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α-Haemolysin of Escherichia coli in IBD: a potentiator of inflammatory activity in the colon
  1. Roland Bücker1,
  2. Emanuel Schulz1,
  3. Dorothee Günzel2,
  4. Christian Bojarski1,
  5. In-Fah M Lee2,
  6. Lena J John1,
  7. Stephanie Wiegand1,
  8. Traute Janßen3,
  9. Lothar H Wieler3,
  10. Ulrich Dobrindt4,
  11. Lothar Beutin5,
  12. Christa Ewers6,
  13. Michael Fromm2,
  14. Britta Siegmund1,
  15. Hanno Troeger1,
  16. Jörg-Dieter Schulzke1
  1. 1Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
  2. 2Institute of Clinical Physiology, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
  3. 3Department of Veterinary Medicine, Institute of Microbiology and Epizootics, Freie Universität Berlin, Berlin, Germany
  4. 4Institute of Hygiene, University of Münster, Münster, Germany
  5. 5Bundesinstitut für Risikobewertung, Berlin, Germany
  6. 6Department of Veterinary Medicine, Institute of Hygiene and Infectious Diseases of Animals, Justus-Liebig-Universität Giessen, Giessen, Germany
  1. *Correspondence to
    Professor Jörg-Dieter Schulzke, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12203, Germany; joerg.schulzke{at}charite.de

Abstract

Objective α-Haemolysin (HlyA) influences host cell ionic homeostasis and causes concentration-dependent cell lysis. As a consequence, HlyA-producing Escherichia coli is capable of inducing ‘focal leaks’ in colon epithelia, through which bacteria and antigens translocate. This study addressed the role of HlyA as a virulence factor in the pathogenesis of colitis according to the ‘leaky gut’ concept.

Design To study the action of HlyA in the colon, we performed oral administration of HlyA-expressing E coli-536 and its isogenic α-haemolysin-deficient mutant (HDM) in three mouse models: wild type, interleukin-10 knockout mice (IL-10−/−) and monoassociated mice. Electrophysiological properties of the colonised colon were characterised in Ussing experiments. Inflammation scores were evaluated and focal leaks in the colon were assessed by confocal laser-scanning microscopy. HlyA quantity in human colon biopsies was measured by quantitative PCR.

Results All three experimental mouse models infected with HlyA-producing E coli-536 showed an increase in focal leak area compared with HDM. This was associated with a decrease in transepithelial electrical resistance and an increase in macromolecule uptake. As a consequence, inflammatory activity index was increased to a higher degree in inflammation-prone mice. Mucosal samples from human colon were E coli HlyA-positive in 19 of 22 patients with ulcerative colitis, 9 of 9 patients with Crohn's disease and 9 of 12 healthy controls. Moreover, focal leaks were found together with 10-fold increased levels of HlyA in active ulcerative colitis.

Conclusions E coli HlyA impairs intestinal barrier function via focal leak induction in the epithelium, thereby intensifying antigen uptake and triggering intestinal inflammation in vulnerable mouse models. Therefore, HlyA-expressing E coli strains should be considered as potential cofactors in the pathogenesis of intestinal inflammation.

  • Epithelial Barrier
  • Epithelial Permeability
  • Bacterial Pathogenesis
  • Bacterial Enterotoxins
  • Ulcerative Colitis

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