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Gut Barrier Dysfunction-A Primary Defect in Twins with Crohns Disease Predominantly Caused by Genetic Predisposition
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0002-6820-0215
Örebro University, Örebro, Sweden .
Aleris Medilab, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
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2018 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 12, no 10, p. 1200-1209Article in journal (Refereed) Published
Abstract [en]

Background and Aims: The aetiology of Crohns disease is poorly understood. By investigating twin pairs discordant for Crohns disease, we aimed to assess whether the dysregulated barrier represents a cause or a consequence of inflammation and to evaluate the impact of genetic predisposition on barrier function. Methods: Ileal biopsies from 15 twin pairs discordant for Crohns disease [monozygotic n = 9, dizygotic n = 6] and 10 external controls were mounted in Ussing chambers to assess paracellular permeability to (51)Chromium [Cr]-EDTA and trancellular passage to non-pathogenic E. coli K-12. Experiments were performed with and without provocation with acetylsalicylic acid. Immunofluorescence and ELISA were used to quantify the expression level of tight junction proteins. Results: Healthy co-twins and affected twins displayed increased Cr-51-EDTA permeability at 120 min, both with acetylsalicylic acid [p amp;lt; 0.001] and without [p amp;lt; 0.001] when compared with controls. A significant increase in Cr-51-EDTA flux was already seen at 20 min in healthy monozygotic co-twins compared with controls [p amp;lt;= 0.05] when stratified by zygosity, but not in healthy dizygotic co-twins. No difference in E. coli passage was observed between groups. Immunofluorescence of the tight junction proteins claudin-5 and tricellulin showed lower levels in healthy co-twins [p amp;lt; 0.05] and affected twins [p amp;lt; 0.05] compared with external controls, while ELISA only showed lower tricellulin in Crohns disease twins [p amp;lt; 0.05]. Conclusion: Our results suggest that barrier dysfunction is a primary defect in Crohns disease, since changes were predominantly seen in healthy monozygotic co-twins. Passage of E. coli seems to be a consequence of inflammation, rather than representing a primary defect.

Place, publisher, year, edition, pages
Oxford University Press, 2018. Vol. 12, no 10, p. 1200-1209
Keywords [en]
Crohns disease; barrier function; genetics
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:liu:diva-154129DOI: 10.1093/ecco-jcc/jjy045ISI: 000455271000008PubMedID: 29659773OAI: oai:DiVA.org:liu-154129DiVA, id: diva2:1283576
Note

Funding Agencies|Swedish Research Council-Medicine [VR-MH 2014-02537, 521-2011-2764]; Region Ostergotland, ALF research funds of Linkoping University

Available from: 2019-01-29 Created: 2019-01-29 Last updated: 2019-08-06

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