Fig. 9

ABX-treatment induced changes in gut-metabolites provides metabolic support for microglial neuroprotective phenotype in male AD mice. Schematic to show metabolic and epigenetic coordination of microglial translatome in ABX-treated APPPS1-21-CD11br male mice. The upregulated DEPs identified from the proteomic analysis are represented in red (bold). Microglial polarization states and immune functions are regulated by their metabolic adaptation. ABX-treatment showed increase in Slc2a3 (glucose transporter), Pfkl (glucose metabolism), Gpd2 (Calcium-responsive, increases glucose oxidation to fuel the production of acetyl co-A); Pcx (catalyzes formation of oxaloacetate required for biosynthetic pathways); Bdh1 (interconversion of acetoacetate and β-hydroxybutyrate, the two major ketone bodies produced during fatty acid metabolism); Ndufa9, Ndufb10 (NADH: ubiquinone oxidoreductase, Complex I, Electron transport Chain to synthesize ATP); Gpx1 (antioxidant activity). This metabolic shift can support production of stable intermediates to maintain the oxidative status and energetics of the cell. Acetyl-CoA that serves as universal substrate for the acetylation of histones by Histone acetyl transferases (HAT) results in open chromatin structure for positive transcriptional regulation. NAD⁺ functions as a cofactor for Sirtuin (SIRTs) histone deacetylase (HDAC) enzymes leading to heterochromatin formation [92]. Metabolites derived from gut bacteria (ligands for Aryl hydrocarbon receptor (AHR) & G protein coupled receptors (GPR)) including SCFAs like succinate, amino-acid derivatives like desaminotyrosine and Tryptophan metabolites like Kynurenic acid and Indole-3-lactic acid can improve the cellular energy state required for microglial immune modulation. The rescue in the expression of Atp6v0d1 (lysosomal v-ATPase component) in ABX-treated male AD mice indicates that this metabolic flexibility is crucial for mitochondrial and lysosomal crosstalk to facilitate Aβ clearance by lysosomal acidification