Lactobacillus ameliorates myocardial ischemia-reperfusion injury by regulating butyrate production

Background Myocardial ischemia/reperfusion (I/R) injury impairs the efficacy of reperfusion therapy for acute myocardial infarction[1]. Evidence has confirmed that Lactobacillus can ameliorate, myocardial I/R injury by inhibiting apoptosis, inflammation, oxidative stress, and ferroptosis[2]. However, the roles of microbiota-metabolite interactions in myocardial I/R injury have not been explored. Purpose This study aimed to elucidate the effects of Lactobacillus on the gut microbiota composition and short-chain fatty acid (SCFA) production in I/R rats, and to investigate the therapeutic potential of short-chain fatty acids in I/R-induced cardiac damage. Methods Following Lactobacillus gavage for 4 weeks, I/R was induced in Sprague-Dawley rats. The diversity, composition and abundance of gut microbiota were detected by 16S rRNA sequencing. Targeted metabolomics of short-chain fatty acids (SCFAs) in serum was determined by liquid chromatographytandem mass spectrometry (LC-MS/MS). Furthermore, sodium butyrate was administered to rats for 21 days before myocardial I/R injury was induced. The protective efficacy of sodium butyrate against I/R injury was assessed by Evans-TTC staining, echocardiographic detection, HE staining and immunofluorescent staining. Results Lactobacillus significantly reshaped the composition of gut microbiota according to the PCoA of β-diversity, and remodeled gut microbiota at both phylum and genus levels. Linear discriminant analysis Effect Size (LEfSe) analysis identified Desulfovibrionales enrichment as a hallmark of I/R-induced dysbiosis, which was reversed by Lactobacillus. Through the detection of targeted metabolomics, butyric acid and other SCFAs, were found to be upregulated by Lactobacillus gavage, compared with the IR group. Similarly, the abundance of several butyrate-producing bacteria was upregulated under the influence of Lactobacillus. Notably, butyrate supplementation significantly improved cardiac function, as evidenced by increased left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), along with decreased left ventricular end-diastolic diameter (LVIDs) and end-systolic volume (LVESV), and attenuated myocardial infarct size compared with the I/R group. HE staining also demonstrated that butyrate treatment markedly attenuated myocardial structural damage, preserved myofibrillar arrangement, and reduced inflammatory infiltration, while immunofluorescence staining confirmed a concomitant reduction in myocardial macrophage infiltration. Conclusions Administration of Lactobacillus altered the composition, abundance of gut microbiota and the production of butyrate in rats with myocardial I/R injury. The Lactobacillus-butyrate axis is associated with the pathogenesis of myocardial I/R injury, and exogenous butyrate exerts cardioprotective effects by improving cardiac function and reducing infarct size, offering a novel microbiota-targeted therapy for I/R injury.