Protective Effect of Ursolic Acid on the Intestinal Mucosal Barrier in a Rat Model of Liver Fibrosis

Wang Zhang,Xuan Zhu,Bimin Li,Yipeng Wan,Anjiang Wang,Dakai Gan,Chenkai Huang,Jie Jian,Fangyun Luo,Meichun Jiang,Sizhe Wan

doi:10.3389/fphys.2019.00956

Abstract

Oxidative stress mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) plays an important role in intestinal mucosal barrier damage in various disease states. Recent evidence suggests that intestinal mucosal barrier damage and intestinal dysbiosis occur in mice with hepatic fibrosis induced by CCl4 or bile duct ligation. Another study showed that ursolic acid (UA) attenuates experimental colitis via its anti-inflammatory and antioxidant activities. The goal of this study was to investigate the effects of UA on the intestinal mucosal barrier in CCl4-induced hepatic fibrosis in rats and identify its associated mechanisms. Male Sprague-Dawley rats were randomly divided into the following 3 groups (n = 10/group): the control, CCl4 model and UA treatment groups. Rats were sacrificed at 72 h after the hepatic fibrosis model was established and assessed for liver fibrosis, intestinal injury, enterocyte apoptosis, bacterial translocation, system inflammation, intestinal oxidative stress, and tight junction protein and NOX protein expression. The results demonstrated that UA attenuated the following: (i) liver and intestinal pathological injury; (ii) cleaved caspase-3 expression in the ileal epithelial cells; (iii) serum lipopolysaccharide and procalcitonin levels; (iv) intestinal malondialdehyde levels; and (v) the expression of the NOX protein components NOX2 and P67phox in ileal tissues. Furthermore, our results suggested that UA improved intestinal dysbiosis and the expression of the tight junction proteins Claudin 1 and Occludin in the ileum of rats. These results indicate that UA has protective effects on the intestinal mucosal barrier in rats with CCl4-induced liver fibrosis by inhibiting intestinal NOX-mediated oxidative stress. Our findings may provide a basis for further clinical studies of UA as a novel and adjuvant treatment to cure liver fibrosis.

Highlights

Liver fibrosis is a wound-healing response to chronic liver injury that develops into liver cirrhosis or liver cancer, which is associated with significant morbidity and mortality
Heavy deposits of collagen were observed in the livers of rats from the CCl4 model group and were accompanied by disordered hepatic lobular structures and severe hepatocyte necrosis, whereas these changes were suppressed in the ursolic acid (UA) treatment group
The hydroxyproline content of rat serum in the UA treatment group declined compared to the CCl4 model group (Figure 1E)

Summary

Introduction

Liver fibrosis is a wound-healing response to chronic liver injury that develops into liver cirrhosis or liver cancer, which is associated with significant morbidity and mortality. Intestinal mucosal barrier damage and dysbiosis have been reported to occur in mice with hepatic fibrosis induced by CCl4 or bile duct ligation (Fouts et al, 2012). Effects of UA on Microbiota mucosal barrier damage and intestinal dysbiosis contributes to the translocation of bacteria and/or bacterial products (Fouts et al, 2012; Hartmann et al, 2012), the latter of which induce hepatic stellate cell (HSC) activation and contribute to liver fibrosis (Seki et al, 2007; Hartmann et al, 2012). Restoring intestinal barrier function and preventing bacterial translocation has great significance for inhibiting the progression of liver fibrosis and improving the prognosis of patients with chronic liver disease

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