In a new study published in Cell Reports titled, “C9orf72 in myeloid cells prevents an inflammatory response to microbial glycogen,” researchers from Case Western Reserve University have identified a link between gut bacteria and the deterioration of the brain in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Results identified bacterial sugars that cause neurodegenerative immune responses, providing a mechanism for therapeutic intervention.
The human gastrointestinal tract is a large source of neuromodulatory factors and represents the largest site of microbial–host interactions, with an estimated 100 trillion microorganisms interfaced by 70%–80% of the body’s immune cells. Disruption to the microbe-immune-brain axis may contribute to neurodegeneration risk. However, how the gut microbiome is altered in patients with ALS is not understood.
“We found that harmful gut bacteria produce inflammatory forms of glycogen, and that these bacterial sugars trigger immune responses that damage the brain,” said Aaron Burberry, PhD, assistant professor in the department of pathology at the Case Western Reserve School of Medicine and co-corresponding author of the study.
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. While most causes of ALS and FTD cases are unknown, researchers have investigated the role of genetics, environmental issues, brain injuries and diet in neurodegeneration.
The authors reported that 70% of the 23 ALS/FTD patients examined had dangerous glycogen levels. Only one third of patients without the brain diseases displayed 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. New treatments can break down harmful sugars in the gut while opening the door to developing drugs that target the connection between the digestive system and the brain.
Alex Rodriguez-Palacios, DVM, PhD, assistant professor in the Digestive Health Research Institute at the School of Medicine and co-corresponding author of the study, said reducing the harmful sugars “improved brain health and extended lifespan.”
The discovery is particularly significant for 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 do not, identifying gut bacteria as a key environmental trigger.
The study was possible due to Case Western Reserve’s unique ability to conduct studies using germ-free mouse models, which allowed the researchers to study how specific gut bacteria affect brain diseases. While traditional methods could only accommodate a few mice at a time, the design allows large-scale microbiological studies for understanding the complex communication between the gut and brain.
Burberry says the team will next conduct larger studies surveying gut microbiome communities in ALS/FTD patients before and after disease onset to understand when and why harmful microbial glycogen is produced. He notes that clinical trials to determine whether glycogen degradation in ALS/FTD patients could slow disease progression are supported by the findings and could begin in a year.
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