Mechanistic of combination of Bifidobacterium brevis in improvement of chronic unpredictable mild stress-induced depression in rats based on gut microbiota and non-targeted metabolomics
Objective This study aimed to investigate the antidepressant mechanisms of combination of Bifidobacterium brevis,based on 16S rDNA technology and metabolomics technology.Methods Select 36 rats at random and divide them into four groups:control group,model group,BBC group(Bifidobacterium bifidum BBr60∶Bifidobacterium bifidum BBi32∶Lactobacillus reuteri BL21∶Streptococcus thermophilus ST36=1∶1∶1∶1,1.5×10-9 CFU·d-1)and Fluoxetine and Mirtazapine Tablets(positive drug,1.0 mg·kg-1),except the control group,to establish a CUMS depression rat model with chronic unpredictable mild stress.After the model was successfully established,the rats were ig administered BBC or Fluoxetine and Mirtazapine Tablets for four weeks.The rat depressive behaviors were evaluated by the sucrose preference test,forced swimming test,and open field test,and the levels of 5-hydroxytryptamine(5-HT),dopamine(DA),and norepinephrine(NE)in the serum were determined by enzyme-linked immunosorbent assay(ELISA).The number and morphological changes of neurons in the hippocampal CA1 and CA3 regions were observed by hematoxylin-eosin(HE)staining.The effects of BBC on the gut microbiota and metabolites of depressed rats were explored by 16S rDNA amplicon sequencing and non-targeted metabolomics,and the correlation between differential gut microbiota and metabolites was established by Spearman's coefficient.Results Compared with the model group,BBC effectively ameliorated depressive-like behaviors(P＜0.05 and 0.01),enhanced the levels of 5-HT and DA in the serum and increased the number of neurons in rats.It also restored gut microbiota dysbiosis,particularly by modulating taxa such as Bacilli class,Lactobacillales order,Lactobacillaceae family,and Lactobacillus genus(P＜0.05、0.01).The key biomarkers associated with the antidepressant effect identified through fecal metabolomics included l-hydroxy-2-naphthoic acid,glycyrrhizin A,and N-acetylhistamine,while serum metabolomics revealed key biomarkers such as docosapentaenoic acid,cis-11-eicosenoic acid,and 3'-O-methylbatanin Ⅲ.Significant associations were found between Lactobacillus and Clostridia_UCG-014 and differential metabolites.The enriched pathways included unsaturated fatty acid biosynthesis,tryptophan metabolism,butanoate metabolism,and nicotinate and nicotinamide metabolism,among others.Conclusion BBC alleviates depression-related symptoms induced by chronic stress by modulating gut microbiota and regulating associated metabolic pathways.
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