Multipronged Therapeutic Mechanisms of Chinese Herbal Medicine QHD in the Treatment of NAFLD

Abstract

Clinical studies have demonstrated the therapeutic efficacy of the Chinese herbal medicine Qushi Huayu Decoction (QHD) in the treatment of non‐alcoholic fatty liver disease (NAFLD). It has been suggested that QHD reduces hepatic lipid accumulation through its regulatory effect on liver fat metabolism. Herein, to better understand the pharmaceutical mechanisms of QHD, we aimed to investigate the effect of QHD on gut‐liver axis using systems biology approaches. High‐fat diet (HFD) ‐induced rat NAFLD models were treated with QHD or a mixture of two active components of QHD (geniposide and chlorogenic acid, GC). Liver pathology and blood biochemistry were conducted to evaluate the effects of QHD and GC therapy. To understand the molecular mechanisms of the therapeutic effects, global microarray expression analysis of the liver genes was conducted and validated by quantitative RT‐PCR. To evaluate the effect of GC therapy on the gut microbiome and NAFLD, we used NAFLD rats induced by HFD and dextran sulfate sodium (DSS) to ensure increased gut permeability. With both NAFLD rat models, QHD and GC treatments caused reduced weight gain, liver fat, liver transaminases, and lymphocyte infiltration. We also observed down‐regulation of genes and pathways in lipid metabolism and inflammation, consistent with the beneficial effects of QHD and GC therapy. Decreased expression of genes for lipid synthesis, and increased expression of genes for production of the antioxidant glutathione represent two possible mechanisms for QHD and GC therapy. GC treatment decreased serum LPS in NAFLD rats, which is not explained by the change of microbiota composition, as microbiome analysis revealed increased abundance of Gram‐negative bacteria in GC treated rats. Rather, decreased serum LPS and TLR4 signaling in the liver could be explained by reduced mucosal damage in the colon of GC‐treated rats. In the gut of GC‐treated rats, increased abundance of Treg‐inducing bacteria may down‐regulate inflammatory signals and consequently improve gut barrier function. Our study provides strong support that QHD and its active components simultaneously target lipid synthesis, the anti‐oxidative mechanism and gut microbiota, offering a possible treatment for NAFLD.Support or Funding InformationThis work is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (U01 DK061728, to S.S.B.), the Peter and Tommy Fund, Inc., Buffalo, NY (to S.S.B. and L. Z.), the National Natural Science Foundation of China (No. 81374031, to Q. F.), the National Natural Science Foundation of China (No. 81173404, to Y. H.) and a departmental start‐up fund (to L.Z.).