The effects of a semen cuscutae flavonoids-based antidepressant treatment on microbiome and metabolome in mice

Background: Depression is a prevalent psychiatric disorder and one of theleading causes of disability worldwide. Previous studies have shown that SemenCuscutae flavonoids (SCFs) exert antidepressant e#ects by modulating themicrobiota-neuroinflammation axis and ameliorating hippocampal metabolicdisturbances. However, the impact of SCFs on gut microbiota and relatedmetabolomics remains largely undefined. Given that the gut microbiota has beenproven to play a significant role in the etiology of depression and serves as apromising target for its treatment in humans, this study aims to elucidate theantidepressant e#ects of SCFs and to investigate how they modulate microbialand metabolic pathways to alleviate depressive symptoms.Materials and methods: Chronic unpredictable mild stress (CUMS)-inducedmice were used as a depression model. The normal mice and CUMS-inducedmice were treated with either vehicle or with SCFs. A range of standardizedbehavioral assays and physiological indicators were employed to evaluate theantidepressant e#ects of SCFs. Upon the confirmation of the e#ectiveness of theSCFs treatment, the composition, richness, and diversity of the fecal microbiotawere assessed using 16S rRNA gene sequencing. Additionally, fecal metabolicprofiling was analyzed using UHPLC-MS/MS-based metabolomics. Multivariatedata analysis was subsequently performed to identify di#erential metabolites andcharacterize alterations in fecal metabolites. Furthermore, a correlation analysisbetween di#erential metabolites and key microbiota was conducted.Results: SCFs significantly ameliorated depressive behaviors and thedysregulated diversity of fecal microbiota induced by CUMS. SCFsenhanced the gut microbiota structure in the CUMS group by increasingthe Firmicutes/Bacteroidota ratio, significantly elevating the abundance ofFirmicutes, Lactobacillus, Limosilactobacillus, and Actinobacteria while reducingthe abundance of Bacteroidota and Bacteroides in CUMS-treated mice. Fecalmetabolomics analyses revealed that SCFs could modulate metabolic pathways,including aldosterone synthesis and secretion, arachidonic acid metabolism,and primary bile acid biosynthesis.