Abstract: OBJECTIVE   To explore the changes of fecal metabonomics in the depressed rats with chronic unpredictable mild stress (CUMS) by ¹H-NMR metabonomics technology, evaluate the antidepressant effects of Sinisan containing Bupleuri Radix and Paeoniae Radix Alba before and after vinegar-processing, and discuss the effect enhancement mechanism and processing connotation of Sinisan containing vinegar-processed Bupleuri Radix and vinegar-processed Paeoniae Radix Alba.METHODS   The depressed rat model was established using the CUMS program, and the changes of fecal metabonomics in depressed rats under different administration conditions were investigated by ¹H-NMR technology.RESULTS   The CUMS depressed rat model was successfully replicated. The results of metabonomics showed that, compared to the control group, a total of 17 metabolites were changed in the rats of the model group. Compared to the model group, there were significant changes in the depressed rats intervened by Sinisan and Sinisan containing Bupleuri Radix and Paeoniae Radix Alba after vinegar-processing. Compared to the Sinisan group, a total of 6 metabolites, including lactic acid, α-glucose, β-glucose, formic acid, acetic acid, and threonine, were changed in the feces of the rats intervened by Sinisan containing Bupleuri Radix and Paeoniae Radix Alba after vinegar-processing. Meanwhile, a total of 6 metabolic pathways, including pyruvate metabolism, glycolysis or gluconeogenesis, methane metabolism, glyoxylate and dicarboxylate metabolism, glycine, serine and threonine metabolism, aminoacyl-tRNA biosynthesis, were influenced as well.CONCLUSION   Sinisan containing Bupleuri Radix and Paeoniae Radix Alba after vinegar-processing shows better antidepressant effect, which may be related to energy metabolism, amino acid metabolism, immune regulation, and intestinal flora.