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

Abstract

• 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 .

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