Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases

• Published in: Gut Vol. 71; no. 3; pp. 580 - 592
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.03.2022; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Antibiotics; Ascites; Ascites - microbiology; Bacteria; Bacterial infections; bacterial translocation; Bacterial Translocation - physiology; Biodegradation; Biopsy; Caco-2 Cells; Cadherins - metabolism; Case-Control Studies; Cell junctions; Cirrhosis; Coculture Techniques; Colon - microbiology; Colon - pathology; Colonoscopy; E coli; E-cadherin; Epithelial cells; Epithelium; Escherichia coli; Escherichia coli - physiology; Female; Hepatology; Humans; Infections; Intercellular Junctions; Intestine; Liver; Liver cirrhosis; Liver Cirrhosis - complications; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Lymph nodes; Male; Medical innovations; Mortality; Occludin - metabolism; Pathogenesis; Patients; Peptide Hydrolases; Peritonitis; Peritonitis - etiology; Peritonitis - metabolism; Proteasomes; Proteinase; Proteins; Proteus mirabilis - physiology; Statistical analysis; Ubiquitin; Ubiquitination; United States > US; Berlin Germany; Germany; bacterial translocation; peritonitis; E. coli; liver cirrhosis
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2020-321663

ObjectiveSpontaneous 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.DesignSince 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 Escherichia coli (E. coli) and Proteus mirabilis (P. mirabilis) were isolated from ascites of patients with liver cirrhosis and co-cultured with Caco-2 cells to characterise bacteria-to-cell effects.ResultsSBP-derived E. coli and P. mirabilis 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.ConclusionPatients 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.