Bacterial translocation in patients with liver cirrhosis is promoted by bacteria-mediated mechanisms targeting essential functions of the epithelial barrier

Background Spontaneous bacterial peritonitis (SBP) is a severe complication of liver cirrhosis. A crucial event in SBP development is bacterial translocation from the intestine to mesenteric lymph nodes. We characterized the interplay of intestinal epithelial cells with SBP-inducing bacteria and focussed on effects on cell-cell-contacts and cellular stress responses. Method Mucus layer and protein levels of E-cadherin, occludin, p53 and p73 were examined in colonic biopsies from patients with liver cirrhosis and control patients who underwent screening colonoscopy. In vitro, Caco-2 and HCT-116 cells were co-cultured with Escherichia coli (E. coli; ATCC25922, O6:Hnt or patient-derived E. coli). Protein regulation of E-cadherin, occludin, p53 and p73 was evaluated by Western Blot. Cell cycle regulation and cell death were investigated by flow cytometry. Results Patients with liver cirrhosis display a reduced mucus thickness, diminished levels of E-cadherin and occludin and markedly reduced levels of p53 and p73 in their colonic mucosa. In vitro, direct contact of Caco-2 or HCT-116 cells with E. coli induced degradation of E-cadherin and occludin, cell cycle arrest and enhanced epithelial cell death by a non-apoptotic mechanism. Upon co-cultivation both cell lines initially upregulated p53 and p73, whereas a reduction of these proteins was observed thereafter. This mechanism was dependent on MDM2 and coincided with cell death induction. Conclusion Impaired epithelial integrity facilitates bacterial translocation in patients with liver cirrhosis. Active downregulation of cell junction components and p53 proteins by SBP-inducing bacteria suggests a bacteria-mediated mechanism targeting essential functions of the intestinal epithelium to drive development of SBP. Publication History Article published online: 18 January 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany