Scope Long‐term feeding of a high‐fat diet (HFD) causes gastrointestinal inflammation and gut microbiota disturbance, leading to the increased occurrence of obesity and anxiety. In the present study, the effects of heat‐labile Lactobacillus sakei OK67, tyndallized OK67 (tOK67), and heat‐stable Lactobacillus sakei PK16 on HFD‐induced obesity and anxiety in mice are examined. Methods and results Obesity is induced in mice by feeding with HFD. Oral administration of live OK67, tOK67, or PK16 reduces HFD‐induced body and liver weights and blood triglyceride, total cholesterol, corticosterone, and lipopolysaccharide levels. These treatments also suppress HFD‐induced NF‐κB activation and increased HFD‐suppressed AMP‐activated protein kinase (AMPK) activation and SIRT‐1 expression in the liver. OK67 or PK16 treatment alleviates HFD‐induced anxiety‐like behaviors and increases BDNF expression and NF‐κB activation in the hippocampus. Moreover, OK67 or PK16 treatment suppresses HFD‐induced colitis and suppresses the Proteobacteria population and fecal lipopolysaccharide levels in mice. OK67 or PK16 treatment inhibits NF‐κB activation and induced AMPK activation and SIRT‐1 expression in lipopolysaccharide‐stimulated Caco‐2 cells. Overall, the antiobesity and anxiolytic effects of live OK67 are more potent than those of tOK67. Conclusion Lactobacillus sakei can alleviate HFD‐induced obesity, colitis, and anxiety by regulating gut microbiota‐mediated AMPK and NF‐κB activation and SIRT‐1 expression.

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