Study On The Mechanism Between Dynamic Alteration Of Gut Microbiome With Depression And Antidepressant Efficacy In Mice

Background:Depression is a major mental illness that interacts with genes and the environment.It has the characteristics of high prevalence,recurrence and disability.The global prevalence of depression is about 4.4%,and the number of patients affected is as high as 322 million,which has become the leading cause of disability worldwide.There are many theories on the pathogenesis of depression in the past,but none of them can fully explain the exact mechanism of depression.At present,antidepressants are commonly used for the treatment of depression,and only less than half of depression patients can be completely relieved after the first treatment.Therefore,the factors that influence the efficacy of antidepressants needs to be clarified urgently.In recent years,a number of studies have confirmed that the gut microbiome can influence brain function,behavior and the occurrence of brain diseases through the "gut-brain" axis.Gut microbiome disorder has also become a new entry point for the study of the pathogenic mechanism of depression.The rise of the concept of pharmacomicrobiomics has also brought more attention to the interaction between gut microbes and drugs.Therefore,exploring the relationship between gut microbes and the pathogenesis of depression and the efficacy of antidepressants will provide new insights into the pathogenesis of depression and provide a theoretical basis for optimized treatment and precision medicine for depression.Objectives:1.To explore the difference of gut microbiome between CUMS mice and control group.2.To explore the effect of escitalopram on the gut microbiome,and the relationship between the differential microbiota and antidepressant efficacy.3.In order to find out the effect of escitalopram on the serum metabolic phenotype of depressed mice,and explore the metabolic phenotypes between different treatment response groups.4.Explore the mechanism of gut microbiome that mediate the antidepressants that act through participating in the host metabolism pathway.Methods:1.The depression-related behavioral indicators was used to evaluate depression-like behavior in mice and the efficacy of escitalopram,and then mice were divided into drug-responder group and non-responder group.2.Using 16 S r RNA high-throughput sequencing technology to analyze the dynamic changes of gut microbiome between the CUMS group and the control group,to find the key microbial changes in the dynamic process of CUMS stress.3.Using 16 S r RNA high-throughput sequencing technology to analyze the gut microbes of the CUMS group and the drug intervention group,to explore the effect of escitalopram on the gut microbes of depressed mice and the differences in gut microbes between different treatment response groups.4.The serum metabolic phenotypes of the escitalopram intervention group and the control group based on the GC-MS metabonomics study were analyzed,aim to find the differences in the metabolic phenotypes between the groups.5.Spearman correlation analysis of differential microbiota and metabolites were conducted to explore the relationship between gut microbiome and metabolites.Results:1.Compared with the control group,the sucrose preference ratio in SPT of CUMS mice was significantly reduced,and the immobility time in FST was significantly increased.After the intervention of escitalopram,compared with the CUMS group,the preference for sugar water in the drug responder group was significantly higher,and immobility time in FST was significantly reduced.2.There are significant differences in β-diversity and gut microbial composition between the depressed mice and the control group.Compared with the control group,a total of 92 different OTUs were found.The OTUs enriched in the depression group mainly belonged to the Laospirillaceae,Bacteroidaceae and Rikenellaceae,while the OTUs enriched in the control group mainly belonged to the Erysipelotrichaceae and Lactobacillaceae.3.Escitalopram can affect the microbial composition of in mice.In the second week of medication,the phylum Bacteroides remain stable,and abundance of Rikenellaceae was reduced.After the intervention of escitalopram,the composition of gut microbiome was significantly different among different treatment response groups.Among them,Lachnospiraceae is mainly enriched in the ESC-R group,while Lactobacillaceae is mainly enriched in the ESC-NR group.4.Compared with the CUMS group,a total of 109 differential metabolites were identified in the escitalopram responder group(ESC-R)and a total of 118 differential metabolites were identified in the nonresponder group(ESC-NR),and there are 14 different metabolites between ESC-R and ESC-NR groups.Regardless of whether the drug intervention is effective or not,escitalopram can up-regulate linoleic acid,tocopherol acetate,and down-regulate metabolites such as glutamic acid and oxoglutaric acid.These metabolites mainly involved in amino acid metabolism and lipid metabolism.In addition,differential metabolites may participate in the production of differences in the efficacy of escitalopram through alanine,aspartate and glutamate metabolism pathways.5.Differential gut microbiota can affect the efficacy of antidepressants by affecting the energy metabolism,oxidative stress and lipid metabolism pathway of the host.Conclusions:1.Depressed mice are accompanied by significant gut microbial disorders which showed dynamic changes.2.Escitalopram can affect the composition of gut microbiome in mice,and the different therapeutic effects of escitalopram are also related to the differences in gut microbiome.3.Escitalopram can significantly affect the serum metabolic phenotype of depressed mice.Differential gut microbiota can influence the efficacy of antidepressants through specific metabolic pathways.