Abstract
Inflammatory bowel diseases (IBDs) are chronic debilitating conditions without cure, the etiologies of which are unknown, that shorten the lifespans of 7 million patients worldwide by nearly 10%. Here, we found that decreased autonomic parasympathetic tone resulted in increased IBD susceptibility and mortality in mouse models of disease. Conversely, vagal stimulation restored neuromodulation and ameliorated colitis by inhibiting the posttranslational modification SUMOylation through a mechanism independent of the canonical interleukin-10/α7 nicotinic cholinergic vagal pathway. Colonic biopsies from patients with IBDs and mouse models showed an increase in small ubiquitin-like modifier (SUMO)2 and SUMO3 during active disease. In global genetic knockout mouse models, the deletion of Sumo3 protected against development of colitis and delayed onset of disease, whereas deletion of Sumo1 halted the progression of colitis. Bone marrow transplants from Sumo1-knockout (KO) but not Sumo3-KO mice into wild-type mice conferred protection against development of colitis. Electric stimulation of the cervical vagus nerve before the induction of colitis inhibited SUMOylation and delayed the onset of colitis in Sumo1-KO mice and resulted in milder symptoms in Sumo3-KO mice. Treatment with TAK-981, a first-in-class inhibitor of the SUMO-activating enzyme, ameliorated disease in three murine models of IBD and reduced intestinal permeability and bacterial translocation in a severe model of the disease, suggesting the potential to reduce progression to sepsis. These results reveal a pathway of vagal neuromodulation that reprograms endogenous stress-adaptive responses through inhibition of SUMOylation and suggest SUMOylation as a therapeutic target for IBD.