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Oral Administration of Plant Exosome-Like Nanoparticles Inhibits Brain Inflammation by Targeting Microglial Cells and Gut Akkermansia Muciniphila in Obese Mice

Diet influences brain function via inflammatory pathways. However, the molecular mechanisms by which diet intake modulates neuroinflammation are poorly understood. Here we show that garlic exosome-like nanoparticles (GaELNs) inhibited systemic as well as brain inflammatory activity and reverses the insulin resistance in a high-fat diet (HFD) induced mouse obesity model. Oral administration of GaELNs and outer membrane vesicles (OMVs) released from GaELNs manipulated Akkermansia muciniphila are selectively taken up by microglial cells and inhibits its activation. Mechanistically, GaELNphosphatidic acid (PA) (36:4) is required for the uptake of GaELNs via binding microglial brain acid‐soluble protein 1 (BASP1). Formation of the GaELNs/BASP1 complex is required for inhibition of c-Myc mediated expression of STING. Inhibition of STING activity leads to reducing the expression of an array of inflammatory cytokines including IFN-g. IFN-g induces the expression of IDO-1, which in turn IDO-1 mediated metabolites activate the AhR pathway that contributes to insulin resistance. Oral administration of GaELNs decreases the level of IDO-1 metabolites, kynurenine (KYN) which promotes insulin resistance via the AhR pathway in HFD mice. The significance in increased fecal KYN was further demonstrated in the fecal samples of type 2 diabetes patients. Our results further show that the OMVs released from GaELNs treated Akkermansia muciniphila inhibits the expression of microglial IFN-g and prevents KYN mediated IRS-1 and 2 expression in microglial cells. Collectively, these results demonstrate how nanoparticles from a healthy diet can reverse high-fat diet induced brain inflammation and reveal a link between brain microglia/gut microbiota to brain inflammatory disease outcomes via diet-derived exosome-like nanoparticles.