Xylo-oligosaccharides Improves Depression-like Behavior In Mice And Its Mechanism

Depression is a highly heterogeneous psychological disorder characterized by marked low mood and pleasure deficits.There is inconsistency in the response of depressed patients to antidepressant medications,the lack of uniform biomarkers of the disorder,and the pathogenesis as well as pathophysiological mechanisms are unclear.A large number of studies have demonstrated that depression can be improved by regulating intestinal flora,which provides a new idea for the prevention and treatment of depression.Xylo-oligosaccharides(XOS)as prebiotic can regulate intestinal flora,this study attempted to investigate the preventive and improvement effects of XOS on depression and its physiological mechanisms.The main contents and findings were listed as follows.Firstly,the preventive effects of different doses of XOS on depressive and anxious behaviors in healthy mice were investigated.The results showed that XOS intervention significantly improved anxiety and depression-like behaviors in mice in the elevated plus maze,forced swimming and tail suspension tests(p<0.05),increased serum concentrations of 5-hydroxytryptophan,a precursor of neurotransmitters that play a role in the mood regulation.Analysis of the gut microbiota revealed that XOS intervention increased beneficial bacteria such as Bifidobacterium,Faecalibaculum,Butyricoccus,Odoribacter,Lachnospiraceae＿NK4A136＿group and Parvibacter and reduced the abundance of Dubosiella,Turicibacter,and Erysipelotrichales,while increasing the fecal levels of acetate,propionate and butyrate.It was shown that intervention of XOS prevents anxiety-depressive behaviors and acts through the regulation of intestinal flora and short chain fatty acids(SCFAs).Then,the effect of different doses of XOS on the depressive and anxiety-like behaviors in chronic unpredictable mild stress mice was investigated.The results showed that XOS intervention significantly improved anxiety and depression-like behaviors,restored neurotransmitter levels(5-hydroxytryptamine,5-hydroxytryptophan and γ-aminobutyric acid)and hypothalamic-pituitary-adrenal axis hyperactivity,and significantly increased colonic tryptophan(Trp)and kynurenine levels in stressed mice.Analysis of gut microbiota revealed that XOS intervention ameliorated stress-induced intestinal flora disorders,increasing the relative abundance of Akkermania,Bifidobacterium,and Lactobacillus and butyrate-producing bacteria(Roseburia and Eubacterium)as well as decreasing the relative abundance of Desulfovibrio,while SCFAs content and its receptors Gpr43 and Gpr109 a expression were significantly increased(p<0.05).These results suggested that the expression of Crhr1 and Nr3c1 in the hippocampus can be indirectly altered by modulating the composition of the gut microbiota and the levels of functional metabolites(SCFAs and Trp)to change the levels of neurotransmitters in the brain and thus regulating mood.This may be one of the mechanisms by which XOS improves depressive behaviorFinally,transcriptomic techniques were used to further explore the mechanism of XOS intervention.The results showed that XOS intervention significantly modulated genes encoding signaling pathways such as NOD-like receptor,cytokine-cytokine interaction,axon guidance,axon regeneration,glutamatergic synapses,Gn RH,MAPK and c AMP signaling pathway.It was shown that the antidepressant effect of XOS is associated with stimulation of immunogenesis modulation of the nervous system,signaling molecule interactions and signal transduction.In conclusion,XOS has a good effect on the prevention and improvement of depressive behavior in mice,especially at low doses(0.23 g/kg/day),mainly through the regulation of intestinal flora and functional metabolite levels,which in turn stimulates immunogenesis as well as regulates the nervous system,signaling molecule interactions and signal transduction.