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As tissue macrophages of the central nervous system (CNS), microglia constitute the pivotal immune cells of this organ. Microglial features are strongly dependent on environmental cues such as commensal microbiota. Gut bacteria are known to continuously modulate microglia maturation and function by the production of short-chain fatty acids (SCFAs). However, the precise mechanism of this crosstalk is unknown. Here we determined that the immature phenotype of microglia from germ-free (GF) mice is epigenetically imprinted by H3K4me3 and H3K9ac on metabolic genes associated with substantial functional alterations including increased mitochondrial mass and specific respiratory chain dysfunctions. We identified acetate as the essential microbiome-derived SCFA driving microglia maturation and regulating the homeostatic metabolic state, and further showed that it is able to modulate microglial phagocytosis and disease progression during neurodegeneration. These findings indicate that acetate is an essential bacteria-derived molecule driving metabolic pathways and functions of microglia during health and perturbation. [Display omitted] • Altered metabolic features of microglia in the absence of host microbiota • Bacteria-derived acetate modulates metabolic features of microglia during steady state • Acetate regulates microglial functions during neurodegeneration Acetate is the critical microbiome-derived SCFA driving microglia maturation and regulating the homeostatic metabolic state. In addition, acetate modulates microglial phagocytosis of amyloid beta and disease progression in a mouse model for Alzheimer's disease. [ABSTRACT FROM AUTHOR]