Function And Mechanism Of Gut Microbiota On The Development And Treatment Of Depression

Depression is a mental disorder with a high rate of suicide and recurrence.Depression affects about 10%of the world’s population.The pathogenesis of depression may be related to genetic,neuroendocrine,biochemical,immune and environment,but the exact pathogenesis has not yet been identified.Gut microbiota has an important impact on the physical and mental health of the host.They not only participate in the physiological activities of the body,but also affect the central nervous system through the microbiotabrain-gut axis.In recent years,the correlation between gut microbiota and depression has become one of the research hotspots.In this study,the gut microbiota was used as the target to study the establishment of chronic restraint stress(CRS)depression mouse model,the changes of gut microbiota,neurotransmitters,SCFAs and cytokines,the correlation between gut microbiota and depression,and the efficacy and mechanism of gut microbiota in the treatment of depression.The main research results are as follows:1.Construction of CRS depression mouse model and analysis of gut microbiota,neurotransmitters,SCFAs and cytokines:The depression mouse model was established by CRS method,and the depression-like behavior of mice was tested by classical behavioral test.The diversity of gut microbiota was analyzed by 16S rRNA sequencing,and the neurotransmitters in hypothalamus and short chain fatty acids(SCFAs)in feces and cytokines in serum were measured.The results of classical behavioral tests showed that there were significant differences in open field test,forced swimming test and sucrose preference test between the normal group(NOR)and CRS group(p<0.01),indicating that the depression mouse model was successfully constructed,indicating that the depression mouse model was successfully constructed.Compared with NOR group,the bacterial diversity of CRS group was significantly decreased(p<0.05),4 phyla,15 families and 15 genera were different.Compared with the NOR group,the CRS group had significantly higher levels of Gamma aminobutyric acid(GABA),Norepinephrine(NE),5hydroxytryptamine(5-HT),and 5-hydroxyindoleacetic acid(5-HIAA),and three SCFAs(acetic acid,propionic acid,and valeric acid)were significantly decreased(p<0.01),and three inflammatory factors including Inter leukin(IL)-6,IL-1β and Tumour necrosis factor-α(TNF-α)were significantly increased(p<0.01).CRS mice showed altered behavior with reduced intestinal flora diversity,significantly lower levels of neurotransmitters and SCFAs,and significantly higher levels of inflammatory factors.2.Correlation between gut microbiota and depression and its efficacy and mechanism in the treatment of depression:By transplanting fresh feces from normal mice to depressed mice and fresh feces from depressed mice to normal mice,the depression-like behaviors of mice before and after fecal transplantation were examined by classical behavioral experiments after transplantation,and the diversity of intestinal flora and changes in the content of neurotransmitters,SCFAs and cytokines in each group of mice were analyzed to investigate the role and mechanism of intestinal flora in the development and treatment of depression.The results showed that there were significant differences in the number of entries into the central area between the depressed group(DEP)and the depressed transplant group(DEP+FMT),the control group(CON),and the control transplant group(CON+FMT)mice(p<0.05).In forced swimming test and sucrose preference test,there were significant differences between DEP group and DEP+FMT group,CON group and CON+FMT group(p<0.01).These results suggest that fecal microbiota transplantation can influence the behavior of mice to some extent.There were significant differences in Shannon and Simpson between DEP group and CON group,DEP+FMT group and DEP group,CON+FMT group and CON group(p<0.01).There was significant difference in Chao index between DEP group and CON group(p<0.01),indicating a significant difference in the alpha diversity of mouse gut microbiota.By analyzing the beta diversity of mouse gut microbiota,the PCoA analysis based on OTU level showed that the species composition of the four groups was significantly different(p<0.001).The metagenomic biomarkers identified by LEf Se method showed that there were 19,32,15 and 7 dominant flora in CON,DEP,CON+FMT and DEP+FMT groups,respectively.Based on the phylum level analysis,the composition of intestinal flora of mice in each group was similar.Firmicutes/Bacteroidetes ratio plays an important role in maintaining the homeostasis of normal intestinal flora,and the increase of F/B ratio is usually associated with inflammation.Compared with CON group,F/B ratio was significantly increased in DEP group(p<0.01);Compared with DEP group,the F/B ratio of DEP+FMT group was significantly decreased(p<0.01).At the family level,Lachnospiraceae,Rumenococcaceae and Oscillospiraceae were the main difference flora in each group.Among them,Lachnospiraceae were associated with 5-HT levels,Ruminococcaceae catabolized carbohydrates to produce SCFAs,and Lachnospiraceae,Oscillospiraceae,and Ruminococcaceae were associated with anxiety and depression-like behaviors.Fecal transplantation significantly increased the neurotransmitter levels of GABA,5-HT,NE,and 5-HIAA in the DEP+FMT group of mice,and significantly reduced the contents of GABA,5-HT,NE and 5-HIAA in mice of CON+FMT group(p<0.01).Alistipes in the intestine of mice in DEP group was significantly higher than that in CON group.Increased abundance ofAlistipes can disrupt the 5-HT balance.The contents of acetic acid,propionic acid and valeric acid in feces of DEP+FMT group were significantly increased(p<0.01).The contents of acetic acid,propionic acid and valeric acid in CON+FMT group were significantly decreased(p<0.01).In addition,the levels of inflammatory cytokines such as IL-6,TNF-α and IL-1β in the serum of DEP+FMT group were significantly higher than those of DEP group(p<0.01).The levels of inflammatory cytokines such as IL-6,TNF-αand IL-1β in the CON+FMT group were significantly lower than those in the CON group(p<0.01).Lachnospiraceae_NK4A136_group and Oscillospiraceae were positively correlated with GABA production.Clostridia_UCG-014 and Candidatus_Saccharimonas were positively correlated with 5-HT and NE production.Blautia and Roseburia were negatively correlated with IL-6 and IL-1β.Lachnospiraceae(including Roseburia,Blautia)are involved in the decomposition of SCFAs.The gut microbiota of DEP+FMT and CON+FMT mice changed after fecal microbiota transplantation,which confirmed the correlation between gut microbiota and depression,and fecal microbiota transplantation can effectively improve the gut microbiota of depression mice.Through two ways of fecal microbiota transplantation,it was confirmed that gut microbiota could affect the central nervous system,substance metabolism and immune function of mice.