Bacterial peptidoglycan serves as a critical modulator of the gut-immune-brain axis in Drosophila

•In line with our prior studies in mice, gut bacteria-derived PGN fragments disseminate and reach the Drosophila brain.•Sensing of circulating PGN fragments triggers immune and stress signaling pathways in the central nervous system.•Gut derived PGN fragments primarily induce an inflammatory response in perineurial glia at the brain-circulation interface.•Continuous activation of immune signaling in perineurial glia correlates with neurological decline and reduced lifespan. Metabolites and compounds derived from gut-associated bacteria can modulate numerous physiological processes in the host, including immunity and behavior. Using a model of oral bacterial infection, we previously demonstrated that gut-derived peptidoglycan (PGN), an essential constituent of the bacterial cell envelope, influences female fruit fly egg-laying behavior by activating the NF-κB cascade in a subset of brain neurons. These findings underscore PGN as a potential mediator of communication between gut bacteria and the brain in Drosophila, prompting further investigation into its impact on all brain cells. Through high-resolution mass spectrometry, we now show that PGN fragments produced by gut bacteria can rapidly reach the central nervous system. In Addition, by employing a combination of whole-genome transcriptome analyses, comprehensive genetic assays, and reporter gene systems, we reveal that gut bacterial infection triggers a PGN dose-dependent NF-κB immune response in perineurial glia, forming the continuous outer cell layer of the blood–brain barrier. Furthermore, we demonstrate that persistent PGN-dependent NF-κB activation in perineurial glial cells correlates with a reduction in lifespan and early neurological decline. Overall, our findings establish gut-derived PGN as a critical mediator of the gut-immune-brain axis in Drosophila.