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Open AccessArticle

Tilivalline- and Tilimycin-Independent Effects of Klebsiella oxytoca on Tight Junction-Mediated Intestinal Barrier Impairment

1
Medical Department of General, Visceral and Vascular Surgery, Charité – Universitätsmedizin Berlin, 12203 Berlin, Germany
2
Institute of Clinical Physiology/Nutritional Medicine, Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité – Universitätsmedizin Berlin, 12203 Berlin, Germany
3
Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria
4
BioTechMed-Graz, Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria
5
Division of Gastroenterology and Hepatology, Medical University of Graz, A-8036 Graz, Austria
6
Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité – Universitätsmedizin Berlin, 12203 Berlin, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(22), 5595; https://doi.org/10.3390/ijms20225595
Received: 4 September 2019 / Revised: 6 November 2019 / Accepted: 7 November 2019 / Published: 8 November 2019
(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)
Klebsiella oxytoca causes antibiotic-associated hemorrhagic colitis and diarrhea. This was attributed largely to its secreted cytotoxins tilivalline and tilimycin, inductors of epithelial apoptosis. To study whether Klebsiella oxytoca exerts further barrier effects, T84 monolayers were challenged with bacterial supernatants derived from tilivalline/tilimycin-producing AHC6 or its isogeneic tilivalline/tilimycin-deficient strain Mut-89. Both preparations decreased transepithelial resistance, enhanced fluorescein and FITC-dextran-4kDa permeabilities, and reduced expression of barrier-forming tight junction proteins claudin-5 and -8. Laser scanning microscopy indicated redistribution of both claudins off the tight junction region in T84 monolayers as well as in colon crypts of mice infected with AHC6 or Mut-89, indicating that these effects are tilivalline/tilimycin-independent. Furthermore, claudin-1 was affected, but only in a tilivalline/tilimycin-dependent manner. In conclusion, Klebsiella oxytoca induced intestinal barrier impairment by two mechanisms: the tilivalline/tilimycin-dependent one, acting by increasing cellular apoptosis and a tilivalline/tilimycin-independent one, acting by weakening the paracellular pathway through the tight junction proteins claudin-5 and -8. View Full-Text
Keywords: antibiotic-associated hemorrhagic colitis; tight junction; claudin; apoptosis; Klebsiella oxytoca antibiotic-associated hemorrhagic colitis; tight junction; claudin; apoptosis; Klebsiella oxytoca
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Hering, N.A.; Fromm, A.; Bücker, R.; Gorkiewicz, G.; Zechner, E.; Högenauer, C.; Fromm, M.; Schulzke, J.-D.; Troeger, H. Tilivalline- and Tilimycin-Independent Effects of Klebsiella oxytoca on Tight Junction-Mediated Intestinal Barrier Impairment. Int. J. Mol. Sci. 2019, 20, 5595.

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