Compromised Ileal Mucus Barrier Due to Impaired Epithelial Homeostasis Caused by Notch1 Signaling in Cirrhotic Rats.

Abstract

In liver cirrhosis, intestinal mucus barrier is rarely studied. This study aimed to investigate whether mucus barrier in ileum is altered in cirrhotic rats and its underlying mechanisms. Thioacetamide was injected to induce liver cirrhosis in rats. Serum from portal vein blood, and ileum and liver tissues were obtained for further analysis. Goblet cell-like Ls174T cells were cultured for in vitro experiments. The ileal mucus was thin, loose, and porous with small bubbles in cirrhotic rats. mRNA expressions of Muc2 and TFF3 were also down-regulated in cirrhotic rats. Bacteria located near to crypts and LPS were increased in the serum from portal vein in cirrhotic rats. Smaller theca area and few goblet cells were found in cirrhotic rats compared with control. Increased proliferation of ileal epithelia was observed in cirrhotic rats. Notch1, Dll1, and Hes1 expressions were enhanced, and KLF4 expression was suppressed in ileum of cirrhotic rats. In Ls174T cells, EDTA and NICD plasmid induced NICD and Hes1 expression and suppressed KLF4 concomitantly, and mucus expression almost vanished in these cells. NICD plasmid induced more proliferation in Ls174T cells. Oppositely, after DBZ treatment, NICD and Hes1 were inhibited along with augmentation of KLF4 and increased mucous expression in Ls174T cells, while proliferation of the cells was suppressed. In cirrhotic rats, mucus barrier was impaired. This might be attributed to increased proliferation and decreased differentiation of epithelia, which might be mediated by Notch1-Hes1-KLF4 signaling.