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Mechanisms of epithelial barrier dysfunction in gastrointestinal infectious diseases

Subject Area Gastroenterology
Term from 2010 to 2025
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 175142815
 
Final Report Year 2025

Final Report Abstract

The aim of this project was to investigate intestinal infections and the resulting inflammation in order to decipher pathomechanisms in the interaction between pathogens and intestinal mucosa that are responsible for diarrhea and malabsorption, as well as increased antigen uptake and pathogen translocation. The elucidation of relevant pathomechanisms and regulatory influences on intestinal transport and barrier functions should lay the foundation for rational therapy and diagnostics. Miniaturized Ussing chambers were used to directly measure diseased human colon mucosa infected with Clostridioides difficile (C. diff.), and epithelial resistance was recorded using impedance spectroscopy. In a group of antibiotic-associated diarrhea patients with mucosal redness and edema and without detection of pseudomembranes, a reduction in epithelial resistance was observed, but no increase in macromolecule permeability. Accordingly, the course of the disease was self-limiting and mild. In parallel, the C. diff. toxins TcdA and TcdB, as well as the hypervirulent toxin CDT, were investigated in various model systems. After uptake via LSR as a receptor, CDT acted via the myosin light chain (MLC) on the perijunctional actin ring and thus affected the tight junction proteins claudin-4 and tricellulin. The large toxins TcdA and TcdB had barrier effects even at low, sublytic concentrations, when studied in two-dimensionally differentiated stem cell cultures (colon organoids), resulting in alterations of claudin-1, -2, -12, occludin and tricellulin. This model subsequently also enabled studies of ENaC-dependent sodium transport under the influence of C. diff. toxins and after exposure to cytokines. In this manner, interleukin-22 was identified as an inhibitor of ENaC-dependent sodium transport. Binding of the binary toxin CDT to the tight junction protein LSR (angulin-1) induced synergistic effects with TcdA/TcdB in the colon organoid model, revealing a door-opening function. Furthermore, several studies that had already begun in the previous period were published. These include studies on intestinal barrier function in post-infectious irritable bowel syndrome (IBS) following Campylobacter infection, as well as on diarrheal and mixed-type IBS. This also applies to the colon organoid model for investigating the pathomechanisms of pathogens such as Giardia lamblia. Furthermore, the development of focal leaks induced by the E. coli hemolysin HlyA could be explained by PIP2-dependent polarization effects in the epithelium, and the claudin-1-dependent tight junction disruption caused by the blue-green algal toxin microcystin-LR could be explained by hyperphosphorylation of the myosin light chain (MLC). Based on these studies on the pathomechanisms of barrier disruption, barrier-protective substances are to be developed and tested. For this purpose, individual food ingredients such as myrrh and epigallocatechin-3- gallate were investigated with regard to their mechanisms of action during this funding period.

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