Hydroxypropyl-beta-Cyclodextrin embedded resveratrol regulates gut microbiota to prevent NAFLD via activating AMPK signaling pathway

Non-alcoholic fatty liver disease (NAFLD) has become a globally rising issue that can cause liver-related morbidity and mortality. Recent studies have revealed that a high-fat diet (HFD) highly contributes to the prevalence and progression of NAFLD via impacting gut microbiota and lipid metabolism signal pathways. Resveratrol (RSV), a natural bioactive compound, has exhibited potential for preventing and alleviating NAFLD. However, due to the poor bioavailability of RSV, its strengths and underlying mechanisms for NAFLD therapeutic potential are poorly understood. To address this, we utilized Hydroxypropyl-beta-Cyclodextrin (HBC) to encapsulate RSV to enhance its water solubility and conducted prevention and intervention experiments in HFD-fed mice. The results showed that the HBC has significantly enhanced the water solubility of RSV by 250-fold and the HBC-RSV better prevented and alleviated the liver steatosis, obesity and abnormal lipid metabolism induced by HFD than RSV alone. Meanwhile, combining HFD and HBC-RSV or RSV prevented HFD mice progressing to NAFLD. Besides, further investigation indicated that RSV could resist liver injury and obesity by modulating gut microbiota, raising the levels of short-chain fatty acids (SCFAs) and activating AMP-activated protein kinase (AMPK) signaling pathway. The activated pathway down-regulated sterol receptor element binding protein 1c (SREBP1c) and acetyl-coenzyme A carboxylase (ACC) to decrease lipid synthesis and up-regulated peroxisome proliferators-activated receptorα (PPARα) to promote the fatty acid oxidation, thus preventing NAFLD. Our findings suggested that water solubility-enhanced RSV beneficially modulated gut microbiota, altered gut microbiota-derived SCFAs, and activated lipid metabolism regulatory pathways, providing potential for NAFLD prevention and alleviation.