Studies on Panax notoginseng saponins-modulated gut-fat and gut-liver crosstalk for obesity and NAFLD therapy

Abstract

Obesity and non-alcoholic fatty liver disease (NAFLD) are the worldwide epidemic diseases among population, and had the increased morbidity rate in recent years. Therapeutic intervention for obesity and NAFLD focused on the behaviour approaches and pharmacological approaches. Behaviour therapy are still the main and effective treatment of obesity and NAFLD, though rebound of body weight is often seen in obese patients receiving behaviour therapy, while risk of severe side effects of western medicine is highly concerned. Alternatively, herbal medication has become a considerable effective strategy that deserves great effort to explore. Recent studies have revealed that an important role of gut microbiome on obesity development and NAFLD establishment. My study aims to understand the modulating effects of a commonly used herbal product Panax notoginseng Saponins (PNS) on gut microbiota and ascertain the gut-adipose and gut-liver modulation of PNS on treat obesity and NAFLD. PNS exerted the most remarkable suppressive effect on high fat diet (HFD)-induced adiposity as observed from significant inhibition on adipocyte accumulation. Meanwhile, PNS shaped the murine gut microbiome associated with the increased abundances of Parabacteroides distasonis and Akkermansia muciniphila. PNS exerted a minimal effect on antibiotics-induced microbiome-depleted mice, which indicated that the anti-obesity effect of PNS was mediated by gut microbiota. The modulating effects of PNS on gut microbiota were involved the promotion of thermogenesis in brown adipocytes and the browning process in white adipocytes via activating leptin-AMPK/STAT3 signalling pathway. The in vitro study using differentiated C3H101/2 cells confirmed that the leptin/AMPKα/STAT3 pathway was involved in the browning process of white adipocytes. Meanwhile, leptin activation is involved in the anti-obesity effects of PNS and leptin defective lead to the negative influence of PNS-induced gut microbiota on thermogenesis and browning of white adipose tissue (WAT), resulting in PNS’s failure on fat reduction. Transplantation of fecal microbiota extracted from PNS-treated mice lead to reduced adiposity and improvement in the browning of WAT, which confirmed the correlation between PNS-modulated gut microbiota and the beige adipocytes construction in obesity. Additionally, PNS exerted hepatoprotective effect against the obesity-associated NAFLD in obese mice by reducing the procession of hepatic steatosis and hepatic fibrosis. The anti-NAFLD effects of PNS was associated with the deceleration of gut-to-liver translocation of microbiota-derived short chain fatty acids (SCFAs) products and the reverse of leaky gut by the restoration of ZO-1 and Claudin-1 protein expression. PNS inhibited the TLR4 signaling pathway in gut-liver axis, which in turn abolished by the addition of bacteria-derived lipopolysaccharide (LPS). In conclusion, the modulation effects of PNS on gut microbiota and the barrier function were involved in therapeutic intervention on adipose tissue and liver. The altered gut microbiota promoted the WAT browning via leptin/AMPKα/STAT3 pathway and the increased of gut permeability improved the NAFLD in obese mice in the TLR4/MyD88-dependent manner. The successful demonstration of my research can present valuable experimental evidence of the therapeutic application of PNS in obese and NAFLD patients.（479 words）