Abstract: This study aimed to investigate the effects of postbiotic, derived from Lactiplantibacillus plantarum IOB602 (LP602) on depression-like behaviors in mice induced by chronic unpredictable mild stress (CUMS). Specific pathogen-free (SPF) C57BL/6 mice were randomly divided into five groups: control, CUMS model, placebo, postbiotic, and positive drug (fluoxetine). Following the establishment of CUMS model, all groups received a two-week gavage intervention. Initially, the anti-depressant effects of postbiotic LP602 were assessed by using behavioral tests. Subsequently, enzyme-linked immunosorbent assay (ELISA) was employed to detect monoamine neurotransmitters and the hypothalamic-pituitary-adrenal axis (HPA). Finally, 16S rDNA sequencing was utilized to analyze gut microbiota composition, gas chromatography (GC) was used to measure short-chain fatty acids (SCFAs), and hematoxylin-eosin (H&E) staining and immunofluorescence techniques were employed to assess the function of the intestinal barrier. The results showed that postbiotic LP602 significantly increased the sucrose preference of CUMS mice and the time spent in the central area, while significantly reducing the immobility time in the forced swimming test (FST) and the tail suspension test (TST). Furthermore, the postbiotic significantly increased the levels of monoamine neurotransmitters including 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) in the serum and hippocampus. Conversely, the serum levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosterone (CORT) were significantly decreased by the postbiotic. Analysis of the gut microbiota revealed that postbiotic intervention modulated the structure and composition of the gut microbiota in mice under CUMS, notably increasing the relative abundance of Erysipelotrichaceae and Dubosiella and reducing the relative abundance of Firmicutes and Staphylococcaceae. Moreover, the concentrations of acetic acid, butyric acid, isobutyric acid, propionic acid, valeric acid, and isovaleric acid in the feces of mice were all significantly increased. Furthermore, the postbiotic mitigated small intestine damage and significantly enhanced the expression of the immunofluorescent protein ZO-1. Therefore, postbiotic LP602 effectively improved depression-like behaviors induced by CUMS in mice, possibly by increasing monoamine neurotransmitter levels, correcting the abnormal activation of the HPA, and regulating the gut microbiota.

Key words: chronic unpredictable mild stress, postbiotics, depression-like behavior, gut microbiota, neurotransmitter