Gut butyrate deficiency impairs microglial amyloid clearance via HDAC2-mediated…

Gut dysbiosis in Alzheimer’s disease reduces butyrate-producing bacteria (Faecalibacterium prausnitzii, Roseburia intestinalis), causing systemic butyrate deficiency. Butyrate normally acts as an endogenous histone deacetylase (HDAC) inhibitor; decreased butyrate allows HDAC2 to suppress histone acetylation at promoters of anti-inflammatory genes in microglia, impairing their ability to phagocytose and clear amyloid-beta plaques. This HDAC2-mediated epigenetic silencing reduces expression of genes encoding phagocytic receptors (TREM2, CR3) and lysosomal enzymes, creating a feed-forward loop where accumulated amyloid further disrupts gut barrier integrity and exacerbates dysbiosis. Oral supplementation with butyrate or butyrate-producing bacterial consortia would restore microglial epigenetic regulation and enhance amyloid clearance.