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Conversely, vagal stimulation restored neuromodulation and ameliorated colitis by inhibiting the posttranslational modification SUMOylation through a mechanism independent of the canonical interleukin-10\/\u03b17 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\n            <jats:italic>Sumo3<\/jats:italic>\n            protected against development of colitis and delayed onset of disease, whereas deletion of\n            <jats:italic>Sumo1<\/jats:italic>\n            halted the progression of colitis. Bone marrow transplants from\n            <jats:italic>Sumo1<\/jats:italic>\n            -knockout (KO) but not\n            <jats:italic>Sumo3<\/jats:italic>\n            -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\n            <jats:italic>Sumo1<\/jats:italic>\n            -KO mice and resulted in milder symptoms in\n            <jats:italic>Sumo3<\/jats:italic>\n            -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.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adl2184","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T18:58:11Z","timestamp":1732129091000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":29,"title":["Vagal stimulation ameliorates murine colitis by regulating SUMOylation"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9589-4155","authenticated-orcid":true,"given":"Ayman","family":"Youssef","sequence":"first","affiliation":[{"name":"Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA."},{"name":"Autonomic Dysfunction Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0755-225X","authenticated-orcid":true,"given":"Ata Ur","family":"Rehman","sequence":"additional","affiliation":[{"name":"Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6465-1488","authenticated-orcid":true,"given":"Mohamed","family":"Elebasy","sequence":"additional","affiliation":[{"name":"Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8851-1352","authenticated-orcid":true,"given":"Jatin","family":"Roper","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Duke University, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shehzad Z.","family":"Sheikh","sequence":"additional","affiliation":[{"name":"University of North Carolina, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, NC 27599, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4240-229X","authenticated-orcid":true,"given":"Jorn","family":"Karhausen","sequence":"additional","affiliation":[{"name":"Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA."},{"name":"Humanitas Research Hospital, Rozzano, MI 20089, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5719-4393","authenticated-orcid":true,"given":"Wei","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7702-7549","authenticated-orcid":true,"given":"Luis","family":"Ulloa","sequence":"additional","affiliation":[{"name":"Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm12020641"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.10.001"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1503\/cmaj.190976"},{"key":"e_1_3_2_5_2","first-page":"A661","article-title":"Sepsis in the settings of inflammatory bowel disease: Studying the outcomes of more than 8 million patients","volume":"162","author":"Aldiabat M.","year":"2022","unstructured":"M. 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