Modulation of the microbiota-lipid-brain axis by modified Chaihu-Longgu-Muli Decoction ameliorates chronic stress-induced depression.

BACKGROUND AND AIMS: Modified Chaihu-Longgu-Muli Decoction (mCLMD) has well-established clinical antidepressant efficacy, yet its precise systemic mechanisms of action remain incompletely characterized. Here, we employed an integrated multi-omics strategy to delineate the mechanisms by which mCLMD exerts antidepressant-like effects via modulation of the gut microbiota-lipid-brain axis.

EXPERIMENTAL PROCEDURES: Rats exposed to chronic unpredictable mild stress (CUMS) were administered graded doses of mCLMD. Depressive-like behaviors were assessed using the sucrose preference test, forced swim test, and open field test. To delineate the underlying mechanisms, we integrated network pharmacology analysis, 16S rRNA gene sequencing, serum metabolomics, and targeted validation of hippocampal signaling pathways.

RESULTS

mCLMD administration dose-dependently reversed CUMS-induced depressive-like behaviors in rats. Consistent with network pharmacology predictions, 16S rRNA sequencing revealed that mCLMD ameliorated CUMS-induced gut dysbiosis, characterized by reduced relative abundance of pro-inflammatory genera (Colidextribacter, Oscillibacter) and enrichment of beneficial taxa (Romboutsia, Lactobacillus). Metabolomic profiling demonstrated concomitant restoration of dysregulated lipid and neurosteroid profiles in serum. Correlation analysis identified that reduced abundance of stress-associated pathobionts was tightly linked to decreased levels of peripherally derived neurosteroids with neurotoxic potential (e.g., pregnenolone), while enrichment of beneficial commensals correlated with elevated levels of neuroprotective endocannabinoid precursors (including 1-stearoyl-2-arachidonoylglycerol). These peripheral immunometabolic alterations were accompanied by the transcriptional upregulation of the hippocampal cAMP-BDNF-TrkB signaling pathway and restoration of monoaminergic neurotransmission.

CONCLUSION

The antidepressant effects of mCLMD are strongly associated with systemic remodeling of the gut microbiota-lipid-brain axis. These therapeutic effects potentially stem from both the direct pharmacological activity of mCLMD's bioactive compounds and indirect modulation of the gut microbiota and host metabolism. Collectively, our findings provide robust preclinical evidence underpinning the clinical application of mCLMD in the management of major depressive disorder.