Abstract Limiting inflammatory cell recruitment is a key focus in the search for new therapies in inflammatory bowel dis-eases (IBD). Our work documents that enhanced conjugation with Small Ubiquitin-like MOdifiers (SUMO) within the intestinal epithelium effectively blunts intestinal inflammation through broad reprogramming of responses regulating the tissue influx of immune cells. However, how SUMOylation is physiologically regulated is unkown, limiting our ability to harness this endogenous, protective mechanism for experimental and therapeutic use. Based on our preliminary findings, we hypothesize that intestinal SUMOylation is induced by stimulation of the vagus nerve identifying SUMOylation as a potentially critical anti-inflammatory effector mechanism of the brain-gut axis. Vagus nerves stimulation is used control inflammation and is endorsed by the NIH and WHO. Our objective is to define SUMOylation as a critical anti-inflammatory effector mechanism of this neuromodulatory intervention and in doing so, to develop specific approaches that harness SUMOylation for control of dysregulated intestinal in-flammation in IBD. Specifically: In Aim 1, we will determine the ability of vagus nerve stimulation to enhance SUMOylation in mice, and define the spleen as a key relay station of this pathway. In Aim 2, we will target major SUMO isoforms 1, 2 or 3, using our novel conditional knockout and transgenic mouse strains and establish the importance of intestinal epithelial SUMOylation for vagal anti-inflammatory ef-fects in two complementary murine models of IBD. Successful completion of these aims will constitute a major advance towards our long-term goal to translate our basic findings on SUMOylation as an endogenous, protective tissue response into novel anti-inflammatory ther-apies in IBD. By providing the mechanistic link to bioelectric stimulation techniques such as vagus nerve stimu-lation and electroacupuncture, we will not only greatly enhance the understanding of inflammatory control mech-anisms of the brain-gut axis, but will lay the foundation to the greater acceptance and improved targeting of bioelectric medicine in the therapy of dysregulated inflammation.