Outer Membrane Vesicles Released from Garlic Exosome‐like Nanoparticles (GaELNs) Train Gut Bacteria that Reverses Type 2 Diabetes via the Gut‐Brain Axis

Abstract Gut microbiota function has numerous effects on humans and the diet humans consume has emerged as a pivotal determinant of gut microbiota function. Here, a new concept that gut microbiota can be trained by diet‐derived exosome‐like nanoparticles (ELNs) to release healthy outer membrane vesicles (OMVs) is introduced. Specifically, OMVs released from garlic ELN (GaELNs) trained human gut Akkermansia muciniphila (A. muciniphila) can reverse high‐fat diet‐induced type 2 diabetes (T2DM) in mice. Oral administration of OMVs released from GaELNs trained A. muciniphila can traffick to the brain where they are taken up by microglial cells, resulting in inhibition of high‐fat diet‐induced brain inflammation. GaELNs treatment increases the levels of OMV Amuc‐1100, P9, and phosphatidylcholines. Increasing the levels of Amuc‐1100 and P9 leads to increasing the GLP‐1 plasma level. Increasing the levels of phosphatidylcholines is required for inhibition of cGas and STING‐mediated inflammation and GLP‐1R crosstalk with the insulin pathway that leads to increasing expression of Insulin Receptor Substrate (IRS1 and IRS2) on OMV targeted cells. These findings reveal a molecular mechanism whereby OMVs from plant nanoparticle‐trained gut bacteria regulate genes expressed in the brain, and have implications for the treatment of brain dysfunction caused by a metabolic syndrome.