Lipopolysaccharide Regulates Mouse Antidepressant-like Behavior And The Expression Of Glucocorticoid Receptor Pathway Genes In Hippocampus

Background: Gut microbiota plays an important role in the immune system,metabolism and digestion,and has a significant effect on the nervous system.Recent studies have revealed that abnormal gut microbiota induces abnormal behaviors,which may be associated with the hypothalamic–pituitary–adrenal(HPA)axis,lipopolysaccharide(LPS)and the glucocorticoid receptor pathway genes in the hippocampus.Objectives: 1.The specific pathogen free(SPF)mice were fed with Escherichia coli–derived lipopolysaccharide(LPS),to explore whether gut microbiota affects mouse behaviors through LPS.2.To explore which glucocorticoid receptor pathway genes in hippocampus are affected by gut microbiota.3.By comparing the relationship between mouse behavioral phenotypes and the expression of the glucocorticoid receptor pathway genes in hippocampus,to explore whether gut microbiota regulates mouse behaviors through the glucocorticoid receptor pathway genes in the hippocampus,and to explore which gene is more important.Methods: We quantified the basal serum cortisol levels in germ-free(GF)mice,and examined glucocorticoid receptor pathway genes in hippocampus using real-time PCR to explore the genes affected by gut microbiota.Moreover,we investigated the behavioral changes in an Escherichia coli–derived lipopolysaccharide treatment mice by behavioral tests,and also validated the differential genes by real-time PCR and quantified the basal serum cortisol levels in the Escherichia coli–derived lipopolysaccharide treatment mouse model and the fecal ?depression microbiota‘ transplantation(FMT)mouse model.Results: The E.coli LPS-treatment mice showed antidepressant-like behavior,but did not show antianxiety-like behavior,whereas GF mice showed antianxiety-and antidepressant-like behaviors.However,?depression microbiota‘ recipient mice exhibited anxiety-and depressive-like behaviors.Additionally,six glucocorticoid receptor pathway genes(Slc22a5,Aqp1,Stat5 a,Ampd3,Plekhf1 and Cyb561)were upregulated in GF mice,and of these only two(Stat5a and Ampd3)were upregulated in E.coli LPS-treatment mice,whereas the shared gene,Stat5 a,was downregulated in ?depression microbiota‘ recipient mice.Furthermore,basal serum cortisol levels were decreased in E.coli LPS-treatment mice but not in GF mice and ?depression microbiota‘ recipient mice.Conclusions: These results indicate that the Escherichia coli–derived LPS regulates mouse antidepressant-like behavior and the expression of the glucocorticoid receptor downstream pathway genes in hippocampus,and also indicate the gut microbiota may lead to behavioral abnormalities in mice by affecting the glucocorticoid receptor downstream pathway genes in hippocampus through the LPS.Herein,we proposed a new insight into the molecular mechanisms by which gut microbiota influences depressive-and anxiety-like behaviors.