Sini decoction (SND) mitigates depressive-like behaviors through dual modulation of serotonergic biosynthesis and promotes intestinal stem cell regeneration

• SND alleviated depression by modulating gut microbiota and serotonin metabolism. • SND has trophic effects on intestinal organoids and enhances epithelium regeneration. • SND uniquely restored both gut microbial balance and intestinal epithelial homeostasis. • This study highlights SND’s systemic repair effects in chronic stress-related diseases. Depression is a common chronic mood disorder, and recent research has shown growing interest in herbal medicine for its treatment. Sini decoction (SND) has been used in treatment practice for hundreds of years. Though SND demonstrates therapeutic potential for depression, its molecular pathways and dual effects on neural signaling (e.g., 5-HT neurotransmission) and gut microbiota homeostasis remain unexplored. This study examines the unresolved mechanisms of SND's antidepressant effects, focusing specifically on its interactions with intestinal stem cell dynamics and the gut-brain axis. Depression was modeled using chronic mild stress. After SND treatment, behavioral changes were assessed using the tail suspension test, forced swimming test, sucrose preference test, and open field test. 5-HT levels in different brain regions were detected, and gut microbiota alterations were measured by 16S rRNA sequencing. The effect of SND on intestinal stem cells was then studied. SND alleviated depression-induced body weight loss and behavioral impairments while enhancing serotonin metabolism. Gut microbiota analysis revealed SND significantly increased the abundance of Adlercreutzia, Allobaculum, Blautia , and Parabacteroides , which are microbial genera with the potential to assist the body in coping with depressive stress. These microbial changes showed strong correlations with serotonin levels and behavioral parameters. Furthermore, SND stimulated intestinal stem cell proliferation and differentiation, exerting long-term effects on epithelial regeneration. Our findings indicate that SND exerts antidepressant effects potentially through modulating the gut-brain-microbiota axis, highlighting its dual role in microbial regulation and intestinal homeostasis.