Researchers here provide evidence for glycogen produced by the gut microbiome to contribute to age-related neurodegeneration. A mutation associated with amyotrophic lateral sclerosis and frontotemporal dementia appears to make the inflammatory consequences of microbiome-derived glycogen worse, thus potentially explaining its relevance to disease. But the prevalence of the microbes involved in the production of glycogen in the gut microbiome of patients with these conditions suggests that every older person is impacted by this mechanism to some degree, with that degree being dependent on the exact composition of the gut microbiome. This is one of a range of studies showing at least some correlation between gut microbiome composition and specific age-related conditions, and as illustrated here, researchers are starting to move beyond correlation to explore the mechanisms responsible.
Gut dysbiosis and neural inflammation occur in patients with amyotrophic lateral sclerosis (ALS), including those with a causal mutation in chromosome 9 open reading frame 72 (C9ORF72). How gut commensals interact with common ALS genotypes to impart risk of neural degeneration remains unclear. Here, we identify 10 phylogenetically diverse bacterial strains that promote cytokine release in a C9orf72-dependent manner. Metatranscriptomics implicated the glycogen biosynthesis pathway as a driver of inflammation.
Colonization of germ-free C9orf72-deficient mice with Parabacteroides merdae that produced inflammatory glycogen enhanced monocytosis, blood-brain barrier breakdown, and T cell infiltration into the central nervous system. Enzymatic digestion of glycogen in the gut promoted survival of C9orf72-deficient mice and dampened microglial reactivity in the brain.
A survey of human fecal samples demonstrated that inflammatory forms of glycogen were present in gut contents from 15/22 patients with ALS, 1/1 patient with C9ORF72 frontotemporal dementia (FTD), and 4/12 healthy controls. Together, the results of this work identify bacterial glycogen as a modifiable mediator of immune homeostasis in the gut and brain.
Link: https://doi.org/10.1016/j.celrep.2025.116906
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