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Structural weakening of the colonic mucus barrier is an early event in ulcerative colitis pathogenesis

Journal article
Authors Sjoerd van der Post
Karolina S. Jabbar
George M. H. Birchenough
Liisa Arike
Noreen Akhtar
Henrik Sjövall
Malin E V Johansson
Gunnar C. Hansson
Published in Gut
Volume 68
Issue 12
Pages 2142-2151
ISSN 0017-5749
Publication year 2019
Published at Institute of Biomedicine
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 2142-2151
Language en
Links dx.doi.org/10.1136/gutjnl-2018-3175...
Keywords mucin, cells, inflammation, secretion, proteome, layers, crypt, Gastroenterology & Hepatology
Subject categories Gastroenterology and Hepatology

Abstract

Objective The colonic inner mucus layer protects us from pathogens and commensal-induced inflammation, and has been shown to be defective in active UC. The aim of this study was to determine the underlying compositional alterations, their molecular background and potential contribution to UC pathogenesis. Design In this single-centre case-control study, sigmoid colon biopsies were obtained from patients with UC with ongoing inflammation (n=36) or in remission (n=28), and from 47 patients without colonic disease. Mucus samples were collected from biopsies ex vivo, and their protein composition analysed by nanoliquid chromatography-tandem mass spectrometry. Mucus penetrability and goblet cell responses to microbial stimulus were assessed in a subset of patients. Results The core mucus proteome was found to consist of a small set of 29 secreted/transmembrane proteins. In active UC, major structural mucus components including the mucin MUC2 (p<0.0001) were reduced, also in non-inflamed segments. Active UC was associated with decreased numbers of sentinel goblet cells and attenuation of the goblet cell secretory response to microbial challenge. Abnormal penetrability of the inner mucus layer was observed in a subset of patients with UC (12/40; 30%). Proteomic alterations in penetrable mucus samples included a reduction of the SLC26A3 apical membrane anion exchanger, which supplies bicarbonate required for colonic mucin barrier formation. Conclusion Core mucus structural components were reduced in active UC. These alterations were associated with attenuation of the goblet cell secretory response to microbial challenge, but occurred independent of local inflammation. Thus, mucus abnormalities are likely to contribute to UC pathogenesis.

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