دورية أكاديمية
أعرض في EDS

A Colonic Organoid Model Challenged with the Large Toxins of Clostridioides difficile TcdA and TcdB Exhibit Deregulated Tight Junction Proteins.

التفاصيل البيبلوغرافية
العنوان: A Colonic Organoid Model Challenged with the Large Toxins of Clostridioides difficile TcdA and TcdB Exhibit Deregulated Tight Junction Proteins.
المؤلفون: Schneemann M; Clinical Physiology, Nutritional Medicine, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany., Heils L; Clinical Physiology, Nutritional Medicine, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany., Moos V; Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany., Weiß F; Clinical Physiology, Nutritional Medicine, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany., Krug SM; Clinical Physiology, Nutritional Medicine, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany., Weiner J; Core Unit Bioinformatics (CUBI), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany., Beule D; Core Unit Bioinformatics (CUBI), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany., Gerhard R; Institute of Toxicology, Hannover Medical School, 30625 Hannover, Germany., Schulzke JD; Clinical Physiology, Nutritional Medicine, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany., Bücker R; Clinical Physiology, Nutritional Medicine, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany.
المصدر: Toxins [Toxins (Basel)] 2023 Nov 04; Vol. 15 (11). Date of Electronic Publication: 2023 Nov 04.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101530765 Publication Model: Electronic Cited Medium: Internet ISSN: 2072-6651 (Electronic) Linking ISSN: 20726651 NLM ISO Abbreviation: Toxins (Basel) Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel : MDPI
مواضيع طبية MeSH: Bacterial Toxins*/toxicity , Bacterial Toxins*/metabolism , Clostridioides difficile*/metabolism, Humans ; Tight Junction Proteins/metabolism ; Tight Junctions/metabolism ; Clostridioides ; Colon ; Diarrhea ; Inflammation/metabolism ; Organoids ; Intestinal Mucosa
مستخلص: Background: Clostridioides difficile toxins TcdA and TcdB are responsible for diarrhea and colitis. Lack of functional studies in organoid models of the gut prompted us to elucidate the toxin's effects on epithelial barrier function and the molecular mechanisms for diarrhea and inflammation.
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.
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معلومات مُعتمدة: GRK 2318 - 318905415 (project C01) Deutsche Forschungsgemeinschaft; DFG Schu 559/11-5 - 175142815 Deutsche Forschungsgemeinschaft; TRR241 - 375876048 project B06 Deutsche Forschungsgemeinschaft
فهرسة مساهمة: Keywords: RNA-seq pathway analysis; actin; channel-forming claudin-2; claudin; cytokines; intestinal epithelial human colonic organoid monolayer; leak flux diarrhea; leaky gut; super-resolution STED microscopy; tricellulin
المشرفين على المادة: 0 (Tight Junction Proteins)
0 (Bacterial Toxins)
تواريخ الأحداث: Date Created: 20231124 Date Completed: 20231127 Latest Revision: 20240227
رمز التحديث: 20240227
مُعرف محوري في PubMed: PMC10674794
DOI: 10.3390/toxins15110643
PMID: 37999506
قاعدة البيانات: MEDLINE
الوصف
تدمد:2072-6651
DOI:10.3390/toxins15110643