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Major unexplained symptoms of GWI include functional gastrointestinal disorders and undiagnosed illnesses, including neurologic disorders. Exposure to the antinerve gas drug pyridostigmine bromide (PB) is linked to the development of GWI, but the exact mechanisms remain unclear. Here, we tested the hypothesis that PB alters gut function by disrupting the neural and immune systems of the intestine. We exposed male and female mice to physiologically comparable amounts of PB that match the dose, route, and time frame of exposure experienced by Gulf War veterans and assessed the acute and chronic impacts on gastrointestinal functions, the functional architecture of the enteric nervous system, and immune responses in the gut and brain. Exposure to PB drove acute alterations to colonic motility and structure in both male and female mice that transitioned to chronic changes in gut functions. PB drove acute alterations to enteric neural and glial activity, glial reactivity, and neuron survival with glial reactivity persisting into the chronic phase in male mice. Despite having no effect on colonic permeability, exposure to PB caused major shifts in the expression of proinflammatory cytokines and chemokines in the colon and brain that suggest immunosuppressive effects. Interestingly, immune disruption was still evident in the colon and brain in female animals at 1 mo following exposure to PB. Together, our results show that the paradigm of PB exposure experienced by veterans of the Persian Gulf War contributes to long\u2010lasting pathophysiology by driving enteric neuroinflammation, promoting immunosuppression, and altering functional anatomy of the colon in a sex\u2010dependent manner.\u2014Hernandez, S., Fried, D. E., Grubi\u0161i\u0107, V., McClain, J. L., Gulbransen, B. D. Gastrointestinal neuroimmune disruption in a mouse model of Gulf War illness. FASEB J. 33, 6168\u20136184 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201802572r","type":"journal-article","created":{"date-parts":[[2019,2,21]],"date-time":"2019-02-21T14:00:44Z","timestamp":1550757644000},"page":"6168-6184","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Gastrointestinal neuroimmune disruption in a mouse model of Gulf War illness"],"prefix":"10.1096","volume":"33","author":[{"given":"Siomara","family":"Hernandez","sequence":"first","affiliation":[{"name":"Department of Physiology Michigan State University  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Fried","sequence":"additional","affiliation":[{"name":"Department of Physiology Michigan State University  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Grubi\u0161i\u0107","sequence":"additional","affiliation":[{"name":"Department of Physiology Michigan State University  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathon L.","family":"McClain","sequence":"additional","affiliation":[{"name":"Department of Physiology Michigan State University  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Gulbransen","sequence":"additional","affiliation":[{"name":"Department of Physiology Michigan State University  East Lansing Michigan USA"},{"name":"Neuroscience Program Michigan State University  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,2,21]]},"reference":[{"key":"e_1_2_10_2_1","volume-title":"Gulf War Illness and the Health of Gulf War Veterans: Scientific Findings and Recommendations","author":"Binns J.","year":"2008"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/AJP.0000000000000611"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/152.10.992"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0304-3959(02)00342-1"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/milmed\/164.5.327"},{"key":"e_1_2_10_7_1","first-page":"2494","article-title":"High prevalence of chronic gastrointestinal symptoms in a National Guard Unit of Persian Gulf veterans","volume":"91","author":"Sostek M. 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