In this investigation, we first demonstrated based on a comprehensive analysis that SGKL treatment significantly contributes to the improvement of depression‐like phenotypes in CRS‐stimulated rats by altering metabolites associated with gut microbiota, in which the PI3K/Akt/mTOR pathway is the key therapeutic target of SGKL treatment that mediates metabolite changes, inflammation, and microglial activation. Here, AKT1 is linked to depressive symptom measurement.