Abstract 11083: Post-Infarction Cardiac Protection by Gut Butyrate-Producers

Abstract

Background The gut microbiota and their metabolites have been shown to contribute to the development of coronary artery diseases. However, little is known about their roles in post-injury cardiac repair. Here, we investigated the gut microbiota and plasma metabolomes distinct in patients with ST-elevation myocardial infarction (STEMI), and explored their roles on adaptive responses, using germ-free (GF) mice and nonhuman primate models. Methods We recruited 70 controls and 77 coronary angiogram-confirmed STEMI patients, and collected their stool and plasma. The stool and plasma of STEMI patients were collected immediately following percutaneous coronary intervention (PCI, STEMIT1) and again at 28 days after PCI (STEMIT2). We used 16S V3-V4 rRNA NGS and shotgun metagenomics to map the gut microbiota and both NMR and LC-MS metabolomics to profile the plasma metabolites. To determine the role of the gut microbiota and their metabolites on post-injury cardiac repair, we inoculated identified bacteria in GF mice and treated specific pathogen free mice with candidate metabolites. Moreover, we validated the microbiome and metabolomics findings in a nonhuman primate coronary ischemia-reperfusion (IR) injury model. Results The 16S V3-V4 rRNA NGS and shotgun metagenomic analysis revealed an enrichment of butyrate-producing bacteria in STEMIT1, as compared to STEMIT2 or to control cases. Fecal microbiome transplantation of STEMI samples in GF mice deteriorated host post-injury cardiac function, showing reduced left ventricle ejection fraction and cardiac mechanics. Moreover, plasma ketogenesis increased in the STEMI patients using NMR and LC-MS metabolomics. The protective effect of butyrate was more profound with intact commensal gut flora. Furthermore, inoculation of butyrate-producers in GF mice elevated plasma ketone body and better preserved post-injury cardiac function. Agreed with the clinical finding, we observed injury-induced elevation of gut butyrate-producers and plasma ketone bodies in the nonhuman primate IR model. Conclusion This study demonstrates the pivotal role of gut butyrate-producers and the derived ketogenesis in post-injury cardiac repair, which may lead to new prevention strategies and treatment for heart failure.