{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:18:33Z","timestamp":1789777113613,"version":"4.0.1"},"reference-count":60,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,4,19]],"date-time":"2017-04-19T00:00:00Z","timestamp":1492560000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK048373"],"award-info":[{"award-number":["DK048373"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of the New York Academy of Sciences"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:p>Increased small intestinal permeability (IP) has been proposed to be an integral element, along with genetic makeup and environmental triggers, in the pathogenies of chronic inflammatory diseases (CIDs). We identified zonulin as a master regular of intercellular tight junctions linked to the development of several CIDs. We aim to study the role of zonulin\u2010mediated IP in the pathogenesis of CIDs. Zonulin transgenic Hp2 mice (Ztm) were subjected to dextran sodium sulfate (DSS) treatment for 7 days, followed by 4\u20137 days' recovery and compared to C57Bl\/6 (wild\u2010type (WT)) mice. IP was measured <jats:italic>in vivo<\/jats:italic> and <jats:italic>ex vivo<\/jats:italic>, and weight, histology, and survival were monitored. To mechanistically link zonulin\u2010dependent impairment of small intestinal barrier function with clinical outcome, Ztm were treated with the zonulin inhibitor AT1001 added to drinking water in addition to DSS. We observed increased morbidity (more pronounced weight loss and colitis) and mortality (40\u201370% compared with 0% in WT) at 11 days post\u2010DSS treatment in Ztm compared with WT mice. Both <jats:italic>in vivo<\/jats:italic> and <jats:italic>ex vivo<\/jats:italic> measurements showed an increased IP at baseline in Ztm compared to WT mice, which was exacerbated by DSS treatment and was associated with upregulation of zonulin gene expression (fourfold in the duodenum, sixfold in the jejunum). Treatment with AT1001 prevented the DSS\u2010induced increased IP both <jats:italic>in vivo<\/jats:italic> and <jats:italic>ex vivo<\/jats:italic> without changing zonulin gene expression and completely reverted morbidity and mortality in Ztm. Our data show that zonulin\u2010dependent small intestinal barrier impairment is an early step leading to the break of tolerance with subsequent development of CIDs.<\/jats:p>","DOI":"10.1111\/nyas.13343","type":"journal-article","created":{"date-parts":[[2017,4,19]],"date-time":"2017-04-19T22:19:06Z","timestamp":1492640346000},"page":"130-142","source":"Crossref","is-referenced-by-count":73,"title":["Zonulin transgenic mice show altered gut permeability and increased morbidity\/mortality in the DSS colitis model"],"prefix":"10.1111","volume":"1397","author":[{"given":"Craig","family":"Sturgeon","sequence":"first","affiliation":[{"name":"Mucosal Immunology and Biology Research Center, Center for Celiac Research, and Division of Pediatric Gastroenterology and Nutrition Massachusetts General Hospital <i>for<\/i> Children  Boston Massachusetts"},{"name":"Graduate Program in Life Sciences University of Maryland School of Medicine  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinggang","family":"Lan","sequence":"additional","affiliation":[{"name":"Mucosal Immunology and Biology Research Center, Center for Celiac Research, and Division of Pediatric Gastroenterology and Nutrition Massachusetts General Hospital <i>for<\/i> Children  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Fasano","sequence":"additional","affiliation":[{"name":"Mucosal Immunology and Biology Research Center, Center for Celiac Research, and Division of Pediatric Gastroenterology and Nutrition Massachusetts General Hospital <i>for<\/i> Children  Boston Massachusetts"},{"name":"European Biomedical Research Institute of Salerno (EBRIS)  Salerno Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,4,19]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra020100"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.299.6710.1259"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.3109\/07853890.2010.514285"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3726"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2016.08.049"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2653"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2000.tb05244.x"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)02169-3"},{"issue":"24","key":"e_1_2_7_10_1","doi-asserted-by":"crossref","first-page":"4435","DOI":"10.1242\/jcs.113.24.4435","article-title":"Human zonulin, a potential modulator of intestinal tight junctions","volume":"113","author":"Wang W.","year":"2000","journal-title":"J. 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