Bacterial translocation is associated with downregulation of Paneth cell antimicrobial peptides in ascitic cirrhotic but not in pre-hepatic portal hypertensive rats

Aims: Many complications in portal hypertension limiting prognosis are triggered by bacterial translocation (BT) which is defined as the migration of bacteria from the intestinal lumen to mesenteric lymph nodes (MLN) and/or other extraintestinal sites. Most translocating bacteria belong to the common intestinal flora which suggests a breakdown of mucosal barrier function. We hypothesized that BT in portal hypertension could be explained by diminished expression of antimicrobial peptides. Methods: Two animal models of portal hypertension with increased BT namely CCl4-induced cirrhosis with ascites and 2-day portal-vein ligated (PVL) rats and corresponding healthy control or sham-operated rats were used. BT to MLN was assessed by standard microbiological techniques. Total RNA and protein was isolated from different intestinal locations and expression of ß-actin, Paneth cell α-cryptdins and ß-defensins was determined by qRT PCR. Antimicrobial activity was assessed using a FACS assay. Results: In cirrhotic rats with BT but not in 2-day PVL with BT, α-cryptdin expression was decreased throughout the entire GI tract, most pronounced in the proximal (p=0,02 crypt5; p=0,01 crypt7) and the distal ileum (p=0,02 crypt5; p=0,008 crypt7). In contrast, other antimicrobials showed no changes or an induction in case of BT at different sites. Antimicrobial activity was consistent with PCR results and showed diminished activity especially in the distal small intestine in experimental cirrhosis with BT. Conclusion: The lack of antimicrobial host defence via diminished Paneth cell defensin expression provides a novel explanation for enhanced bacterial translocation in advanced cirrhosis. This loss of antimicrobial function seems not to be related to portal hypertension per se but rather deterioration of liver function.

bacterial translocation - defensins - gut flora - liver cirrhosis