Lonicerin attenuates high-fat diet-induced hepatic steatosis through modulation of the gut microbiota-bile acid-FXR axis in mice

• Lonicerin was more effective than luteolin in alleviating diet-induced hepatic steatosis in mice. • Lonicerin inhibited hepatic FA synthesis and enhanced fecal lipid excretion. • Lonicerin favorably modulated gut microbiota and enhanced SCFA production. • Lonicerin altered fecal bile acid profiles and activated intestinal FXR-FGF15 pathway to inhibit hepatic FA synthesis. Lonicera japonica Thunb. is widely used in Asian countries as a food ingredient to make healthy drinks, with lonicerin, a flavone O -glycoside, as a predominant bioactive compound. This study investigated lonicerin’s effects on high-fat diet-induced hepatic steatosis in mice, compared to its aglycone luteolin. Results showed that lonicerin significantly reduced diet-induced body weight gain and hepatic lipid accumulation in mice, demonstrating greater efficacy than luteolin. This lipid-lowering effect was due to inhibited hepatic fatty acid (FA) biosynthesis and promoted fecal lipid excretion. Moreover, lonicerin favorably modulated gut microbiota by increasing Dubosiella , Eubacterium_brachy_group , and Bilophila , while reducing the pathogenic Desulfovibrionaceae . These changes led to elevated short-chain fatty acid production and altered fecal bile acid (BA) profiles, likely activating the intestinal FXR-FGF15 pathway to inhibit hepatic FA synthesis. In conclusion, lonicerin alleviated diet-induced hepatic steatosis by promoting fecal lipid excretion and inhibiting hepatic FA biosynthesis through modulating the gut microbiota-BA-intestinal FXR axis.