Construction Of Antibiotic-induced Depression Of Mice And Mechanism Research

Depression is a common mental disease with high morbidity and suicide rate.Antibiotics are commonly used in the clinical treatment of bacterial infections.Overuse of antibiotics can not only induce bacterial resistance,but also increase the risk of depression.Objective: To construct a stable and effective antibiotic-induced depression mice model,and to explore the role of intestinal microbiota,intestinal permeability and astrocytes in antibiotic-induced depression and the specific mechanism.Methods: A variety of antibiotic combinations were used to induce depression in mice by gavage or free drinking.The constructed mice model of antibiotic-induced depression was evaluated and identified by a number of behavioral tests and depression-related neurobiological factors.Metagenomics analysis,q PCR and FMT were performed to determine the role of intestinal microbiota in antibiotic-induced depression in mice.HE staining was used to observe the pathological changes of the colorectal mucosal tissue of depressed mice,and ELISA and Western Blot were used to detect the expression of intestinal permeability-related proteins,and the antibody array was used to detect the expression levels of various cytokines in the blood,and the functional changes of astrocytes in the hippocampus of depressed mice were analyzed by detecting the content of GFAP and GLU in the hippocampus.And the role of inflammation,intestinal permeability and astrocyte function in antibiotic induced depression was discussed.Results: The antibiotic combination AMA(1.25μg/ml natamycin,5mg/ml neomycin sulfate,5mg/ml bacitracin),AMB(24mg/ml bacitracin,24mg/ml neomycin sulfate,9.6mg/ml ampicillin,4.8mg/ml meropenem,1.47mg/ml vancomycin)and AMD that only containing 5mg/ml neomycin sulfate could induce depression-like behavior in mice.By using these three antibiotic combinations,the content of NE,5-HT and BDNF in the hippocampus and PFC tissues of mice were significantly decreased,and the depression induced by the antibiotic combination AMA was significant and stable.The FMT results showed that fecal microbiota from antibiotic-induced depressed mice(i.e.,the AMA,AMB,and AMD groups)was transplanted into normal mice could induce corresponding depression-like behavior and changes of neurobiological factors.Metagenomics analysis showed that community structure in the intestinal tract of antibiotic-induced depression mice was significantly different from that in normal mice,and the intestinal microbiota species diversity in antibiotic-induced depression mice was lower than that in normal mice,the lipoic acid metabolism pathway was significantly activated,and the expression of functional gene lip A was explicitly increased.The results of q PCR showed that the relative expression levels of Akkermansia muciniphila,Bacteroides thetaiotaomicron and Anaerostipes caccae in AMA,AMB and AMD groups were significantly higher than those in the normal group.Compared with the normal mice,the cecum tissue of antibiotic-induced depressed mice was significantly enlarged,the mucosal tissue of colorectal tissue had obvious pathological changes,the content of Zonulin in colorectal tissue and the content of FABP2,LPS and the inflammatory cytokines IL-1β and IL-6 in serum were significantly increased.In addition,the content of GFAP decreased significantly and GLU increased significantly in the hippocampus of antibiotic-induced depressed mice.Conclusion: The specific antibiotic mixtures could induce depression by causing changes in intestinal microbiota of mice.The depressive behavior and neurobiological factors of mice induced by antibiotic solution D(5mg/ml neomycin sulfate)were significantly changed,and an effective antibiotic-induced depression mice model could be constructed.Compared with the normal mice,the antibiotic-induced depressed mice show differences in intestinal microbiota abundance,and high expression of the unique metabolic pathway,and functional gene.The abuse of antibiotics caused changes in intestinal permeability in mice,which in turn caused LPS to enter the blood and the inflammatory response,leading to dysfunction of astrocytes and decreased ability to clear glutamic acid,which may be related to the mechanism of antibiotic-induced depression.