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 (IBD) has been well-established. However, the cellular mechanisms by which psychological stress can influence intestinal inflammation remain mostly enigmatic. Here, we hypothesize that psychological stress regulates intestinal inflammation through the release of small extracellular vesicles derived from astrocytes (AsEVs). In-utero electroporation performed to selectively express an AsEV-associated membrane recombinant protein in rat forebrain astrocytes reveals that this protein is transferred to the gut-associated lymphoid tissue (GALT). Similarly, AsEVs isolated from primary astrocyte cell cultures that were stimulated with vehicle or corticosterone (to emulate a stress condition) trafficked to the GALT. Interestingly, the membrane gut homing receptor CCR9 is present on AsEVs and mediate their association to the CCR9-endogenous ligand CCL25. At the histological level, inflammatory parameters (such as lymph vessel diameter or cell number in them), induced by a stress protocol based on movement restriction, increased by treatment with AsEVs from corticosterone-treated astrocytes. Furthermore, while AsEVs from control astrocyte cultures tends to favor an anti-inflammatory profile of the GALT (i.e., increased Treg/Th17 ratio), AsEVs derived from corticosterone-treated astrocytes have an opposite action. Similarly, in vitro experiments with disaggregated mesenteric lymph nodes reveal the immunomodulatory functions of AsEVs from corticosterone-treated astrocytes. These results start to delineate an entirely new brain-to-gut AsEVs-mediated communication pathway that may impact on stress-induced IBD pathophysiology and other stress-induced comorbidities.