How The Microscopic Residents in Your Gut Could Influence Cognitive Decline

The Context: Your intestines are home to trillions of microbes that help you take in nutrients and maintain a healthy gut, and they are also known to interact with and influence brain function. This “gut-brain connection,” however, is not well understood.

The Study: Gut microbes can affect the hippocampus to speed cognitive decline in mice through accumulation of bacteria called Bilophila, finds a new study in Cell Host & Microbe by NYSCF – Robertson Neuroscience Investigator Elaine Hsiao, PhD, of UCLA. 

Why it Matters: This study illuminates a possible role of gut microbes in cognitive decline and could inform new treatments or preventative measures against it.

Cognitive impairment afflicts millions and is associated with a wide range of disorders such as Alzeimer’s and Parkinson’s disease. Dr. Hsiao’s team aimed to explore how the gut microbiome may impact cognitive decline.

Putting Mouse Intestines to the Test

In their first experiment, the researchers gave mice ketogenic diets (high in fat, low in carbohydrates) or standard diets. They then reduced the mice’s oxygen levels for five days (a way of experimentally inducing cognitive decline) before giving the mice four days to recover.

To test their cognitive ability, the mice were placed in a maze. The mice on the ketogenic diets made an average of 30% more errors than mice given the standard diet. 

But was it just diet that was causing the difference? The team tested mice on ketogenic diets and those on standard diets who were not given oxygen deprivation and found no difference in their ability to navigate the maze. In short, the oxygen deprivation in tandem with the ketogenic diet was what hindered the mice.

“These results highlight the ability of different environmental factors to interact together to impact cognitive behavior in mice,” said lead author Christine Olson, a graduate student in Dr. Hsiao’s lab in an article from UCLA.

Next, the team decided to completely deplete the mice’s microbiomes, administer a ketogenic diet, and then deplete their oxygen levels. Interestingly, these mice made significantly fewer errors in the maze than those whose microbiomes weren’t depleted first.

“This suggests that the microbes associated with the ketogenic diet and hypoxia could contribute to the detrimental effects on cognitive impairment,” noted Olson.

The scientists concluded that a type of bacteria called ‘Bilophila wadsworthia’ changes which genes are turned on or off in the hippocampus – the part of the brain associated with learning and memory – and that these microbes reduce normal cellular signaling.

“Bilophila wadsworthia disrupted hippocampal activity and cognitive behavior in ways similar to how hypoxia and the ketogenic diet together did,” Olson said. 

Dr. Hsiao noted that this work will be important for better understanding cognitive impairment and developing new therapies.

“Identifying early risk factors is critical to enabling early detection and interventions for cognitive impairment,” she said.

Journal Article:

Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia
Christine A. Olson, Alonso J. Iñiguez, Grace E. Yang, Ping Fang, Geoffrey N. Pronovost, Kelly G. Jameson, Tomiko K. Rendon, Jorge Paramo, Jacob T. Barlow, Rustem F. Ismagilov, Elaine Y. Hsiao. Cell Host & Microbe. 2021. DOI: https://doi.org/10.1016/j.chom.2021.07.004

Cover image credit: Alpha Tauri 3D Graphics/Shutterstock