Article ; Online: CDT of
2023 Volume 15, Issue 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. |
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| MeSH term(s) | 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 |
| Chemical Substances | Tight Junction Proteins |
| Language | English |
| Publishing date | 2023-01-07 |
| Publishing country | Switzerland |
| Document type | 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 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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