Qingyi Ren ¹ Chenxi He ¹ Yuhong Sun ¹ Xiaowei Gao ¹ Yan Zhou ¹ Tao Qin ¹ Zhuo Zhang ¹ Xiaodong Wang ² Jun Wang ¹ Siping Wei ^1* Fang Wang ^1*

• ¹ Southwest Medical University, Luzhou, China
• ² Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China

In recent years, a growing body of research on antidepressants has focused on the microbiota-gut-brain axis, which plays a key role in the regulation of depression.Previous studies have suggested that asiaticoside possesses neuroprotective and antidepressive properties; however, the mechanism of its antidepressant action is not fully understood. Therefore, this study aimed to explore whether asiaticoside exerts antidepressant effects through the microbiota-gut-brain axis in a chronic unpredictable mild stress (CUMS) mouse model. Behavioral experiments were conducted to detect depression-like behavior in mice through sucrose preference, forced swimming, and open field tests. Additionally, gut microbial composition and short-chain fatty acid (SCFA) levels in mouse feces were analyzed using 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS). Hippocampal brain-derived neurotrophic factor (BDNF) and 5-hydroxytryptamine receptor 1A (5-HT1A) expression in mice was assessed by western blotting. Changes in serum levels of inflammatory factors, neurotransmitters, and hormones were measured in mice using ELISA. The results revealed that oral administration of asiaticoside significantly improved depression-like behavior in CUMS mice. It partially restored the gut microbial community structure in CUMS mice, altered SCFA metabolism, regulated the hypothalamic-pituitary-adrenal axis (HPA axis) and inflammatory factor levels, upregulated hippocampal BDNF and 5-HT1A receptor protein expression, and increased serum serotonin (5-hydroxytryptamine, 5-HT) concentration. These findings reveal that asiaticoside exerts antidepressant effects via the microbiota-gut-brain axis.