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Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease
  1. S Zeissig1,
  2. N Bürgel1,
  3. D Günzel2,
  4. J Richter2,
  5. J Mankertz1,
  6. U Wahnschaffe1,
  7. A J Kroesen3,
  8. M Zeitz1,
  9. M Fromm2,
  10. J-D Schulzke1
  1. 1Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité, Campus Benjamin Franklin, Berlin, Germany
  2. 2Department of Clinical Physiology, Charité, Campus Benjamin Franklin, Berlin, Germany
  3. 3Department of Surgery, Charité, Campus Benjamin Franklin, Berlin, Germany
  1. Correspondence to:
    J-D Schulzke
    Department of Gastroenterology, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany; joerg.schulzke{at}


Background: Epithelial barrier function is impaired in Crohn’s disease.

Aim: To define the underlying cellular mechanisms with special attention to tight junctions.

Methods: Biopsy specimens from the sigmoid colon of patients with mild to moderately active or inactive Crohn’s disease were studied in Ussing chambers, and barrier function was determined by impedance analysis and conductance scanning. Tight junction structure was analysed by freeze fracture electron microscopy, and tight junction proteins were investigated immunohistochemically by confocal laser scanning microscopy and quantified in immunoblots. Epithelial apoptosis was analysed in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling and 4′,6-diamidino-2-phenylindole staining.

Results: Patients with active Crohn’s disease showed an impaired intestinal barrier function as indicated by a distinct reduction in epithelial resistance. As distribution of conductivity was even, focal epithelial lesions (eg, microerosions) did not contribute to barrier dysfunction. Instead, freeze fracture electron microscopy analysis showed reduced and discontinuous tight junction strands. Occludin and the sealing tight junction proteins claudin 5 and claudin 8 were downregulated and redistributed off the tight junction, whereas the pore-forming tight junctions protein claudin 2 was strongly upregulated, which constitute the molecular basis of tight junction changes. Other claudins were unchanged (claudins 1, 4 and 7) or not detectable in sigmoid colon (claudins 11, 12, 14, 15 and 16). Claudin 2 upregulation was less pronounced in active Crohn’s disease compared with active ulcerative colitis and was inducible by tumour necrosis factor α. As a second source of impaired barrier function, epithelial apoptosis was distinctly increased in active Crohn’s disease (mean (SD) 5.2 (0.5)% v 1.9 (0.2)% in control). By contrast, barrier function, tight junction proteins and apoptosis were unaffected in Crohn’s disease in remission.

Conclusion: Upregulation of pore-forming claudin 2 and downregulation and redistribution of sealing claudins 5 and 8 lead to altered tight junction structure and pronounced barrier dysfunction already in mild to moderately active Crohn’s disease.

  • DAPI, 4′,6-diamidino-2-phenylindole
  • IFN, interferon
  • IL, interleukin
  • H&E, haematoxylin and eosin
  • IBD, inflammatory bowel disease
  • IFN, interferon
  • TNF, tumour necrosis factor
  • TUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling

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  • Published Online First 5 July 2006

  • Funding: This study was supported by grants from Deutsche Forschungsgemeinschaft (DFG graduate scholarship 276/2, DFG Schu 559/7-4), DFG Schu 559/9-1 Deutsche Morbus Crohn/Colitis ulcerosa Vereinigung-DCCV-e.V, the German BMBF/DLR in the medical competence network inflammatory bowel disease, the Sonnenfeld-Stiftung Berlin and the Else Kroener-Fresenius-Stiftung.

  • Competing interests: None.

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