Metagenomics and Metabolomics Integrated to Explore the Protective Mechanisms of Mongolian Medicine Zadi-5 in Myocardial Ischemic Model Rats

ABSTRACT:

Myocardial ischemia(MI) is a pathological state of abnormal energy metabolism due to insufficient blood and oxygen supply to the coronary arteries. The 'gut-heart axis' theory plays an important role in myocardial ischemia occurrence, mechanism, prevention, and cure. Traditional Mongolian medicine posits that 'internal diseases originate from gastrointestinal dysfunction,' linking the intestine, as a key component of the digestive system, to the physiological and pathological changes in the heart. Furthermore, the traditional Mongolian clinical treatment of cardiovascular diseases includes guidelines for digestive system function, corresponding to the modern concept of the gut-heart axis. Accordingly, Zadi-5, a traditional Mongolian medicine, has been used for over 200 years to prevent and treat cardiovascular diseases. However, the mechanism by which gut microbiota and metabolism are regulated to protect an ischemic heart is unclear.

Aim: This study aimed to investigate the potential mechanism by which Zadi-5, through its interaction with gut microbiota and metabolic pathways, alleviates myocardial ischemic injury induced by a high-fat diet and isoproterenol (ISO). 

Methods: Sprague-Dawley rats were divided into control, model, Zadi-5 high-dose, and Zadi-5 low-dose groups. All groups, except for the control group, were subjected to a high-fat diet for 4 weeks. Afterward, all animals received subcutaneous injections of 4 mg/kg ISO daily for 3 days to induce a myocardial infarction (MI) rat model. The pharmacological effects of Zadi-5 against MI were assessed using electrocardiography (ECG), hematoxylin-eosin (HE) staining of the myocardial tissue, and serum levels of cardiac troponin T (cTn-T), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Furthermore, fecal metagenomics and serum untargeted metabolomics were assessed to investigate the protective mechanisms of Zadi-5 in MI. Finally, MetOrigin was used to analyze the correlation between key metabolic pathways and gut microbiota to elucidate the mechanism by which Zadi-5 protects against myocardial ischemia.

Results: Firstly, The MI rat model was successfully established by the ISO and Zadi-5 can significantly preserve the MI injury，according to ECG recording, index of TC, TG, LDL-C, cTn-T, LDH, CK-MB and histopathology results. Secondly, Zadi-5 regulates the gut microbiota diversity and abundance, as well as the glutamine and glutamate metabolism. The mechanism is related to the gut microbiota phylum of Actinobacteria, Firmicutes, Bacteroidetes, Proteobacteroidetes and class of Gammaproteobacteria, Betaproteobacteria, Bacteroidia, Actinomycetes, Clostridia, and Bacilli. Zadi-5 additionally regulates L-glutamic acid, L-glutamine, ornithine, and oxaceprol metabolisms.

Conclusion: Zadi-5 exerts cardioprotective effects in MI rats by improving the dysbiosis of gut microbiota and regulating the glutamate-glutamine metabolism pathway. This may represent just one of the complicated protective mechanisms of Zadi-5 against MI. The cardioprotective mechanisms of Zadi-5 at the molecular and cellular levels will be explored.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS13780 | MetaboLights | 2026-01-27

REPOSITORIES: MetaboLights