The gut microbiota affects amyloid deposition in Alzheimer’s disease models by suppressing immune-mediated Aβ clearance

Abstract The gut microbiota and innate immune system play critical roles in Alzheimer’s disease (AD). Bacteroides is elevated in AD patients and correlates with cerebrospinal fluid levels of Aβ and tau. We found that increased Aβ plaques in Bacteroides fragilis-treated APP/PS1-21 mice were associated with altered cortical expression Aβ processing genes. B. fragilis suppressed peripheral CD4+ T cell production of GM-CSF and IL-4 and transcriptional changes in microglia related to GM-CSF and IL-4 signaling, phagocytosis, and protein degradation. Furthermore, B. fragilis impaired the microglial uptake of intracranially injected Aβ42, whereas Erysipelotrichaceae strains increased uptake. Depleting murine Bacteroidetes with metronidazole decreased amyloid load in aged 5xFAD mice, increased CD4+ T cell GM-CSF production, and activated microglial pathways related to cytokine signaling, phagocytosis and lysosomal degradation. These data suggest that the gut microbiome may contribute to AD pathogenesis by suppressing peripheral cytokines and microglia phagocytic function, leading to impaired immune-mediated Aβ clearance.