Meranzin Hydrate ameliorates “atherosclerotic depression” in ApoE−/− mice by restoring gut microbiota—driven microbial-inflammatory circuitry

Background

Depression and atherosclerosis frequently co-occur, with disrupted gut microbiota–driven inflammatory circuitry emerging as a shared pathogenic mechanism. To address this, we operationally define “atherosclerotic depression” as depression comorbidity with atherosclerosis. Despite its clinical significance, integrated therapeutic strategies remain lacking.

Methods

An ApoE^−/− mouse model combining high-fat diet feeding and acute restraint stress was established to mimic atherosclerosis-associated depression. Animals received Meranzin Hydrate (MH) treatment, followed by comprehensive assessments. Metabolic and vascular endpoints included body weight, serum lipid profiles, and aortic plaque burden (Oil Red O staining). Depressive-like behaviors were evaluated through standardized behavioral tests. BOLD-fMRI with regional homogeneity (ReHo) analysis measured brain functional activity. Gut microbiota profiling was performed by 16S rRNA sequencing to assess α-/β-diversity, Firmicutes/Bacteroidetes ratio, and keystone taxa. Inflammatory and neurotrophic markers were examined via ELISA (5-hydroxytryptamine, brain-derived neurotrophic factor, interleukin-6, endothelial nitric oxide synthase, and ghrelin), while protein and mRNA levels of vascular cell adhesion molecule-1, interleukin-1β, tumor necrosis factor-α, and ghrelin were analyzed by Western blot and RT-PCR.

Results

MH significantly reduced aortic plaque formation, improved lipid profiles, and alleviated depressive-like behaviors. MH restored gut microbiota homeostasis by enhancing α-diversity, normalizing the Firmicutes/Bacteroidetes ratio, and enriching beneficial taxa such as Akkermansia and Allobaculum. These microbiota changes paralleled the reversal of stress- and diet-induced BOLD-fMRI alterations in emotion-regulation regions (hippocampus and prefrontal cortex). Inflammatory circuitry was rebalanced, as evidenced by reduced IL-6, TNF-α, IL-1β, and VCAM-1, alongside restored hippocampal and cardiac 5-HT, BDNF, and ghrelin levels.

Conclusion

MH demonstrates therapeutic potential in alleviating atherosclerosis co-depression by modulating acute mental stress-induced vascular inflammation, neurotrophic factors, brain function, and gut microbiota.