Researchers at Case Western Reserve University have made a discovery that could change the way doctors approach two of the most serious brain diseases. Their research points to an unexpected role for gut bacteria in disease progression.
A research team has identified a clear link between microbes in the digestive system and brain damage seen in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). They discovered that certain bacterial sugars can trigger an immune response that kills brain cells, and importantly, they also identified a way to stop this process.
How ALS and FTD affect the brain
FTD primarily affects the frontal and temporal regions of the brain, leading to changes in personality, behavior, and language. ALS, on the other hand, targets motor neurons, causing progressive muscle weakness and eventually paralysis.
The underlying causes of both symptoms are still not fully understood. Scientists have investigated a variety of possible factors, including genetics, environmental exposures, brain damage, and diet.
Gut-brain mechanisms that explain disease risk
The study, published in Cell Reports, helps answer the long-standing question of why some people develop these diseases and others don’t. Researchers have discovered a molecular pathway linking gut activity to brain damage, especially in people with certain genetic mutations.
“We found that harmful gut bacteria produce an inflammatory form of glycogen (a type of sugar), and these bacterial sugars trigger an immune response that damages the brain,” said Aaron Barbary, an assistant professor in the Department of Pathology at Case Western Preparatory School of Medicine.
Of the 23 ALS/FTD patients studied, 70% had elevated levels of this harmful glycogen. In contrast, only about a third of people without these diseases showed similar levels.
New treatment goals and patient expectations
These findings may have immediate clinical relevance. By identifying harmful intestinal sugars as the cause of the disease, researchers now have a new therapeutic target. The study also highlights the potential of biomarkers that could help doctors identify patients who may benefit from gut-focused treatments.
The results open the door to new treatments aimed at breaking down these harmful sugars in the digestive system. They are also supporting the development of drugs designed to act on the connections between the gut and the brain, offering hope for slowing or preventing disease progression.
Alex Rodríguez Palacios, assistant professor at the School of Medicine’s Institute for Digestive Health, said the researchers were able to reduce these harmful sugars in their experiments, which “improved brain health and extended lifespan.”
Why some genetic carriers develop the disease
This finding is particularly important for people with the C90RF72 mutation, the most common genetic cause of ALS and FTD. Not everyone with this mutation develops the disease, but this study helps explain why.
The findings suggest that gut bacteria act as environmental triggers that influence whether genetically at-risk individuals develop the disease.
Unique research method yields groundbreaking results
This research was made possible by advanced experimental techniques at the university’s Institute of Pathology and Digestive Health. The scientists used a germ-free mouse model that was kept in completely germ-free conditions without the presence of bacteria. This approach allows researchers to isolate the influence of specific microorganisms on disease.
The program is led by Fabio Cominelli, a distinguished university professor and director of the Institute for Digestive Health. It relies on an innovative “cage-in-cage” sterile housing system developed by Rodríguez Palacios, a rare feature that made this research possible.
This setup allows for large-scale studies of the microbiome, making it possible to investigate how the gut and brain communicate. Traditional methods typically allow researchers to study only a few animals at a time.
Next steps and potential clinical trials
“To understand when and why harmful microbial glycogen is produced, the research team will next conduct a large-scale study examining the gut microbiome community of ALS/FTD patients before and after the onset of the disease,” Barbary said. “Clinical trials to determine whether glycogenolysis in ALS/FTD patients can slow disease progression are also supported by our findings and could begin within a year.”
