. They focused on a concept called interoception, which is the way the brain senses the body’s internal states.
Unlike external senses such as sight and hearing, interoception relies on internal pathways such as the vagus nerve. This long bundle of nerve fibers acts as a high-speed communication line between the internal organs and the brain. It sends continuous updates from the stomach and intestines to an area of the brain called the hippocampus. The hippocampus is the main center for forming and storing new memories.
The researchers suspected that the gut microbiome, made up of hundreds of species of bacteria that live in the digestive tract, might influence this internal communication. As animals age, the specific types of bacteria present in their intestines naturally change. The research team sought to determine whether these bacterial changes could alter the signals sent along the vagus nerve.
If the gut microbiome influences neural signaling, it may explain why cognitive performance declines over time. “Our study highlights that processes in the brain can be modulated by peripheral intervention,” Professor Levy said in a press release. She pointed out that because the digestive system is easily reached with oral treatments, altering the chemicals produced by gut bacteria could be an attractive way to control brain function.
To investigate the relationship between gut bacteria and memory, researchers placed young mice in the same cage as older mice. Because mice naturally ingest faeces from their environment, young animals quickly acquire the gut bacteria of older animals. After living together for a month, the young mice’s microbial communities were very similar to those of the old mice. The researchers then tested the young animals’ cognitive abilities.
The research team used a novel object recognition test that assesses the mice’s natural curiosity and ability to recall familiar items. They also placed the mice in a special maze that requires spatial memory to find the exit. Young mice with older microbiomes performed worse on both tasks. They showed little curiosity about unfamiliar objects and struggled to navigate mazes, behaving much like older rats.
To separate the effects of the bacteria from the social stress of living with older animals, the researchers conducted a transplant experiment. The researchers collected feces from older mice and transferred it to the stomachs of younger mice, who were kept in a completely sterile environment. These young, previously germ-free mice also lost the ability to form memories after ingesting the old bacteria. Older mice raised in a germ-free environment without gut bacteria maintained their vivid memories into old age.
The team then gave broad-spectrum antibiotics to young mice that had acquired the old microbiome. The antibiotics wiped out the newly introduced bacteria. After this treatment, the young mice regained their memory and easily completed maze and object recognition tests. Remarkably, older mice treated with the same antibiotic also experienced recovery of memory function.
The researchers then worked to identify the specific bacteria that cause cognitive decline. By cataloging the microbial changes that occur over the lifespan of mice, they noticed a steady increase in a bacterial species called Parabacteroides goldstein. When the researchers introduced just this particular bacterium into the digestive tracts of young mice, the mice developed memory problems. This effect did not occur with other types of bacteria.
The research team analyzed the chemical byproducts produced by Parabacteroides goldstein to understand how it affects the human body. They discovered that these bacteria produce large amounts of a particular type of fat molecule, medium-chain fatty acids. When the researchers fed these isolated fat molecules to young mice, the mice immediately showed signs of memory loss. This molecule acted as a signal to change the local environment of the intestine.
In the gastrointestinal tract, these fat molecules interact with bone marrow cells, a type of white blood cell that patrols the intestines for threats. Fatty acids bind to specific receptors on the outside of white blood cells. Once attached, white blood cells begin to release inflammatory chemicals. The researchers noted that this inflammatory response was localized to the intestine and nearby fat deposits, rather than spreading throughout the bloodstream.
This local inflammation directly affected the nearby vagus nerve. The research team used advanced imaging techniques to monitor electrical activity in the vagus nerve in real time. They observed that inflammatory chemicals blunted the ability of nerves to send electrical signals to the brain. Because the vagus nerve sent fewer signals, the hippocampus became less active and could no longer properly encode new memories.
To prove that this blocked neural pathway was the root of the problem, researchers tried to bypass inflammation. They gave older mice capsaicin, the chemical that makes chili peppers spicy, which naturally stimulated the sensory fibers of the vagus nerve. They also tested gut hormones known to activate the same neural pathways. When the vagus nerve was artificially stimulated, old mice performed just as well on memory tests as young mice.
The research team also used genetic technology to remove fatty acid receptors from the white blood cells of certain mice. Without these receptors, white blood cells cannot detect bacterial fat molecules and trigger an inflammatory response. These genetically modified mice maintained sharp memories even when their guts became colonized with old bacteria. By blocking inflammation, they succeeded in protecting the vagus nerve from damage.
Although these results provide a new perspective on aging, all experiments were conducted in animal models. Researchers note that it remains unclear whether the very same bacterial species and fatty acids cause memory loss in humans. The precise biological chain of events linking chronic enteritis and decreased neuronal excitability also requires further investigation. The anatomical pathways connecting the brainstem and hippocampus have not yet been fully mapped.
Future research will investigate how these mechanisms affect the human body and whether targeted therapies can help people experiencing cognitive decline. Scientists are particularly interested in seeing if changes in diet or specific bacterial treatments can safely reduce enteritis in older adults.
“Our hope is that we can ultimately translate these findings into the clinic to combat age-related cognitive decline in people,” Tice said in a press release. Additionally, devices that electrically stimulate the vagus nerve have already been approved for conditions such as epilepsy, and may hold promise for memory protection in the future.
The study, “Intestinal receptor dysfunction causes age-related cognitive decline,” was authored by Timothy O. Cox, Ashwarya S. Devason, Alan de Araujo, Sydney Mason, Madhav Subramanian, Andrea FM Salvador, Hélène C. Descamps, Junwon Kim, Yixu Zhu, Zhu, Zhuy, Juy, and Sun Won-Suk. Song, Adrian Cortez-Martin, Nathan T. Henderson, Kuei Ping Phan, Thao Nguyen, Wisat Sey Lee, Iboro C. Umana, Maria Sakuta, Ryan J. Lerman, Steven Wisser, J. Andrew D. Nelson, Ilona Golinker, Alana M. McSween, Eric F. Homan, Anna L. Patel, Anna L. Homan, and Wisas Seley. Babu, Clara Sklar, Niklas Blank, Kefter Hoxha, Lavinia Boccia, Andrea C. Wong, Klaas Bahnsen, Jihee Kim, Natalie Biderman, Dina Abbasian, Clarissa Schaeffler, Christopher Petucci, Fiona E. McAllister, Amber L. Alhadeff, Mark V. Fussillo, Nicholas Hill, and J. Nicholasjan. Betry, Guillaume de Lartigue, Virginia Y.-M. Lee, Marian Levy, and Christophe A. Theis.
