Objective Based on the theory of “heart-small intestine relationship” and the “gut-heart axis” hypothesis, this study applies Mendelian randomization (MR) and bioinformatics approaches to investigate gut microbiota with genetic causal effects on myocardial infarction (MI), explore underlying mechanisms, and predict potential interventional traditional Chinese medicines. Methods Genome-wide association study (GWAS) and gene expression data for gut microbiota and MI were obtained from the MiBioGen, IEU GWAS and GEO databases. MR analysis was primarily performed using the inverse variance weighted (IVW) method. Potential mechanisms were explored through gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses. Core genes were screened via machine learning algorithms. Potential traditional Chinese medicines were predicted by integrating the Coremine database, and their properties (four qi), flavors (five tastes), meridian tropism, and functions were statistically analyzed. Results MR analysis revealed six gut microbiota taxa with genetically causal associations with MI: Butyricicoccus (a protective factor, OR < 1, P < 0.05), Lachnoclostridium, Ruminococcaceae UCG014, Odoribacter, Oxalobacter, and Sellimonas (risk factors, OR > 1, P < 0.05).The core genes were mainly enriched in signaling pathways including the ephrin receptor signaling pathway, calcium signaling pathway, and mitogen activated protein kinases (MAPK) signaling pathway. A total of 596 potential traditional Chinese medicines were predicted. Their properties (four qi) were predominantly warm, followed by cold and neutral; their flavors (five tastes) were primarily sweet, with bitter and pungent also being notable. The main therapeutic functions identified were clearing heat and detoxifying. Representative medicines included Renshen (Ginseng Radix et Rhizoma), Sanqi (Notoginseng Radix et Rhizoma), and Huanglian (Coptidis Rhizoma). Related classical prescriptions encompassed Xiaochaihu Decoction (小柴胡汤) and Taohong Siwu Decoction (桃红四物汤). Conclusion This study reveals the genetic causal relationship and molecular mechanisms through which gut microbiota mediates the occurrence of MI. It enriches the modern biological connotation of the “heart-small intestine relationship” theory. The predicted traditional Chinese medicines provide new strategies for the traditional Chinese medicine-based prevention and treatment of MI and offer a reference for further investigation into the “gut-heart axis”.

myocardial infarction  /  gut microbiota  /  heart-small intestine relationship  /  gut-heart axis  /  Mendelian randomization  /  Ginseng Radix et Rhizoma  /  Notoginseng Radix et Rhizoma  /  Coptidis Rhizoma  /  Xiaochaihu Decoction  /  Taohong Siwu Decoction