Qushi Huayu Decoction Ameliorates Non-Alcoholic Steatohepatitis Induced by High-Fat Diet in Mouse Associated with Regulation on Microbiota Composition and Mitogen-Activated Protein Kinase Pathways in the Intestine

Abstract

Background: Gut microbiota is increasingly recognized as the key participant in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) by translocation of its products, especially lipopolysaccharide (LPS), via the dysfunctional intestinal barrier. Qushi Huayu decoction (QHD), a traditional Chinese medicine, is developed specially for NAFLD and used in clinic in China for more than a decade and previously found to ameliorate non-alcoholic steatohepatitis (NASH) induced by high-fat diet (HFD) in mice accompanied with inhibited metabolic endotoxemia and hepatic LPS signaling. In the present study, the mechanism of LPS gut-leakage inhibition by QHD in NASH was investigated. Methods: Effects of QHD on gut microbioa and intestinal barrier were evaluated in NASH induced by HFD in mice. 16S rRNA sequencing was employed to analyze the gut microbiota composition. The colonic phosphoprotein profile was screened via the Phospho Explorer Antibody Array and verified in NASH and intestinal barrier dysfunctional mouse induced by LPS to identify the potential signaling pathway responsible for tight junction regulation. Findings: QHD ameliorated NASH accompanied with regulating the gut microbiota composition, protecting intestinal tight junctions and inhibiting LPS gut-leakage without decreasing the abundance of identified Gram-negative bacteria. The validated data of phosphorylated proteins suggested that mitogen-activated protein kinase (MAPK) pathway is predominantly responsible for the colonic tight junction regulation by QHD. Interpretation: Gut microbiota regulation associated with the therapeutic effects of QHD on NASH, while protection on colonic tight junctions is the main cause of QHD inhibition on LPS gut-leakage in NASH, which was predominantly mediated by MAPK pathway. Funding Statement: This work was supported by Science and Technology Commission Shanghai Municipality (17PJ1408900), National Natural Science Foundation of China (No. 81370094, 81001575, 81673750, 81830119). Declaration of Interests: The authors state: No. Ethics Approval Statement: The animal study protocols were approved by the animal studies ethics committee of Shanghai University of Traditional Chinese Medicine.