Abstract
Ginseng, the root and rhizome of Panax ginseng C. A. Mey., is a famous herbal medicine, and its major ginsenosides exert beneficial effects on nonalcoholic fatty liver disease (NAFLD). Due to the multicomponent and multitarget features of ginsenosides, their detailed mechanisms remain unclear. This study aimed to explore the role of ginsenosides on NAFLD and the potential mechanisms mediated by the gut microbiota and related molecular processes. C57BL/6J mice were fed a high-fat diet (HFD) supplemented or not supplemented with ginsenoside extract (GE) for 12 weeks. A strategy that integrates bacterial gene sequencing, serum pharmacochemistry and network pharmacology was applied. The results showed that GE significantly alleviated HFD-induced NAFLD symptoms in a dose-dependent manner. Furthermore, GE treatment modulated the HFD-induced imbalance in the gut microbiota and alleviated dysbiosis-mediated gut leakage and metabolic endotoxemia. Additionally, 20 components were identified in the mouse plasma after the oral administration of GE, and they interacted with 82 NAFLD-related targets. A network analysis revealed that anti-inflammatory effects and regulation of the metabolic balance might be responsible for the effects of GE on NAFLD. A validation experiment was then conducted, and the results suggested that GE suppressed NF-κB/IκB signaling activation and decreased the release and mRNA levels of proinflammatory factors (TNF-α, IL-1β and IL-6). Additionally, GE promoted hepatic lipolytic genes (CPT-1a), inhibited lipogenic genes (SREBP-1c, FAS, ACC-1) and improved leptin resistance. These findings imply that the benefits of GE are involved in modulating the gut microbiota, enhancing the gut barrier function, restoring the energy balance, and alleviating metabolic inflammation. Moreover, GE might serve as a potential agent for the prevention of NAFLD through the integration of prebiotic, anti-inflammatory and energy-regulatory effects.
Highlights
Nonalcoholic fatty liver disease (NAFLD), which is a chronic and multifactorial liver disease, is becoming a growing health problem worldwide (Younossi et al, 2016)
A small reduction in the mean daily caloric intake was detected in the groups that consumed ginsenoside extract (GE) (Figure 1C), which suggested that the delayed body weight gain caused by GE might be related to changes in caloric intake to a certain extent
These results demonstrated that the effect of GE on dietary-induced nonalcoholic fatty liver disease (NAFLD) is achieved by modulating the gut microbiota, by facilitating the prevalence of beneficial bacteria (Parabacteroides, Muribaculaceae, Akkermansia, and Ruminococcus_torques_group) and decreasing the prevalence of harmful bacteria (Lachnospiraceae and Helicobacter)
Summary
Nonalcoholic fatty liver disease (NAFLD), which is a chronic and multifactorial liver disease, is becoming a growing health problem worldwide (Younossi et al, 2016). The disease gradually evolves into a broad spectrum of liver diseases, including nonalcoholic steatohepatitis, liver fibrosis, cirrhosis, and even hepatocellular carcinoma (Friedman et al, 2018). A widely accepted hypothesis regarding multiple parallel hits explains NAFLD pathogenesis, including insulin resistance, hepatic lipid accumulation, inflammatory reaction, oxidative stress, gut microbiota, and genetic predisposition (Friedman et al, 2018; Kolodziejczyk et al, 2019). The existing therapeutic strategy only aims to control the progression of obesity, diabetes, and dyslipidemia by adjusting lifestyle factors, increasing insulin sensitivity, reducing inflammation, and protecting liver cells and does not yield ideal therapeutic effects. Natural extracts and phytochemicals have gradually attracted attention due to their extraordinary hepatoprotective abilities (Cremonini et al, 2018; Tang et al, 2018; Li et al, 2019)
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