LAUSR

Obesity can lead to depression via the microbiota‐gut‐brain axis. Icariside II (ICS II), a flavonoid compound derived from the traditional Chinese medicine Herbal Epimedium, exerts excellent neuroprotective effects. However, the pharmacological effects and underlying mechanisms of ICS II in obesity‐induced depression remain unexplored. The present study aims to investigate whether ICS II can mitigate depression induced by a high‐fat diet (HFD) in mice through modulating the microbiota‐gut‐brain axis. Metabolic parameters were reflected through changes in body weight and blood lipids, while depressive phenotypes were evaluated through behavioral tests and neurotransmitter analysis. The microbiota composition was analyzed by 16S ribosomal RNA gene sequencing, and short chain fatty acids (SCFAs) were detected by liquid chromatography–tandem mass spectrometry. The gut barrier and brain blood barrier (BBB) functions were observed by pathological methods. Fecal microbiota transplantation was used to demonstrate the causality of microbiota‐mediated effects. The results showed that ICS II alleviated obesity status and depressive‐like behaviors. ICS II reshaped gut microbiota and increased SCFAs. Meanwhile, ICS II relieved gut barrier impairment and systemic inflammation. In the brain, ICS II alleviated neuroinflammation and BBB injury. Intriguingly, fecal microbiota from ICS II‐treated HFD mice improved depressive‐like behaviors, intestinal barrier dysfunction, and BBB damage compared with those receiving microbiota from HFD mice. Our findings reveal for the first time that ICS II improves the obesity‐related metabolic dysregulation and alleviates HFD‐induced depression via the microbiota‐gut‐brain axis. Overall, this study indicates that ICS II is a potential candidate compound for treating obesity‐related mental diseases.