An integrated analytical strategy combining UPLC-QTOF-MS-based metabolomics and 16S rRNA sequencing to explore the mechanism of Shenqi Jieyu decoction in coronary heart disease complicated by depression in ApoE-/- mice.

Abstract

Coronary heart disease combined with depression (dual-heart disorder) exhibits high morbidity and poor prognosis, lacking safe unified therapeutic agents. Shenqi Jieyu Decoction (SQJY) relieves depressive and cardiovascular symptoms in percutaneous coronary intervention (PCI) patients, yet its underlying multiple potential mechanisms remain unclear. In this study, an ApoE-/- mouse model of dual-heart disorder was induced via high-fat diet combined with chronic unpredictable mild stress (CUMS). Behavioral testing, aortic pathological staining, hippocampal neurochemistry, and ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS)-based untargeted metabolomics of serum and cecal contents were integrated with 16S rRNA sequencing, establishing an integrated multi-omics workflow to examine the potential modulatory effects of SQJY and to explore its possible mechanism. Behavioral and pathological assays indicated that SQJY alleviated atherosclerosis and depression-like phenotypes, elevated hippocampal 5-hydroxytryptamine (5-HT), dopamine (DA) and brain-derived neurotrophic factor (BDNF), and suppressed neuroinflammatory cytokines. 16S sequencing suggested SQJY remodeled dysregulated gut microbiota toward a more balanced profile. Metabolomics identified disturbed sphingolipid and glycerophospholipid metabolism as important metabolic signatures that H-SQJY group corrected more extensively in cecal content (68 of 265 metabolites) than in serum (8 of 103). Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2)-based prediction of microbial functions was integrated, and Spearman correlation analysis showed significant associations between predicted microbial functions, differential gut microbes and lipid metabolites. Collectively, SQJY showed concurrent potential cardioprotective and antidepressant effects, possibly through restoring gut microbial homeostasis and modulating lipid metabolic disorders. These correlative and predicted findings provide preliminary evidence for the potential application of SQJY in dual-heart disorder.

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