BACKGROUND: Gan-Mai-Da-Zao decoction (GMDZ), a traditional Chinese formulation used as both food and medicines, exhibits antidepressant effects. However, its underlying mechanisms, particularly those involving the gut-brain axis, remain unclear.
PURPOSE: To integrate gut microbiota profiling, metabolomics, and neuroinflammation to systematically elucidate GMDZ's antidepressant mechanisms.
STUDY DESIGN AND METHODS: Mice with depression-like behaviors were induced using a chronic unpredictable mild stress (CUMS) approach. Behavioral tests, multi-omics approaches (metabolomics, 16 s rRNA sequencing), and molecular biology techniques (histopathology, immunofluorescence, ELISA, qPCR, Western blot) were employed to investigate GMDZ's multi-target mechanisms.
RESULTS: We identified 108 bioactive components, with 58 detected in plasma and 43 in the cerebral cortex, confirming systemic exposure and cerebral penetration of key constituents. GMDZ significantly ameliorated depressive-like behaviors and attenuated associated neuronal and colonic pathological damage. Mechanistically, GMDZ exerted its antidepressant effects through three novel and interconnected pathways: (1) Modulating gut microbiota composition and altering fecal and plasma metabolite profiles; (2) Reducing peripheral and central pro-inflammatory cytokines levels and suppressing NLRP3 inflammasome pathway activation; and (3) Enhancing blood-brain barrier (BBB) integrity by up-regulating occludin and claudin-5.
CONCLUSION: GMDZ exerts antidepressant effects via a novel multi-target regulatory mechanism involving the microbiota-metabolite-inflammation axis. This study significantly advances our understanding of GMDZ's gut-brain axis mechanism and offers a new paradigm for mechanistic investigations of traditional Chinese medicine.
