Bacterial glycogen acts as a modifiable mediator of immune homeostasis in the gut and brain, with C9orf72 in myeloid cells preventing an inflammatory response to microbial glycogen, and inflammatory glycogen being detected in gut contents from 15/22 ALS patients compared to 4/12 healthy controls.
Key Findings
Results
Ten phylogenetically diverse bacterial strains promote cytokine release in a C9orf72-dependent manner.
The 10 strains were identified through a screen for bacteria that promote cytokine release dependent on C9orf72 function.
The strains were phylogenetically diverse, suggesting this is not a lineage-specific phenomenon.
C9orf72 function in myeloid cells was specifically implicated in the inflammatory response.
Results
Metatranscriptomics implicated the glycogen biosynthesis pathway as a driver of C9orf72-dependent inflammation.
Metatranscriptomic analysis was used to identify bacterial pathways associated with the inflammatory response.
The glycogen biosynthesis pathway was identified as a key driver among the implicated bacterial metabolic routes.
This finding linked microbial carbohydrate metabolism to host immune responses in the context of C9orf72 deficiency.
Results
Colonization of germ-free C9orf72-deficient mice with glycogen-producing Parabacteroides merdae enhanced monocytosis, blood-brain barrier breakdown, and T cell infiltration into the CNS.
Germ-free C9orf72-deficient mice were colonized with Parabacteroides merdae strains that produced inflammatory glycogen.
Colonization resulted in enhanced monocytosis, indicating systemic immune activation.
Blood-brain barrier breakdown was observed, indicating peripheral inflammation translated to CNS effects.
T cell infiltration into the central nervous system was also enhanced following colonization.
Results
Enzymatic digestion of glycogen in the gut promoted survival of C9orf72-deficient mice and dampened microglial reactivity in the brain.
Enzymatic digestion was used as an intervention to degrade bacterial glycogen within the gut.
This treatment promoted survival in C9orf72-deficient mice, suggesting glycogen is a pathologically relevant mediator.
Microglial reactivity in the brain was dampened following gut glycogen digestion, linking gut glycogen to neuroinflammation.
These results identify bacterial glycogen as a modifiable target.
Results
Inflammatory forms of bacterial glycogen were detected in fecal samples from 15/22 ALS patients, 1/1 C9ORF72 FTD patient, and 4/12 healthy controls.
A survey of human fecal samples was conducted to assess the presence of inflammatory glycogen.
Inflammatory glycogen was found in 15 out of 22 (68%) patients with ALS.
1 out of 1 patient with C9ORF72 frontotemporal dementia (FTD) had detectable inflammatory glycogen.
Only 4 out of 12 (33%) healthy controls had detectable inflammatory glycogen, suggesting enrichment in disease states.
Results
C9orf72 functions in myeloid cells to prevent an inflammatory response to microbial glycogen.
The study identifies C9orf72's role specifically in myeloid cells as critical for regulating inflammatory responses.
Loss of C9orf72 function in myeloid cells renders the host susceptible to glycogen-driven inflammation.
This mechanism connects a causal ALS/FTD genotype to gut microbiome-derived inflammatory signals.
Conclusions
Gut dysbiosis and microbial glycogen represent potentially modifiable mediators of immune homeostasis in both the gut and brain in the context of ALS-associated C9ORF72 mutations.
The study situates bacterial glycogen as a 'modifiable mediator of immune homeostasis in the gut and brain.'
The findings are relevant to ALS patients including those with causal C9ORF72 mutations.
Enzymatic glycogen digestion as an intervention demonstrates therapeutic modifiability of this pathway.