肠脑轴与肌脑轴视角下基于肠道菌群和代谢组学解析逍遥散与帕罗西汀协同抗抑郁机制OA

OBJECTIVE To elucidate the reduced-dose synergistic antidepressant mechanism of Xiaoyao powder and paroxetine from the dual perspectives of the"gut-brain"axis and the"muscle-brain"axis.METHODS Male SD rats were randomly divided into five groups:control,model,model+Xiaoyao powder(23.1 g·kg-1),model+paroxetine(5 mg·kg-1),and model+Xiaoyao powder+parox-etine(11.5 g·kg-1+2.5 mg·kg-1).Except the control group,these groups were subjected to 28 days of chronic unpredictable mild stress that started 1 hour after daily administration.Body mass was recorded weekly.Depressive-like behaviors were evaluated using the open field test(the number of grid cross-ings and latency to leave the central area were determined),the sucrose preference test(the sucrose preference rate was measured),and the forced swimming test(the immobility duration was recorded).Meanwhile,spatial cognitive function was evaluated using the Morris water maze(the number of plat-form crossings was recorded).16S ribosomal RNA(rRNA)gene sequencing technology was used for gut microbiome analysis to evaluate microbial diversity and compositional structure,and for functional prediction.The metabolomics of skeletal muscles was analyzed to identify differential metabolites and metabolic pathways in the skeletal muscle tissues of rats in each group.Adenosine triphosphate(ATP),adenosine diphosphate(ADP),energy charge levels,and the activities of Na+-K+-ATPase,Ca2+-Mg2+-ATPase,and succinate dehydrogenase(SDH)in brain and skeletal muscle tissues were measured by ELISA.Finally,correlation analysis was used to integrate multi-system and multi-dimensional indicators related to behavioral tests,gut microbiome,skeletal muscle metabolome,and energy metabolism in order to assess the holistic effects of the combined intervention.RESULTS Compared with the control group,body mass,grid crossings in the open field test,numbers of platform crossings in the Morris water maze,and the sucrose preference rate were significantly decreased while the latency to leave the central area and immobility duration were significantly prolonged in the forced swimming test in the model group.The structure and function of the gut microbiota were markedly disrupted,with five differ-ential genera identified among which the relative abundances of Corynebacterium,Jeotgalicoccus,and Aerococcus were significantly increased while those of Coprobacillus and Staphylococcus were signifi-cantly decreased.Skeletal muscle metabolomics found that the levels of tyrosine,cysteine,glycine,glutamine,lactate,3-hydroxypropionic acid,cytidine,betaine,and mannose were higher in the model group than in the control group while those of alanine,succinate,and citrate were significantly reduced,indicating disturbances in the tricarboxylic acid(TCA)cycle and amino acid metabolism-related path-ways.The combination of Xiaoyao powder and paroxetine significantly improved body mass,the sucrose preference rate,and the number of crossings in the open field test while reducing the latency to leave the central area in rats,with effects comparable to full-dose monotherapy and even better than those of the paroxetine group in the Morris water maze and forced swimming tests.Gut microbiota and metabolomics analyses found that the combination markedly reversed the relative abundances of Coprobacillus,Corynebacterium,and Staphylococcus,synergistically reshaping gut microbiota homeo-stasis.The combination also effectively corrected the disordered metabolic profile of skeletal muscles.At the level of energy metabolism,the combination significantly elevated ATP/ADP levels and improved Na+-K+-ATPase,Ca2+-Mg2+-ATPase activities,with effects superior to those of the paroxetine group.Network correlation analysis indicated that changes in gut microbiota,metabolites,and energy metabo-lism indicators were all correlated with behavioral parameters.CONCLUSION At half doses,the combi-nation of Xiaoyao powder and paroxetine can produce antidepressant effects comparable to those of full-dose paroxetine alone.The underlying mechanism involves reshaping the gut microbiota,correcting skeletal muscle metabolic disorders,and restoring energy metabolism along the"gut-brain"and"muscle-brain"axes.