Remodeling the gut-heart axis: Danggui Sini granule mitigates vasospastic coronary heart disease via microbiota-metabolite interactions.

Coronary heart disease (CHD) remains a major global health burden, and residual cardiovascular risk persists despite guideline-based therapies. Danggui Sini Granule (DSG), a granule formulation derived from the classical Danggui Sini Decoction, has been widely used clinically to improve cardiovascular circulation and alleviate ischemic symptoms; however, its gut-heart-axis-related mechanisms remain insufficiently defined. A rat model of vasospastic CHD was established using a high-fat diet combined with acute environmental stress and pituitrin injection, followed by treatment with DSG at different doses. Pharmacodynamic effects were evaluated by electrocardiography, histopathology, serum lipids, and inflammatory markers. Gut microbial alterations were profiled using 16S rRNA sequencing. Serum metabolic changes were characterized by untargeted metabolomics. Network pharmacology and joint pathway enrichment were further used to cross-validate target prediction with metabolite-level readouts and to prioritize gut-microbiota-metabolism-phenotype links. DSG attenuated ST-segment elevation, reduced myocardial histopathological injury, mitigated dyslipidemia, and lowered systemic inflammatory mediators, including TNF-α and IL-6. 16S rRNA analysis showed bidirectional microbiota modulation, with reduced opportunistic/pathogenic genera (e.g., Escherichia, Staphylococcus) and enrichment of potentially beneficial taxa (e.g., Lactobacillus, Clostridium). Metabolomics revealed partial mitigation of CHD-related disturbances, mainly in linoleic acid and arachidonic acid pathways, with restoration of levels of protective lipid mediators including 12,13-DHOME, 3-HIA, and PGE1. Joint pathway analysis integrating reversed metabolites with predicted targets consistently prioritized Lipid and atherosclerosis, PPAR-related metabolic regulation, PI3K-Akt/eNOS-associated vascular protection, and inflammation-related signaling (JAK-STAT and TNF/NF-κB). Furthermore, molecular docking suggested favorable binding affinities between the key components/metabolites (e.g., Quercetin, 12,13-DHOME, PGE1) and core targets within these pathways (including PIK3CA, NOS3, PPARG, TNF, and RELA). DSG demonstrated significant cardioprotective effects in vasospastic CHD rats, which were associated with coordinated gut microbiota remodeling, lipid-metabolic reprogramming, and modulation of inflammation-related pathways. These findings, further suggested by in silico molecular docking, provide a multidimensional framework for understanding the cardioprotective potential of DSG from a gut-heart-axis perspective. Given the associative nature of the current multi-omics data, key causal links should be validated in future targeted intervention studies.