Study On The Molecular Mechanism Of Microbiota Regulating Behavior Of Host

BackgroundThe gut microbiota has a profound impact on the host's development and function.Over the past few years,the effects of the gut microbiota on host systemic immune function and bone physiology have been well described,and emerging evidence demonstrated that the gut microbiota influences host behavior,moreover the presence of the gut microbiota increased motor activity and reduced anxiety-like behavior in rodents.Early research findings through our team have confirmed this phenomenon,and these findings may have wider implication in considering psychiatric disorders in humans.The gut microbiota can regulate host development and behavior,but the mechanism is not elucidated at present.The prefrontal cortex and hypothalamus are meaningful to brain region that is associated with behavior regulation,and dysfunction of this region has been implicated in a range of neuropsychiatric disorders such as depression and schizophrenia.However,the effect of the gut microbiota on prefrontal cortex and hypothalamus which may be a regulatory mechanism to behavioral disorders remains unknown.ObjectivesTo analyze the effect and mechanism of gut microbiota on axonal guidance signaling of prefrontal cortex of host.To analyze the effects of early colonization of gut microbiota on the molecular network of the hypothalamus of the host.To analyze the effect of recolonization of gut microbiota derived from MDD patients on the molecular network of hypothalamus in mice.MethodsGnotobiotic models-germ free mice were applied to explore behavioral phenotypes and possible molecular mechanisms that were evaluated by Realtime-PCR and western blot analysis.Primary cultures of mice cortical neurons were performed to demonstrate the role of Sema3 A on NR1D1 expression.Illumina sequencing and array technologies were applied to explore possible molecular mechanisms which may be a regulatory mechanism for behavioral disorders.ResultsFirstly,early colonization of gut microbiota influences genes expression of axonal guidance signaling in the prefrontal cortex.Recolonization is not sufficient to normalize differentially expressed genes in axonal guidance signaling.Secondly,early colonization of gut microbiota influences the Sema3A/NRP1 signaling pathway in the prefrontal cortex.Sema3 A inhibitsNR1D1 expression through the RhoA/ROCK pathway in primary cortical neurons.Thirdly,early colonization of gut microbiota influences H2-Q1 ?H2-Ab1?H2-DMb2?COL11A2?Dynlt1b?Dynlt1f and Glo1 expression in the hypothalamus.Recolonization is not sufficient to normalize differentially expressed genes except H2-Q1?COL11A2;Fourthly,recolonization with between gut microbiota of normal mice and gut microbiota derived from MDD patients,which promote genes expression of ECM-receptor interaction and Focal adhesion pathways in the hypothalamus.Lastly,recolonization with gut microbiota derived from MDD patients can inhibit genes expression of Oxidative phosphorylation pathways in the hypothalamus.Conclusions:Sema3A-mediated modulation of NR1D1 expression may be involved in the regulation of axonal guidance signaling by the microbiota;Early colonization of microbiota influences immune,protein transport and lactoylglutathione lyase activity;Extracellular matrix function is an important link in the regulation of brain function with gut microbiota;Inhibition of Oxidative phosphorylation pathways in the hypothalamus may be a potential mechanism for gut microbiota to regulate host behavior phenotype.