<title>Abstract</title> <bold>Aim:</bold>Chronic stress plays an important role in the pathophysiology of depression. In this study, we aimed to investigate the therapeutic effects of Bactolac (<italic>Lactobacillus plantarum NBIMCC 8767+Streptococcus thermophilus NBIMCC 8258</italic>) on chronic stress-induced depression in rats. <bold>Methods:</bold>This study was performed in a total of 28 rats, in control (C), stress (S), Bactolac (B), Bactolac+stress (BS) groups (each n=7). Behavioral tests were performed to evaluate depressive behaviors (sucrose preference test, three-chamber sociability test, elevated plus maze test, forced swim test). 5-HT1A, DRD1, ADRA-2A, GABA-A α1, CNR1, NR3C2, NLRP3, MC4R expression levels in hippocampus tissue; NOD1 receptor expression levels in small intestine tissue were determined by RT-PCR method. BDNF levels in hippocampus tissue were determined by elisa kit. Histopathological examinations were performed in cortex and small intestine tissues. <bold>Results:</bold>Bactolac treatment reduced depressive-like behaviors (p&lt;0.05), NLRP3 and MC4R expression levels (p&lt;0.05), neurodegeneration, and glial activity, increased BDNF levels. It had no effect on other parameters examined in stressed rats. <bold>Conclusions:</bold>Chronic stress decreased the expression levels of 5-HT1A, DRD1, ADRA-2A, GABA-A α1, CNR1, NR3C2, NOD1 and BDNF level; increased the expression levels of NLRP3 and MC4R, caused neurodegeneration and glial activity, ultimately led to depressive effects. Bactolac was effective in reducing depressive effects and may be a natural treatment agent for depression.