Introduction Translocation of intestinal bacteria or bacterial products from the gut to mesenteric
lymph nodes is a key process in development of spontaneous bacterial peritonitis (SBP).
Bacterial translocation is facilitated by increased intestinal permeability. We have
shown that bacterial proteases are involved in the degradation of cell-to-cell junction
proteins leading to intestinal destabilization.
Methods To analyze the pathomechanism of SBP, the integrity of intestinal epithelial cells
in presence and absence of E. coli and protease inhibitors was analyzed. 3 different
E. coli-strains were isolated from ascitic fluid of patients with liver cirrhosis
and SBP. The laboratory strain E. coli O6:Hnt served as reference. Bacteria-dependent
regulation of intestinal cell-cell contacts was evaluated by determining RNA and protein
levels of the adherence junction protein E-cadherin and tight junction protein occludin.
We used broad-spectrum inhibitor BB-2516 and selective metalloprotease (MMP)-8 inhibitor
I to block bacterial protease activity.
Results Various E. coli-strains (O6:Hnt, Ont:H41 and O18:H7) destabilized cell-to-cell junction
components of intestinal epithelial cells, indicated by reduced protein levels of
E-cadherin and occludin. Protease inhibitor BB-2516 or MMP-8 inhibitor I stabilized
cell-to-cell junction protein levels. Noteworthy, bacterial protease activity of E.
coli O6:Hnt and patient-derived E.coli O18:H7 decreased upon addition of inhibitors.
Summary (Patient-derived) E. coli destabilize cell-to-cell junctions on protein level in
a protease-dependent manner. Vice versa, protease inhibitors stabilize the epithelial
barrier by targeting bacterial proteases. These data point out to bacterial proteases
as potential novel targets for treatment of SBP.
