Gut-liver axis modulation of Panax notoginseng saponins in nonalcoholic fatty liver disease

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is an obesity-related comorbidity, and it is characterized as a spectrum of liver abnormalities, including inflammation, steatosis, and fibrosis. The gut-liver axis is implicated in the pathogenesis and development of NAFLD. A promising drug agent targeting the gut-liver axis is expected to reverse NAFLD. METHODS: We utilized high-fat diet (HFD)-induced obese mice and obesity-prone Lep(ob) mice to examine the gut-liver regulation of the natural medicine Panax Notoginseng Saponins (PNS) on NAFLD. RESULTS: PNS exhibited potent anti-lipogenesis and anti-fibrotic effects in NAFLD mice, that was associated with the TLR4-induced inflammatory signalling pathway in liver. More strikingly, PNS treatment caused a deceleration of gut-to-liver translocation of microbiota-derived short chain fatty acids (SCFAs) products. PNS-induced TLR4 inhibition and restoration of Claudin-1 and ZO-1 proteins in the gut-liver axis contributed to the reverse of leaky gut, which in turn abolished by the addition of lipopolysaccharide (LPS), an agonist of TLR4. Specifically, hepatic steatosis in HFD-treated mice was attenuated by PNS through regulating AMPKα, but restored by the replenishment of LPS. Meanwhile, the anti-fibrotic effect of PNS was abolished by LPS stimulation via the overproduction of collagen I/IV and α-SMA. CONCLUSION: PNS exerted hepatoprotection against NAFLD in both ob/ob and HFD-induced obese mice, primarily by mediating the gut-liver axis in a TLR4-dependent manner. GRAPHIC ABSTRACT: [Figure: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12072-021-10138-1.