| Background: At present,western medicines are the main treatments of depression.Among them,Selective Serotonin Reuptake Inhibitors(SSRIs)are the most commonly used.Paroxetine,as a first-line SSRIs commonly used in clinic,exhibits significant antidepression effects.However,Paroxetine has significant gastrointestinal side effects,resulting in poor patient compliance,symptom recurrence,treatment regimen suspension,and so forth.Creatively,Chinese scholars combine Traditional Chinese Medicines(TCMs)with SSRIs,and found that such combinations significantly improve gastrointestinal side effects and improve patient compliance.The combinations of TCMs and western medicines is one of the effective strategies to improve the antidepressant efficacies of SSRIs.The combination of Xiaoyaosan and Paroxetine has been widely used.Most studies about them are clinical observations.The scientific nature and internal mechanisms of the combined applications have not been deeply understood,which restricts clinical science and rational medicine applications.In clinic,it has been found that Xiaoyaosan combined with Paroxetine can significantly reduce the gastrointestinal side effects of Paroxetine,improve patient compliance and clinical efficacy.At the same time,our previous study showed that Xiaoyaosan significantly improved the gastrointestinal functions of depressed rats.Based on the above information,we reliminatively explore the anti-depression mechanism of combined medication from the perspective of intestinal microecology,with focusing on intestinal flora and intestinal immunity.Intestinal microbiota play irreplaceable roles in regulating physiological functions of the body.Moreover,gut as the body’s largest immune organ,accounts for 70% the body’s immune functions.Gut is at the forefront of the body’s defense,with nearly half of the immune cells attaching to gut,producing 80% of the body’s antibodies.Therefore,this study intends to reveal the anti-depressive intestinal microecological mechanism of Xiaoyaosan in combination with Paroxetine from the perspectives of behavioral index,intestinal microbiota and intestinal immunity.The results of this study will provide not only new perspectives for understanding and improving the antidepressant effects of Paroxetine from the perspective of intestinal microecology,but also new theoretical basis and experimental support for understanding the science and rationality of the combined applications of TCMs and western medicines on depression.This study will also lay scientific foundation for the improvement of the theoretical system,as well as the optimization and application of the combined use of TCMs and Western medicines.Aims: 1.This study verified the antidepressant effect of Xiaoyaosan combined with Paroxetine from the perspective of basic researches;2.In addition,this study revealed the intestinal microecological mechanism of Xiaoyaosan combined with Paroxetine based on16 S r RNA sequencing and molecular biology techniques;3.In this study,the visualization network of "behavioral index,intestinal microbiota and intestinal immunity" was constructed to systematically and completely explain the mechanisms of antidepressant actions of combination medication.Method: 1.In this study,the optimal dose of Xiaoyaosan and the dosage of Paroxetine was determined according to our previous studies and clinical dose(instruction manual),respectively.The classical CUMS depression model was applied.We tested the effects of Xiaoyaosan combined with Paroxetine,Xiaoyaosan and Paroxetine alone groups on body weight,sugar water preference,and related parameters of depressed rats in lightdark box,forced swimming,open field,and Morris water maze tests,and evaluated the antidepressant effects of each group.2.16 S r RNA sequencing technology was used to analyze the structure,diversity and differential microbiota of intestinal microbiota in cecal contents of rats in the groups of Xiaoyaosan combined with Paroxetine,Xiaoyaosan and Paroxetine alone.3.Molecular biology techniques was used to detect the expression levels of Th17 cells,Treg cells,IL-10,IL-17,IL-22,TGF-β in the intestinal contents of rats in all groups.4.Based on results of Spearman correlation analysis,the visualization network of "behavioral index,intestinal microbiota and intestinal immunity" was constructed.Results: 1.After 28 days of modeling,depressed rats showed low survival desire,anhedonia and decreased ability of autonomous activity,suggesting that the depression model was successfully replicated.Xiaoyaosan combined with Paroxetine can significantly improve the abnormal performance of depressed rats in open field test,sugar water preference test,Morris water maze test,forced swimming test and other indicators.Xiaoyaosan combined with Paroxetine showed stronger effects on improving macro behaviors of depressed rats than Xiaoyaosan and Paroxetine alone.2.The structure composition,diversity and abundance of intestinal microbiota of depressed rats decreased significantly,suggesting that intestinal flora and its functions of rats were disordered and interrupted by CUMS.Xiaoyaosan combined with Paroxetine can significantly increase the abundance of intestinal microbiota,restore the structural composition of intestinal microbiota and improve the diversity of intestinal microbiota of depressed rats.Xiaoyaosan combined with Paroxetine showed stronger regulatory effects on the disordered intestinal flora of depressed effects than Xiaoyaosan and Paroxetine alone.3.In the intestinal tract of depressed rats,Th17 cells and pro-inflammatory factors were significantly expressed while the expression levels of Treg cells and antiinflammatory factors were significantly decreased,indicating unbalanced intestinal immunity of depressed rats.Xiaoyaosan combined with Paroxetine can significantly improve the expression of Treg cells and IL-10,IL-22,TGF-β levels,significantly reduce expression of Th17 cells and IL-17 level.Xiaoyaosan combined with Paroxetine can significantly regulate intestinal immune imbalance of depressed rats.4.The "behavioral index – intestinal microbiota-intestinal immunity" network showed that the Xiaoyaosan combined with Paroxetine reduced the relative abundances of P-Actinobacteria,P-Proteobacteria,P-Tenericutes and F-S24-7,while significantly increased the relative abundances of F-Lactobacillaceae,G-Lactobacillus and G-Blautia.Xiaoyaosan combined with Paroxetine can decrease the expression levels of Th17 m RNA and IL-17,while increased the expression levels of Treg m RNA,IL-22,TGF and IL-10,consequently improving the depressive symptoms of rats.Conclusion: The results showed and confirmed that depressed rats had low survival desire,anhedonia,decreased autonomic activity,disorder of intestinal microbiota,imbalance of intestinal immunity,and other symptoms.Xiaoyaosan combined with Paroxetine has stronger anti-depression effects than Xiaoyaosan and Paroxetine alone,which can significantly improve macro behaviors,disorder of intestinal microbiota,and imbalance of intestinal immunity of depressed rats.At the same time,the “behavioral index-intestinal microbiota-intestinal immunity” visualization network constructed in this study systematically and integrally explains the mechanisms of antidepressant action of Xiaoyaosan combined with Paroxetine.The results provide not only experimental basis for the clinical applications of TCMs and western medicines in the treatment of depression,but also research strategies and schemes for elaborating the effects of combination of TCMs and western medicines from the perspective of intestinal microecology.It also lays theoretical basis for understanding the science and rationality of the anti-depression effects of the combined applications of TCMs and western medicines. |
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