As the body ages, changes in the bacteria living inside the digestive system can lead to a weakened sensory connection between the gut and the brain, which contributes to memory loss. By restoring normal communication along this physiological pathway in mice, researchers were able to reverse age-related cognitive decline and restore memory function. The results of the experiments were published in the journal Nature.
Cognitive decline is one of the most common and challenging aspects of growing older. As human life expectancy increases, memory disorders have become a pressing issue for global health. While traditional research historically focuses on problems occurring directly inside the brain, attention has recently shifted to signals originating outside the central nervous system.
The digestive tract hosts an incredibly diverse ecosystem of bacteria and other microorganisms. This community of microbes produces various biological chemicals that naturally enter the bloodstream or interact with surrounding tissues. The brain constantly monitors the internal physical state of the body through an ability known as interoception.
This internal sensory information travels from the digestive tract up to the central nervous system along the vagus nerve. The vagus nerve acts as a major communication highway connecting the organs in the abdomen to the base of the brain. When we eat, for example, the vagus nerve tells the brain about the nutrients arriving in the gut.
Timothy O. Cox, a microbiome researcher at the University of Pennsylvania, led the investigation alongside colleagues from Stanford University and the Arc Institute. The researchers wanted to understand exactly how changes in gut bacteria over a lifetime influence memory decline. They suspected that an altered microbial environment might disrupt the sensory signals traveling up the vagus nerve in older animals.
To separate the age of the animals from the age of their microbiomes, the researchers transferred gut bacteria from older mice into younger mice. They accomplished this by housing young and old animals together. Because mice naturally consume feces found in their environment, living together leads to a rapid exchange of gut microbes.
After one month of living with aged mice, the young mice experienced noticeable declines in short term memory. The researchers tested memory using a standard object recognition task. In this test, mice are allowed to explore a set of objects, and later, one familiar object is replaced with a novel item. Mice naturally prefer to explore new things.
The young mice exposed to aged gut bacteria behaved like much older animals. They forgot which objects they had already investigated and spent less time exploring newly introduced items. The research team confirmed these results through several orthogonal experiments.
In addition to the object recognition test, the researchers utilized a spatial learning test called the Barnes maze. In this setup, mice must use visual cues in the room to find a hidden escape hole on a brightly lit platform. Young mice exposed to the older microbiome struggled to remember the location of the escape hole over multiple days of testing.
The researchers also gathered fecal matter from old mice and transplanted it into young mice that had been raised in completely sterile environments. These mice had no preexisting bacteria of their own to interfere with the chemical signals in the gut. These young recipients developed immediate memory impairments, matching the outcomes of the co-housing experiment.
Conversely, treating the older animals with broad spectrum antibiotics to eliminate their aged bacteria reversed their memory loss. This suggested that something the aging bacteria produced was actively harming the cognitive abilities of the animals. Next, the researchers set out to identify the specific microbes responsible for these changes.
By sequencing the genetic material in the mouse feces over the course of their lifespans, the team isolated one particular species called Parabacteroides goldsteinii. This bacterium became much more abundant as the mice grew older. When the researchers introduced this specific bacterium into young animals, the mice immediately showed memory deficits.
The team then analyzed the chemical byproducts created by this bacteria in the laboratory. They found that it generated high levels of specific fat molecules known as medium-chain fatty acids. Feeding these fatty acids directly to young mice caused the exact same memory problems seen in the older animals.
The researchers mapped how these fat molecules alter the sensory connection to the brain. Because fatty acids are absorbed into the tissue surrounding the intestines, they come into contact with the local immune system. The fatty acids triggered a specific receptor on the surface of white blood cells located in the gut tissue.
The white blood cells involved in this process are primarily macrophages, which normally act as a cleanup crew for the immune system. When these peripheral macrophages detected the fatty acids, they released inflammatory molecules. This localized inflammation essentially numbed the sensory endings of the vagus nerve.
The researchers proved this theory by measuring calcium signaling in the nerve cells, which showed that the vagus nerve simply stopped firing as vigorously. With the vagus nerve functioning poorly, the brain received weaker internal sensory signals. This lack of sensory input had a direct impact on the hippocampus, a brain region dedicated to learning and memory formation.
Without regular stimulation from the vagus nerve, the cells in the hippocampus failed to activate properly when the mice encountered a new object. To solidify the role of the vagus nerve, the researchers temporarily turned off the nerve using specialized genetic engineering techniques. When they deactivated the sensory neurons connecting the gut to the brain in healthy young mice, the animals developed the same memory issues as the older mice.
The team tested several independent ways to repair this broken communication pathway. The researchers used a specialized diet that temporarily depleted the macrophages from the bodies of the mice. Without the immune cells present to start the inflammatory process, the young mice maintained their normal memory function even after being fed the fatty acids.
They also bred mice that lacked the fatty acid receptors on their immune cells. These genetically modified mice were completely protected from the memory loss. Separately, the researchers found that neutralizing the inflammatory immune molecules with targeted antibodies restored normal brain function.
The researchers then tried using a specialized virus to target and attack the problematic bacteria directly. Administering this bacteria-killing virus reduced the production of the fatty acids and rescued the memories of aged mice. Finally, the researchers bypassed the gut inflammation entirely by artificially stimulating the vagus nerve.
They injected the mice with low doses of capsaicin, a compound found in chili peppers that directly activates peripheral sensory nerves. They also used synthetic gut hormones to stimulate the nerve endings. Activating the vagus nerve in this manner restored normal firing patterns in the hippocampus, allowing the older mice to form new memories.
While the study provides a detailed map of how gut signals affect memory, the experiments were conducted entirely in mouse models. The researchers point out that it remains unknown if the exact same bacterial species and fatty acids drive cognitive decline in older humans. The immune system and the microbiome of humans often behave differently than those of laboratory rodents.
The precise biological pathway that connects the input at the brainstem to the cellular activity in the hippocampus also requires more detailed mapping. There are multiple relay steps in the brain before a signal from the gut reaches the memory centers. Researchers still need to understand exactly how a steady decrease in sensory signaling leads to an overall inability to encode new memories.
Looking ahead, the researchers hope to explore whether specific drugs can mimic these internal sensory signals in humans. They refer to these hypothetical drugs as interoceptomimetics, which would artificially substitute the lost signals from the stomach. Treatments that stimulate the vagus nerve or reduce localized gut inflammation might offer a new avenue to protect brain health.
The study, “Intestinal interoceptive dysfunction drives age-associated cognitive decline,” was authored by Timothy O. Cox, Ashwarya S. Devason, Alan de Araujo, Sydney Mason, Madhav Subramanian, Andrea F. M. Salvador, Hélène C. Descamps, Junwon Kim, Yixuan Zhu, Lev Litichevskiy, Sunhee Jung, Won-Suk Song, Adrián Cortés-Martín, Nathan T. Henderson, Kuei-Pin Huang, Thao Nguyen, Wisath Sae-Lee, Iboro C. Umana, Maria Sacta, Ryan J. Rahman, Stephen Wisser, J. Andrew D. Nelson, Ilona Golynker, Alana M. McSween, Eric F. Hohmann, Shaan Patel, Anna L. Bub, Clara Soekler, Niklas Blank, Kevt’her Hoxha, Lavinia Boccia, Andrea C. Wong, Klaas Bahnsen, Jihee Kim, Natalie Biderman, Dina Abbasian, Clarissa Shoffler, Christopher Petucci, Fiona E. McAllister, Amber L. Alhadeff, Marc V. Fuccillo, Colin Hill, Cholsoon Jang, J. Nicholas Betley, Guillaume de Lartigue, Virginia Y.-M. Lee, Maayan Levy, and Christoph A. Thaiss.