Gan-Mai-Da-Zao decoction ameliorates depressive-like behaviors in CUMS mice via the microbiota-metabolism-inflammation axis

Jun 28, 2025Phytomedicine : international journal of phytotherapy and phytopharmacology

Gan-Mai-Da-Zao herbal mix reduces depression-like behaviors in stressed mice through gut bacteria, metabolism, and inflammation

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Abstract

A total of 108 bioactive components were identified in the study of Gan-Mai-Da-Zao decoction's effects on depression.

GMDZ significantly improved depressive-like behaviors in mice subjected to chronic unpredictable mild stress.
The formulation altered gut microbiota composition and modified levels of metabolites in both fecal and plasma samples.
GMDZ reduced levels of pro-inflammatory cytokines in both peripheral and central systems.
It suppressed activation of the NLRP3 inflammasome pathway, which is associated with inflammation.
GMDZ enhanced the integrity of the blood-brain barrier by increasing levels of occludin and claudin-5.

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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.

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Gan-Mai-Da-Zao decoction ameliorates depressive-like behaviors in CUMS mice via the microbiota-metabolism-inflammation axis

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