A novel brain-to-gut communication pathway mediated by astrocyte-derived small extracellular vesicles modulates stress-induced intestinal inflammation.

The connection between stress-induced mood disorders and inflammatory bowel diseases has long been acknowledged. Here, we hypothesize that psychological stress may regulate intestinal inflammation under stress conditions through the release of small extracellular vesicles derived from astrocytes (AsEVs). Sprague-Dawley rats were stressed by movement restriction. In-utero electroporation was performed to express a recombinant protein (BAP-TM) in astrocytes that is exported in AsEVs. AsEVs were also obtained from primary astrocyte cultures that were stimulated with DMSO or corticosterone (to emulate a stress condition). The inflammatory status in the blood and intestine was assessed by flow cytometry and histology, respectively. We found that recombinant AsEV proteins expressed in brain astrocytes as well as AsEVs harvested from primary astrocyte cultures contain the gut homing receptor CCR9 and target the small intestine in rats. At the histological level, inflammatory parameters (such as lymph vessel diameter or cell number in them) induced by movement restriction are restored to normal levels by treatment with AsEVs derived from primary astrocytes. On the contrary, AsEVs derived from corticosterone-treated astrocytes increase stress-induced intestinal inflammation. Furthermore, AsEVs can modulate the immune balance of the GALT: while AsEVs derived from control astrocyte cultures favor an anti-inflammatory profile (i.e., increased Treg/Th17 ratio), AsEVs derived from corticosterone-treated astrocytes have an opposite action. We here reveal an entirely new brain-to-gut AsEVs-mediated communication pathway that may impact on stress-induced inflammatory bowel pathophysiology. This research paves the way for novel, cutting-edge therapeutic approaches to tackle the complex interplay between stress and intestinal inflammatory diseases.