| Background:Depression is a common type of mental disorder characterized by persistent depression and retardation of thinking significantly.There are many hypotheses for its pathogenesis,such as neurovascular unit instability,hypothalamic-pituitary-adrenal axis hyperfunction,etc..Bile acid(BA)is an important metabolite.It can not only promote the digestion and absorption of fat,but also regulate the physiological functions of liver,intestine and brain.Based on the basic treatment method of "YiqiKaiyu",our research group has developed an approved medical institution preparation"Kaixin-Jieyu Pills"(KJP).Our previous clinical and basic studies have confirmed that the antidepressant effect of KJP is comparable to that of fluoxetine hydrochloride and escitalopram,and its mechanism of action is mainly through the regulation of neurotrophic factors,inflammatory factors,and monoamine neurotransmitters.and other ways to improve neuroplasticity,repair neurovascular units,and inhibit neuroinflammation.This study will explore the role of bile acid metabolism in the pathogenesis of depression through in vivo experiments,and further explore the antidepressant mechanism of KJP.Objective:This study will explore the bile acid metabolism in the "gut-liver-brain axis" of depression and the new antidepressant mechanism of KJP by observing the content of bile acid as well as expression changes of protein and gene of farnesoid X receptor(FXR),fibroblast growth factor 19(FGF19),fibroblast growth factor receptor 4(FGFR4)in the "gut-liver-brain axis" of chronic stress rats,and the regulatory effect of KJP,in order to elucidate the scientific connotation of the pathogenesis of"Yuanqi-Kuixu" and the treatment of "Yiqi-Kaiyu".Methods:40 male SD rats were randomly divided into normal group,model group,fluoxetine group and KJP group.The chronic unpredictable mild stress(CUMS)method was used for 5 weeks to establish a rat depression model.KJP group was given KJP suspension 0.90g/kg/d,fluoxetine group fluoxetine hydrochloride tablet suspension 2.0mg/kg/d,model was established and gavage was given for 3 weeks.During the experiment,the state of the rats was observed,and the body weight and food intake were recorded.After the experiment,the sugar water preference test,open field test,tail suspension test and forced swimming test were used to evaluate the behavioral changes.After sampling,the changes of total bile acid(TBA)in serum and thalamic homogenate of rats were detected.Western blotting and real-time quantitative PCR were used to detect FXR receptors in rat liver and ileum,as well as FXR and FGF19 in hypothalamus,FGFR4 protein and gene expression changes.Result:1.After 5 weeks of modeling,the rats in the model group,fluoxetine group and KJP group decreased significantly compared with the normal group(P<0.001).Compared with the model group,the body weight of the rats in the group(P<0.01)was significantly increased,but there was still a gap compared with the normal group(P<0.01).Compared with the normal group,the average daily food intake of the rats in the model group,fluoxetine group and KJP group was significantly decreased(P<0.001);The food intake was significantly higher than that of the model group(P<0.001)2.In the sugar water consumption experiment,compared with the normal group,the fluoxetine group and the KJP group,the rats in the model group had significantly lower sugar water consumption(P<0.001);The consumption of sugar and water in the fluoxetine group(P<0.001)was significantly higher than that in the model group.In the forced swimming test,the struggling time of the model group was significantly shorter than that of the normal group,the fluoxetine group and the KJP group(P<0.001);while the KJP group(P<0.001)and the fluoxetine group(P<0.001)the swimming struggle time of the rats was significantly longer than that of the model group.In the tail suspension test,the immobility time of the rats in the model group was significantly longer than those in the normal group,the fluoxetine group and the KJP group(P<0.001).It was also significantly shortened in other groups(P<0.001).In forced swimming,open field test,and tail suspension test,the exercise ability of KJP group(P<0.001)and fluoxetine group(P<0.001)were significantly improved,but there was still a gap with the normal group(P<0.05).3.Biochemical test results showed that compared with the normal group,the TBA levels in the model group were significantly increased in serum and thalamus,and the difference was statistically significant(P<0.01).After administration of fluoxetine(P<0.01),and KJP(P<0.01),the TBA content in serum and thalamus was significantly decreased,but there was still a difference with the normal group(P<0.01).Compared with fluoxetine,the metabolism-promoting effect of KJP on BA was still different(P<0.01).4.Western blotting results showed that compared with the normal group,depression induced by CUMS modeling significantly increased the protein expression of FXR in the liver,ileum and hypothalamus,and significantly inhibited the protein expression of FGF-19 and FGFR4 in the hypothalamus.(P<0.001).Compared with the model group,KJP(P<0.05)could effectively inhibit the overexpression of FXR in the liver,intestine and hypothalamus,and could significantly increase the protein level of FGF-19 in the hypothalamus(P<0.001),but it had no significant effect on the protein expression of FGFR-4(P>0.05);Fluoxetine could significantly inhibit the overexpression of FXR in liver and intestinal tissues(P<0.01),and effectively inhibited the expression of FXR in the hypothalamus.Overexpression(P<0.05),and can significantly increase the protein levels of FGF-19 and FGFR-4 in the hypothalamus(P<0.001).In addition,the regulation of FXR in the liver,intestine and hypothalamus by KJP was not significantly different from that in the fluoxetine group(P>0.05),while the regulation of FGF-19(P<0.01),FGFR-4(P<0.05)was different from fluoxetine in its regulatory effect.5.The results of real-time quantitative PCR showed that the gene expression of FXR in the liver,ileum and hypothalamus of the model group rats were significantly increased(P<0.001),while the levels of FGF-19 and FGFR-4 in the hypothalamus were significantly decreased(P<0.001).Compared with the model group,both KJP group and fluoxetine group could significantly inhibit the overexpression of FXR gene in liver and hypothalamus(P<0.001),and could significantly promote FGF-19 and FGFR-4 gene expression in hypothalamus(P<0.01).In addition,there was no significant difference in the regulation ability of KJP on the expression of FXR gene in the liver and hypothalamus compared with fluoxetine(P>0.05),but there was a significant difference in the regulation ability of FXR gene expression in the ileum compared with fluoxetine(P<0.01),the regulation ability of FGF-19 and FGFR-4 gene expression in the hypothalamus was also significantly different from that in the fluoxetine group(P<0.001).Conclusion:1.Under depression,there was BA metabolic disorder in the "gut-liver-brain axis"of rats,and the level of BA negative feedback pathway FXR-FGF19-FGFR4 decreased.2.KJP could effectively promote the metabolism of BA in depressed rats,inhibit the overexpression of FXR receptors in the liver,ileum and hypothalamus,and increase the level of FGF-19 in the hypothalamus.3.KJP might improve bile acid metabolism disorder and exert antidepressant effect by regulating FXR-FGF19 pathway. |
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