BACKGROUND: Obesity has become a global epidemic recognized by the World Health Organization. Probiotics supplementation has been shown to contribute to improve lipid metabolism. However, mechanisms of action of probiotics against obesity are still not clear. FRT4, a probiotic previously isolated from a kind of local yogurt, had good acid and bile salt tolerance and lowered cholesterol . OBJECTIVE: This study aimed to evaluate the effect of FRT4 on serum and liver lipid profile, liver metabolomics, and gut microbiota in mice fed with a high-fat diet (HFD). DESIGN: Mice were fed with either normal diet or HFD for 16 weeks and administered 0.2 mL of 1 × 10 or 1 × 10 CFU/mL dosage of FRT4 during the last 8 weeks of the diet. Cecal contents were analyzed by 16S rRNA sequencing. Hepatic gene expression and metabolites were detected by real-time quantitative polymerase chain reaction (PCR) and metabolomics, respectively. RESULTS: FRT4 intervention significantly reduced the HFD-induced body weight gain, liver weight, fat weight, serum cholesterol, triglyceride, and alanine aminotransferase (ALT) levels in the liver ( 0.05). Liver metabolomics demonstrated that the HFD increased choline, glycerophosphocholine, and phosphorylcholine involved in the glycerophospholipid metabolism pathway. All these changes were reversed by FRT4 treatment, bringing the levels close to those in the control group. Further mechanisms showed that FRT4 favorably regulated gut barrier function and pro-inflammatory biomediators. Furthermore, FRT4 intervention altered the gut microbiota profiles and increased microbial diversity. The relative abundances of , , , , , , and were significantly upregulated. Finally, Spearman's correlation analysis revealed that several specific genera were strongly correlated with glycerophospholipid metabolites ( 0.05). CONCLUSIONS: These findings suggested that FRT4 had beneficial effects against obesity in HFD-induced obese mice and can be used as a potential functional food for the prevention of obesity.