Si-Ni-San alleviates depression-like behavior via regulating the gut microbiota-tryptophan metabolism-AhR/NF-κB...

Si-Ni-San (SNS), a classic herbal formula from the Treatise on Cold Damage Diseases, is used to treat depression by relieving "liver qi stagnation". However, the underlying mechanism remains unclear.

This study aimed to investigate the mechanism by which SNS alleviates depression-like behavior, specifically focusing on its role in modulating gut microbiota and host tryptophan metabolism.

A depression model was induced in mice by chronic unpredictable mild stress (CUMS). The antidepressant effects of SNS were evaluated through behavioral tests. Integrated untargeted and targeted metabolomics, alongside 16S rRNA sequencing, were utilized to identify potential gut-brain signaling molecules. Molecular interactions between the gut-brain signaling molecule and its target were validated by surface plasmon resonance (SPR) and molecular docking. Key protein expression was measured via Western blot and ELISA. Finally, the function of gut microbiome-derived indole-3-acetic acid (IAA) as a key gut-brain signaling molecule was confirmed by oral supplementation experiments.

SNS significantly alleviated CUMS-induced depression-like behaviors. Multi-omics analysis revealed that SNS reversed tryptophan metabolic disorders and elevated gut microbiome-derived IAA levels in both the colon and prefrontal cortex, which was attributed to the enrichment of Lactobacillus. Further investigations confirmed that IAA directly binds to and activates the aryl hydrocarbon receptor (AhR), thereby inhibiting NF-κB pathway-mediated neuroinflammation. Moreover, oral supplementation with IAA replicated the antidepressant effects of SNS and suppressed CUMS-induced neuroinflammation via the AhR/NF-κB signaling pathway.

SNS alleviates depression-like behavior by modulating gut microbiota-mediated tryptophan metabolism to enhance IAA production, thereby activating central AhR signaling and suppressing NF-κB-mediated neuroinflammation.