A significant discovery by Case Western Reserve University researchers could change how doctors treat two of the most devastating neurodegenerative diseases.
The team identified a link between gut bacteria and the deterioration of the brain in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). The researchers discovered that certain bacterial sugars cause immune responses that kill cells—and how to prevent it.
FTD mainly affects the brain’s frontal and temporal lobes, causing changes in a person’s personality, behavior and language. ALS primarily targets motor neurons, resulting in gradual muscle weakness and paralysis.
Most causes of ALS and FTD cases are unknown, although researchers have been examining several potential reasons, including genetics, environmental issues, brain injuries and diet.
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The study, recently published in Cell Reports, solves a long-standing question about neurodegenerative diseases. The team discovered a molecular connection that explains why some people with specific genetic mutations acquire FTD and ALS and others don’t.
“We found that harmful gut bacteria produce inflammatory forms of glycogen (a type of sugar), and that these bacterial sugars trigger immune responses that damage the brain,” said Aaron Burberry, assistant professor in the Department of Pathology at the Case Western Reserve School of Medicine.
Dangerous glycogen levels
Burberry, the study’s senior investigator, reported that 70% of the 23 ALS/FTD patients examined had dangerous glycogen levels. Of those without the brain diseases, only a third had high levels of glycogen.
The study has immediate implications for patient care by identifying new targets to treat ALS and FTD, while providing biomarkers to identify patients who might benefit from gut-targeted therapies.
This discovery paves the way for testing new treatments that break down harmful sugars in the gut, and it opens doors for developing drugs that work on the connection between the digestive system and the brain—potentially offering new hope for patients suffering from these devasting brain diseases.
Harmful sugars
Alex Rodriguez-Palacios, assistant professor in the Digestive Health Research Institute at the School of Medicine, said the team used its findings to then reduce the harmful sugars, which “improved brain health and extended lifespan.”
Their discovery is particularly significant for what is known as C90RF72 mutation carriers—the most common genetic cause of ALS and FTD. The research explains why some people with the mutation develop the diseases while others don’t, identifying gut bacteria as a key environmental trigger.
The university’s Department of Pathology and Digestive Health Research Institute are leading neurovegetative disease research through their unique ability to conduct studies using germ-free mouse models—mice raised in completely sterile environments with no bacteria, allowing researchers to study exactly how specific gut bacteria affect brain diseases.
Cage-in-cage system
Fabio Cominelli, Distinguished University Professor and director of the Digestive Health Research Institute, oversees this program, which relies on an innovative “cage-in-cage” sterile housing system developed by Rodriguez-Palacios—a technical capability that few institutions worldwide possess and that made this discovery possible.
The design makes possible the large-scale microbiological studies necessary to understand the complex communication between the gut and brain—research that would be impossible with traditional methods that can only accommodate a few mice at a time, and a technical capability that few institutions worldwide possess.
“To understand when and why harmful microbial glycogen is produced, the team will next conduct larger studies surveying gut microbiome communities in ALS/FTD patients before and after disease onset,” Burberry said. “Clinical trials to determine whether glycogen degradation in ALS/FTD patients could slow disease progression are also supported by our findings and could begin in a year.”
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