ObjectiveDepression is a common mental illness with a profound impact on physical health. Depression has been associated with a higher risk of bacterial infection； however， whether this relationship is causal and how depression affects infection remains unclear. Therefore， we aimed to investigate the effects of depressive phenotype in infected mice by constructing a chronic unpredictable mild stress （CUMS） model. MethodsMice were induced with CUMS for 4 weeks. The depressive phenotype was evaluated using behavioral tests. Subsequently， the mice were intraperitoneally injected with Klebsiella pneumoniae to establish bacterial infection. Serum and abdominal tissues were collected 48 h after infection. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in the tissues， and enzyme-linked immunosorbent assay （ELISA） was used to measure the levels of inflammatory factors. In addition， the fecal samples collected before infection were analyzed for 16S rDNA gene of gut microbiota， and the expression levels of NF-κB/NLRP3 signaling pathway in colon tissues of uninfected mice were detected. ResultsBehavioral tests showed that compared with the control mice， CUMS mice had significantly lower body weight （P<0.000 1， t=5.426）， lower sucrose preference rate （P<0.001， t=4.937）， increased swimming stationary time （P<0.001， t=16.37）， and decreased time spent in the central area of the open field （P<0.01， t=3.575）. Survival analysis showed that compared with the control mice， the survival rate of CUMS mice significantly decreased after infection （P<0.05）. Additionally， histochemical staining showed that tissue damage in the liver （P<0.05， t=4.025）， kidney （P<0.05， t=2.828）， and mesentery （P<0.01， t=5.367） significantly increased. Furthermore， ELISA results showed that the levels of the inflammatory cytokines IL-6 （P<0.01， t=3.365）， IL-1β （P<0.01， t=4.061）， TNF-α （P<0.01， t=4.460） and LPS （P<0.000 1， t=27.24） were elevated. The difference was statistically significant. According to 16S rDNA sequencing， CUMS-induced changes in the intestinal bacterial community structure of mice， making them significantly different from the control mice. Compared with the control mice， the expression levels of NF-κB （P<0.01， t=6.825） and NLRP3 （P<0.001， t=9.561） were upregulated in CUMS mice. ConclusionThe CUMS model was successfully constructed and CUMS mice developed more severe bacterial infection. Gut microbiota was dysregulated and the expression of NF-κB/NLRP3 signaling pathway was up-regulated in CUMS mice， which was related to the susceptibility to bacterial infection.