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  1. Artikel ; Online: CDT of

    Heils, Lucas / Schneemann, Martina / Gerhard, Ralf / Schulzke, Jörg-Dieter / Bücker, Roland

    Toxins

    2023  Band 15, Heft 1

    Abstract: Background: Clostridioides difficile binary toxin (CDT) defines the hypervirulence of strains in nosocomial antibiotic-induced colitis with the highest mortality. The objective of our study was to investigate the impact of CDT on the intestinal ... ...

    Abstract Background: Clostridioides difficile binary toxin (CDT) defines the hypervirulence of strains in nosocomial antibiotic-induced colitis with the highest mortality. The objective of our study was to investigate the impact of CDT on the intestinal epithelial barrier and to enlighten the underlying molecular mechanisms. Methods: Functional measurements of epithelial barrier function by macromolecular permeability and electrophysiology were performed in human intestinal HT-29/B6 cell monolayers. Molecular analysis of the spatial distribution of tight junction protein and cytoskeleton was performed by super-resolution STED microscopy. Results: Sublethal concentrations of CDT-induced barrier dysfunction with decreased TER and increased permeability for 332 Da fluorescein and 4 kDa FITC-dextran. The molecular correlate to the functional barrier defect by CDT was found to be a tight junction protein subcellular redistribution with tricellulin, occludin, and claudin-4 off the tight junction domain. This redistribution was shown to be MLCK-dependent. Conclusions: CDT compromised epithelial barrier function in a human intestinal colonic cell model, even in sublethal concentrations, pointing to barrier dysfunction in the intestine and leak flux induction as a diarrheal mechanism. However, this cannot be attributed to the appearance of apoptosis and necrosis, but rather to an opening of the paracellular leak pathway as the result of epithelial tight junction alterations.
    Mesh-Begriff(e) Humans ; Epithelial Cells/metabolism ; Clostridioides difficile ; Clostridioides ; HT29 Cells ; Intestinal Diseases ; Gastrointestinal Diseases ; Tight Junctions/metabolism ; Tight Junction Proteins/metabolism ; Intestinal Mucosa/metabolism ; Permeability ; Caco-2 Cells
    Chemische Substanzen Tight Junction Proteins
    Sprache Englisch
    Erscheinungsdatum 2023-01-07
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518395-3
    ISSN 2072-6651 ; 2072-6651
    ISSN (online) 2072-6651
    ISSN 2072-6651
    DOI 10.3390/toxins15010054
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: A Colonic Organoid Model Challenged with the Large Toxins of

    Schneemann, Martina / Heils, Lucas / Moos, Verena / Weiß, Franziska / Krug, Susanne M / Weiner, January / Beule, Dieter / Gerhard, Ralf / Schulzke, Jörg-Dieter / Bücker, Roland

    Toxins

    2023  Band 15, Heft 11

    Abstract: Background: Clostridioides difficile: Methods: Human adult colon organoids were cultured on membrane inserts. Tight junction (TJ) proteins and actin cytoskeleton were analyzed for expression via Western blotting and via confocal laser-scanning ... ...

    Abstract Background: Clostridioides difficile
    Methods: Human adult colon organoids were cultured on membrane inserts. Tight junction (TJ) proteins and actin cytoskeleton were analyzed for expression via Western blotting and via confocal laser-scanning microscopy for subcellular localization.
    Results: Polarized intestinal organoid monolayers were established from stem cell-containing colon organoids to apply toxins from the apical side and to perform functional measurements in the organoid model. The toxins caused a reduction in transepithelial electrical resistance in human colonic organoid monolayers with sublethal concentrations. Concomitantly, we detected increased paracellular permeability fluorescein and FITC-dextran-4000. Human colonic organoid monolayers exposed to the toxins exhibited redistribution of barrier-forming TJ proteins claudin-1, -4 and tricellulin, whereas channel-forming claudin-2 expression was increased. Perijunctional F-actin cytoskeleton organization was affected.
    Conclusions: Adult stem cell-derived human colonic organoid monolayers were applicable as a colon infection model for electrophysiological measurements. The TJ changes noted can explain the epithelial barrier dysfunction and diarrhea in patients, as well as increased entry of luminal antigens triggering inflammation.
    Mesh-Begriff(e) Humans ; Tight Junction Proteins/metabolism ; Bacterial Toxins/toxicity ; Bacterial Toxins/metabolism ; Clostridioides difficile/metabolism ; Tight Junctions/metabolism ; Clostridioides ; Colon ; Diarrhea ; Inflammation/metabolism ; Organoids ; Intestinal Mucosa
    Chemische Substanzen Tight Junction Proteins ; Bacterial Toxins
    Sprache Englisch
    Erscheinungsdatum 2023-11-04
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2518395-3
    ISSN 2072-6651 ; 2072-6651
    ISSN (online) 2072-6651
    ISSN 2072-6651
    DOI 10.3390/toxins15110643
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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