Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis

Abstract

Intestinal barrier dysfunction usually occurred in acute pancreatitis (AP) but the mechanism remains unclear. In this study, RNA sequencing of ileum in L-arginine-induced AP mice demonstrated that phosphoenolpyruvate kinase 1 (Pck1) was significantly up-regulated. Increased Pck1 expression in intestinal epithelial cells (IECs) was further validated in ileum of AP mice and duodenum of AP patients. In AP mice, level of Pck1 was positively correlated with pancreatic and ileal histopathological scores, serum amylase activity, and intestinal permeability (serum diamine oxidase (DAO), D-lactate, and endotoxin). In AP patients, level of Pck1 had a positive correlation with Ranson scores, white blood cell count and C-reactive protein. Inhibition of Pck1 by 3-Mercaptopicolinic acid hydrochloride (3-MPA) alleviated pancreatic and ileal injuries in AP mice. AP + 3-MPA mice showed improved intestinal permeability, including less epithelial apoptosis, increased tight junction proteins (TJPs) expression, decreased serum DAO, D-lactate, endotoxin, and FITC-Dextran levels, and reduced bacteria translocation. Lysozyme secreted by Paneth cells and mucin2 (MUC2) secretion in goblet cells were also partly restored in AP + 3-MPA mice. Meanwhile, inhibition of Pck1 improved intestinal immune response during AP, including elevation of M2/M1 macrophages ratio and secretory immunoglobulin A (sIgA) and reduction in neutrophils infiltration. In vitro, administration of 3-MPA dramatically ameliorated inflammation and injuries of epithelial cells in enteroids treated by LPS. In conclusion, inhibition of Pck1 in IECs might alleviate AP via modulating intestinal homeostasis.