摘要Objectives:To determine the pharmacological impact of hesperidin,the main component of Citri Reticulatae Pericarpium,on depressive behavior and elucidate the mechanism by which hesperidin treats depression,focusing on the gut-brain axis.Methods:Fifty-four Sprague Dawley male rats were randomly allocated to 6 groups using a random number table,including control,model,hesperidin,probiotics,fluoxetine,and Citri Reticulatae Pericarpium groups.Except for the control group,rats in the remaining 5 groups were challenged with chronic unpredictable mild stress(CUMS)for 21 days and housed in single cages.The sucrose preference test(SPT),immobility time in the forced swim test(FST),and number in the open field test(OFT)were performed to measure the behavioral changes in the rats.Enzyme-linked immunosorbent assay was used to determine the levels of 5-hydroxytryptamine(5-HT)and brain-derived neurotrophic factor(BDNF)in brain tissue,and the histopathology was performed to evaluate the changes of colon tissue,together with sequencing of the V3-V4 regions of 16S rRNA gene on feces to explore the changes of intestinal flora in the rats.Results:Compared to the control group,the rats in the model group showed notable reductions in body weight,SPF,and number in OFT(P＜0.01).Hesperidin was found to ameliorate depression induced by CUMS,as seen by improvements in body weight,SPT,immobility time in FST,and number in OFT(P＜0.05 or P＜0.01).Regarding neurotransmitters,it was found that at a dose of 50 mg/kg hesperidin treatment upregulated the levels of 5-HT and BDNF in depressed rats(P＜0.05).Compared to the control group,the colon tissue of the model group exhibited greater inflammatory cell infiltration,with markedly reduced numbers of goblet cells and crypts and were significantly improved following treatment with hesperidin.Simultaneously,the administration of hesperidin demonstrated a positive impact on the gut microbiome of rats treated with CUMS,such as Shannon index increased and Simpson index decreased(P＜0.01),while the abundance of Pseudomonadota and Bacteroidota increased in the hesperidin-treated group(P＜0.05).Conclusion:The mechanism responsible for the beneficial effects of hesperidin on depressive behavior in rats may be related to inhibition of the expressions of BDNF and 5-HT and preservation of the gut microbiota.