Regulation of p53 – a possible bacterial defense mechanism leading to epithelial barrier destabilization in spontaneous bacterial peritonitis?

Background: Spontaneous bacterial peritonitis (SBP) is a life-threatening complication in advancing liver cirrhosis. SBP represents a bacterial infection of ascitic fluid without an intra-abdominal source of infection that could be treated surgically. Translocation of intestinal bacteria or bacterial products from the gut to mesenteric lymph nodes is crucial for SBP, with Escherichia coli (E. coli), Klebsiella pneumoniae, enterococci and streptococci being the most common germs. As soon as a SBP is suspected, patients must be treated with antibiotics. In this context, biomarkers for early SBP diagnosis are in the focus of interest, as they are not available so far. With regard to the development of early recognition systems and therapeutic concepts, pathomechanisms and signaling pathways of bacterial translocation in SPB were explored.

Methods: To investigate effects of intestinal bacteria on epithelial cell junctions, monolayers of human intestinal epithelial cell lines Caco-2 (p53 deficient) and HCT-116 (p53 wildtyp) were cocultured with E. coli at day 5 to 8 post confluence. Infection with E. coli was performed with different MOI (0 – 10) for 40 – 240 minutes. Western Blot analysis was used to analyze changes in intracellular protein levels of Occludin, E-cadherin and the p53 family.

Results: E. coli stimulation of HCT-116 cells resulted in a strong decrease of the tight junction protein Occludin, the adherens junction protein E-cadherin, and, remarkably, also p53. Consistently, following E. coli stimulation Caco-2 cells displayed reduced protein levels of Occludin and E-cadherin. However, in p53-deficient Caco-2 cells this reduction was less distinct compared to p53-wildtyp HCT-116 cells.

Conclusion: These results highlight destabilizing effects of E. coli on intestinal cell junctions. Of specific clinical relevance, a regulation of the tumor suppressor p53 by E. coli was demonstrated. With a more distinctive downregulation in HCT-116 epithelial cells, we hypothesize an involvement of p53 in the regulation of epithelial permeability during bacterial infection. Reduced p53 levels in conjunction with destabilized intestinal epithelial integrity following bacterial infection might represent a mechanism to protect bacteria from intestinal immune responses and therefore to promote bacterial translocation in SBP.