Geniposide and Chlorogenic Acid Combination Ameliorates Non-alcoholic Steatohepatitis Involving the Protection on the Gut Barrier Function in Mouse Induced by High-Fat Diet.

Jing-Hua Peng,Yi-Yang Hu,Yi Fang,Tao Yang,Jing Leng,Qin Feng,Hua-Jie Tian,Yu Zhao

doi:10.3389/fphar.2018.01399

Abstract

Gut-liver axis is increasingly recognized to be involved in the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). The gut microbiota and intestinal permeability have been demonstrated to be the key players in the gut-liver cross talk in NAFLD. Geniposide and chlorogenic acid (GC) combination is derived from a traditional Chinese medicine, Qushi Huayu Decoction (QHD), which has been used in clinic for NAFLD treatment for decades in China and validated in multiple animal models of NAFLD. GC combination previously has been demonstrated to treat NAFLD via modulation on the gut microbiota composition. In the present study, the effects of GC combination on gut barrier function in NAFLD were evaluated, and QHD and sodium butyrate (NaB), the intestinal mucosa protectant, were used as positive control. The therapeutic effect of GC combination on NAFLD were confirmed by amelioration on non-alcoholic steatohepatitis (NASH) induced by high-fat diet (HFD) in mouse, which was comparable to that of QHD. Simultaneously, GC combination was found to reduce the signaling of gut-derived lipopolysaccharide (LPS) including hepatic LPS binding protein, Toll like receptor 4, interleukin-1β, tumor necrosis factor –α, and Kupffer cells infiltration. Furthermore, GC combination reduced LPS and D-lactate in plasma, restoring the colonic tight junction (TJ) expression and inhibited colonic TJs disassembly by down-regulation on RhoA/ROCK signaling in NASH induced by HFD. On the other hand, NASH was also alleviated in NaB group. The results of the present study suggested the important role of protection on gut barrier function in NAFLD treatment, which contributed to the therapeutic effects of GC combination on NASH.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic steatosis lack of secondary causes of hepatic fat accumulation such as alcohol consumption, long-term use of a steatogenic medication or monogenic hereditary disorder (Chalasani et al, 2018)
Obese individuals and animals fed with high-fat diet (HFD) exhibit a change in gut microbiota composition as well as a 2 to 3-fold increase in blood
Bacterial overgrowth in the small intestine was found in non-alcoholic fatty liver disease (NAFLD) patients and serum tumor necrosis factor (TNF)-α level in non-alcoholic steatohepatitis (NASH) patients increased obviously (Wigg et al, 2001)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic steatosis (more than 5% hepatocytes) lack of secondary causes of hepatic fat accumulation such as alcohol consumption, long-term use of a steatogenic medication or monogenic hereditary disorder (Chalasani et al, 2018). The spectrum of histological manifestations of NAFLD includes simple steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (Torres et al, 2012), in which, NASH is the key step and relative to the higher motility in patients of chronic liver disease (Dulai et al, 2017). The gut microbiota and intestinal permeability have been demonstrated to be the key players in the gut-liver cross talk in NAFLD (Cani et al, 2007; Federico et al, 2016; Leung et al, 2016)

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Results

Conclusion