{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T19:52:07Z","timestamp":1787601127313,"version":"build-2736575974"},"reference-count":41,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T00:00:00Z","timestamp":1676937600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["FASEB BioAdvances"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The intestinal microbiome has emerged as a potential contributor to the severity of sickle cell disease (SCD). We sought to determine whether SCD mice exhibit intestinal barrier dysfunction, inflammation, and dysbiosis. Using the Townes humanized sickle cell mouse model, we found a 3\u2010fold increase in intestinal permeability as assessed via FITC\u2010dextran (4\u2009kDa) assay in SS (SCD) mice compared to AA (wild type) mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a04, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). This was associated with 25 to 50% decreases in claudin\u20101, 3, and 15 and zonula occludens\u20101 gene expression (<jats:italic>n<\/jats:italic>\u00a0=\u00a08\u201310, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) in the small intestine. Increased Ly6G staining demonstrated more neutrophils in the SS small intestine (3\u2010fold, <jats:italic>n<\/jats:italic>\u00a0=\u00a05, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) associated with increased expression of TNF\u03b1, IL\u201017A, CXCL1, and CD68 (2.5 to 5\u2010fold, <jats:italic>n<\/jats:italic>\u00a0=\u00a07\u201310, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). In addition, we observed 30 to 55% decreases in superoxide dismutase\u20101, glutathione peroxidase\u20101, and catalase antioxidant enzyme expression (<jats:italic>n<\/jats:italic>\u00a0=\u00a07\u20138, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) concomitant to an increase in superoxide (2\u2010fold, <jats:italic>n<\/jats:italic>\u00a0=\u00a04, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Importantly, all significant observations of a leaky gut phenotype and inflammation were limited to the small intestine and not observed in the colon. Finally, characterization of the composition of the microbiome within the small intestine revealed dysbiosis in SS mice compared to their AA littermates with 47 phyla to species\u2010level significant alterations in amplicon sequence variants. We conclude that the intestinal barrier is compromised in SCD, associated with decreased gene expression of tight junction proteins, enhanced inflammation, oxidative stress, and gut microbiome dysbiosis, all specific to the small intestine.<\/jats:p>","DOI":"10.1096\/fba.2022-00121","type":"journal-article","created":{"date-parts":[[2023,2,12]],"date-time":"2023-02-12T23:43:44Z","timestamp":1676245424000},"page":"199-210","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Intestinal barrier dysfunction in murine sickle cell disease is associated with small intestine neutrophilic inflammation, oxidative stress, and dysbiosis"],"prefix":"10.1096","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6113-7815","authenticated-orcid":false,"given":"Caitlin V.","family":"Lewis","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Sellak","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariem A.","family":"Sawan","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giji","family":"Joseph","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor M.","family":"Darby","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"VanInsberghe","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal R.","family":"Naudin","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Archer","sequence":"additional","affiliation":[{"name":"Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta and Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0415-9487","authenticated-orcid":false,"given":"Rheinallt M.","family":"Jones","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5765-2419","authenticated-orcid":false,"given":"W. 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