Gut Bacteria Sugars Trigger Immune Attacks Linked to ALS and Frontotemporal Dementia
Researchers at Case Western Reserve University School of Medicine published a study Tuesday in *Cell Reports* identifying sugars produced by gut bacteria as triggers for immune attacks linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). According to the study led by Aaron Burberry, PhD, these bacterial glycogen molecules provoke inflammation that damages brain cells, especially in individuals with deficient C9orf72 gene function.
The study, titled “C9orf72 in myeloid cells prevents an inflammatory response to microbial glycogen,” was published Tuesday in *Cell Reports* by researchers at Case Western Reserve University School of Medicine. Led by Aaron Burberry, PhD, professor of immunology and microbiology, the research identified glycogen molecules produced by certain gut bacteria as key triggers of inflammatory immune responses linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
The findings show that these bacterial glycogen molecules provoke inflammation that damages brain cells, particularly in individuals with deficient function of the C9orf72 gene, a common genetic risk factor for ALS and FTD.
According to the study, harmful gut bacteria produce inflammatory forms of glycogen, a sugar molecule that can cross the gut barrier and enter circulation due to disruptions in intestinal integrity. This bacterial glycogen activates neuroimmune responses involving microglia, inflammasomes, complement proteins, and cytokines, leading to inflammation and neuronal damage. The inflammatory response is especially pronounced in cells lacking C9orf72 function, which normally acts in myeloid immune cells to suppress this reaction to microbial glycogen, the researchers said.
Experimental evidence presented in the study demonstrated that degrading bacterial glycogen reduced inflammation in cellular models and extended survival in C9orf72-deficient mouse models of ALS. Burberry and his team noted that treatment strategies targeting glycogen degradation could potentially slow disease progression. The research also indicated that certain gut bacteria are responsible for producing this inflammatory glycogen, and that manipulating the microbiome to reduce these bacteria or their glycogen products might offer therapeutic benefits.
Additional findings from related studies highlight the complex role of the gut-brain axis in ALS. Research involving SOD1^G93A^ mouse models of ALS showed an altered ratio of Firmicutes to Bacteroides bacteria and disrupted gut barrier function, which contributes to systemic inflammation and neurodegeneration, according to a 2023 study from the University of California, San Diego. These mice exhibited reductions in short-chain fatty acids (SCFAs), metabolites produced by beneficial gut bacteria that regulate central nervous system immune cells, including microglia. Probiotic supplementation in these models increased SCFA levels and restored microbiota balance, improving intestinal barrier integrity.
In particular, butyrate-producing bacteria such as *Butyrivibrio fibrisolvens* were found to be diminished in ALS mouse models. Supplementation with butyrate restored the intestinal barrier and reduced inflammatory markers, according to a 2023 publication in *Frontiers in Neuroscience*. The autophagy-lysosomal pathway, implicated in cellular waste clearance, was also affected, with increased accumulation of the protein p62 observed in the spinal cords of ALS models, suggesting impaired cellular clearance mechanisms contribute to disease pathology.
The gut microbiota’s influence extends beyond metabolic effects; dysregulation of gut ecology induces brain-gut signaling changes, endotoxemia, and systemic inflammation, the researchers said. Abnormal Paneth cells and elevated levels of the pro-inflammatory cytokine IL-17 were detected in the intestines and blood of ALS mice, further linking immune dysregulation to disease progression. These findings align with the growing body of evidence that alterations in gut microbiota contribute to ALS and FTD through immunologic, metabolic, and neuronal signaling pathways.
Therapeutic approaches targeting the microbiome have shown promise in preclinical models. Antibiotic treatment, phage therapy, and probiotic supplementation have been reported to inhibit inflammation and delay ALS progression in animal studies, according to a 2023 review by neuroscientists at Johns Hopkins University. Post-antibiotic therapies and dietary interventions aimed at modulating the gut microbiota are under investigation as potential strategies for managing ALS and FTD.
Burberry’s team plans to conduct larger studies surveying the gut microbiome in ALS and FTD patients before and after disease onset to better understand microbial contributions to pathogenesis. “We aim to analyze the microbiome community structure and identify why certain bacteria produce inflammatory glycogen,” Burberry said in a statement. The researchers emphasized the importance of clinical trials to test glycogen-degrading treatments, which could begin within the next year, pending regulatory approval.
Background context for these findings includes the recognition that C9orf72 gene mutations are the most common genetic cause of ALS and FTD, accounting for approximately 40% of familial cases. The gene’s role in regulating immune responses has been increasingly studied, with this latest research providing new insight into how microbial factors influence disease mechanisms. The study adds to a growing understanding that the gut microbiome and its metabolic products play a significant role in neurodegenerative diseases, supporting ongoing efforts to develop microbiome-based therapies for ALS subtypes.
