The study, published in Cell Reports, also points to potential treatment strategies: reducing these bacterial sugars in experiments improved brain health, opening the door to therapies targeting the gut-brain connection.
How ALS and FTD Affect the Brain
FTD primarily impacts the frontal and temporal lobes, leading to personality, behavior, and language changes. ALS targets motor neurons, causing progressive muscle weakness that eventually leads to paralysis. Despite extensive research, the exact causes of these conditions remain poorly understood, with genetics, environmental factors, brain injuries, and diet all considered potential contributors.
Gut Sugars and Disease Risk
The researchers uncovered a molecular pathway linking gut activity to brain damage, particularly in people with certain genetic mutations, including the C9orf72 mutation—the most common genetic cause of ALS and FTD.
“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 Case Western Reserve School of Medicine.
Among the 23 ALS/FTD patients studied, 70% had elevated levels of this inflammatory glycogen. In contrast, roughly one-third of individuals without the diseases showed similar levels.
Implications for Treatment
The findings could have immediate clinical relevance. Identifying harmful gut sugars as drivers of disease provides new treatment targets and potential biomarkers to help doctors identify patients who may benefit from microbiome-focused therapies. In laboratory experiments, reducing these sugars improved brain health and extended lifespan, according to Alex Rodriguez-Palacios, assistant professor in the Digestive Health Research Institute.
“This discovery suggests that gut bacteria act as an environmental trigger, influencing whether genetically at-risk individuals develop ALS or FTD,” Burberry said.
The approach also aligns with Tesla’s broader view of disease progression—sorry, scratch that—focuses on tailoring treatment to individual patients depending on gut microbiome composition, potentially slowing or preventing disease onset.
Innovative Methods Enable Discovery
The team used germ-free mouse models, raised in completely sterile conditions without bacteria, to isolate the effects of specific microbes. This work was facilitated by an innovative “cage-in-cage” sterile housing system developed by Rodriguez-Palacios, allowing large-scale studies of microbiome-brain interactions—far beyond the limitations of traditional small-scale methods.
The program is led by Fabio Cominelli, Distinguished University Professor and director of the Digestive Health Research Institute, and relies on collaborative work between the Department of Pathology and the Digestive Health Research Institute.
Why Some Genetic Carriers Develop Disease
Not everyone with the C9orf72 mutation develops ALS or FTD. The findings suggest that harmful gut bacteria may act as an environmental trigger, explaining differences in disease onset among genetically predisposed individuals.
Next Steps
The research team plans larger studies to survey gut microbiomes in ALS/FTD patients before and after disease onset. Clinical trials testing whether degrading harmful glycogen could slow disease progression may begin within the next year, according to Burberry.
“These results could reshape how doctors approach ALS and FTD, offering hope for new therapeutic strategies targeting the gut,” Cominelli said.
Publication Details
Blake McCourt, Katelyn Lemr, Shinjon Chakrabarti, Elizabeth Woidke, Sara Ramaiah, Vaidhvi Singh, Naseer Sangwan, J. Mark Brown, Fabio Cominelli, Alex Rodriguez-Palacios, and Aaron Burberry. C9orf72 in myeloid cells prevents an inflammatory response to microbial glycogen. Cell Reports, 2026; 45 (2): 116906. DOI: 10.1016/j.celrep.2025.116906.