Abstract

Objective: Wulanwendusu-11 (WLWDS-11) is a commonly used Mongolian medicine for treating cardiovascular diseases. However, its regulating effect on intestinal flora-host metabolism in relieving chronic myocardial ischemia-reperfusion injury (MIRI) is still unclear. Therefore, this study aims to systematically explore the cardioprotective mechanism of WLWDS-11 from the perspective of metabolic interaction between intestinal microbiota and host.Methods: C57BL/6J mice were randomized into six experimental groups: MIRI model, sham surgery, and treatment groups for compound Danshen dripping pills (CDDP) plus three dosages of WLWDS-11 (denoted WLWDS-11-L, WLWDS-11-M, and WLWDS-11-H). General physiological indicators of mice in each group were observed, body weight, myocardial structure and pathological features were assessed by electrocardiogram, plasma cardiac enzyme levels. The cardiac function of mice was obtained by echocardiography. Immunohistochemical staining was used to detect the pathological changes in the heart. Immunofluorescence assay was used to detect the degree of apoptosis. Metabolomics and metagenomics were used to analyze treatment effects on intestinal microbiota and metabolites. Integrated analysis of the enriched oxidative phosphorylation and necrosis and apoptosis pathways. qRT-PCR and western blot were used to detect the expression of COX4I1, NDUFB8, SDHA, TFAM, RIPK1, RIPK3, MLKL and TNF-α.Results: WLWDS-11 (especially in high dose) can significantly improve the cardiac function, reduce the area of myocardial infarction and weaken apoptosis and fibrosis in MIRI mice. Metabolomic profiling revealed extensive metabolic alterations, pathway analysis implicated arginine/proline and unsaturated fatty acid metabolism, and hierarchical clustering identified specific correlations between differential flora (e.g., Kosakonia, Helicobacter spp.) and key metabolites. Integrated multi-omics analysis demonstrated that MIRI induces gut microbiota dysbiosis and