• Medientyp: E-Artikel
  • Titel: Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases
  • Beteiligte: Haderer, Marika; Neubert, Philip; Rinner, Eva; Scholtis, Annika; Broncy, Lucile; Gschwendtner, Heidi; Kandulski, Arne; Pavel, Vlad; Mehrl, Alexander; Brochhausen, Christoph; Schlosser, Sophie; Gülow, Karsten; Kunst, Claudia; Müller, Martina
  • Erschienen: BMJ, 2022
  • Erschienen in: Gut
  • Sprache: Englisch
  • DOI: 10.1136/gutjnl-2020-321663
  • ISSN: 0017-5749; 1468-3288
  • Schlagwörter: Gastroenterology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec><jats:title>Objective</jats:title><jats:p>Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of liver cirrhosis with a 1-year mortality of 66%. Bacterial translocation (BT) from the intestine to the mesenteric lymph nodes is crucial for the pathogenesis of SBP.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Since BT presupposes a leaky intestinal epithelium, the integrity of mucus and epithelial cell junctions (E-cadherin and occludin) was examined in colonic biopsies from patients with liver cirrhosis and controls. SBP-inducing <jats:italic>Escherichia coli</jats:italic> (<jats:italic>E. coli</jats:italic>) and <jats:italic>Proteus mirabilis</jats:italic> (<jats:italic>P. mirabilis</jats:italic>) were isolated from ascites of patients with liver cirrhosis and co-cultured with Caco-2 cells to characterise bacteria-to-cell effects.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>SBP-derived <jats:italic>E. coli</jats:italic> and <jats:italic>P. mirabilis</jats:italic> led to a marked reduction of cell-to-cell junctions in a dose-dependent and time-dependent manner. This effect was enhanced by a direct interaction of live bacteria with epithelial cells. Degradation of occludin is mediated via increased ubiquitination by the proteasome. Remarkably, a novel bacterial protease activity is of pivotal importance for the cleavage of E-cadherin.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Patients with liver cirrhosis show a reduced thickness of colonic mucus, which allows bacteria-to-epithelial cell contact. Intestinal bacteria induce degradation of occludin by exploiting the proteasome of epithelial cells. We identified a novel bacterial protease activity of patient-derived SBP-inducing bacteria, which is responsible for the cleavage of E-cadherin structures. Inhibition of this protease activity leads to stabilisation of cell junctions. Thus, targeting these mechanisms by blocking the ubiquitin-proteasome system and/or the bacterial protease activity might interfere with BT and constitute a novel innovative therapeutic strategy to prevent SBP in patients with liver cirrhosis.</jats:p></jats:sec>