Qiliqiangxin Capsule ameliorates post-myocardial infarction heart failure: associations with gut microbiota remodeling, altered fecal short-chain fatty acid profiles, and myocardial HDAC3-associated histone acetylation and JNK/TGF-β-related signaling.

Abstract

Qiliqiangxin Capsule (QLQX) is a guideline-recommended adjunctive therapy for heart failure with reduced ejection fraction, but mechanisms underlying post-myocardial infarction heart failure (post-MI HF) remain incompletely defined, particularly gut-heart microbial metabolism. This study aimed to characterize the gut microbial and fecal short-chain fatty acid (SCFA) alterations associated with the cardioprotective effects of QLQX and to determine whether gut-associated factors contribute functionally to its therapeutic effects in post-MI HF. A rat model of post-MI HF was established by permanent ligation of the left anterior descending coronary artery. Cardiac function, ventricular remodeling, histopathological injury, and inflammatory indices were evaluated after QLQX treatment. An integrated analytical strategy comprising fecal 16S rRNA gene sequencing, targeted fecal SCFA quantification, untargeted fecal and myocardial metabolomics, myocardial transcriptomics, and targeted protein analyses was used to characterize gut and cardiac responses. A publicly available human ST-segment elevation myocardial infarction transcriptomic dataset was included for exploratory pathway-level comparison. Spearman correlation analysis with Benjamini-Hochberg false discovery rate correction was performed to examine associations among microbial taxa, SCFAs, inflammatory markers, and cardiac functional indices. Molecular docking and molecular dynamics simulations were used to assess the structural plausibility of selected candidate interactions, and surface plasmon resonance (SPR) was performed to experimentally evaluate the predicted interaction between isobutyrate and JNK1. Antibiotic treatment and fecal microbiota transplantation (FMT) were further performed to evaluate the functional contribution and transferability of gut-associated fecal factors. QLQX improved cardiac dysfunction, adverse ventricular remodeling, myocardial injury, and inflammatory responses in post-MI HF rats. Treatment reshaped the fecal microbial community and altered the fecal SCFA profile, including restoration of butyrate and isobutyrate. Selected SCFAs and bacterial taxa were associated with inflammatory markers and cardiac functional indices. Integrated omics and protein analyses further showed that these gut-associated alterations were accompanied by coordinated changes in myocardial cAMP, nuclear HDAC3 abundance, histone H3 acetylation, AMPK/mTOR signaling, and JNK/TGF-β related molecular indices. SPR analysis further demonstrated concentration-dependent binding of isobutyrate to JNK1, with an equilibrium dissociation constant (KD) of 5.89 × 10⁻⁵ M. Antibiotic treatment attenuated the therapeutic response to QLQX, whereas FMT from QLQX-treated donors partially transferred the protective phenotype, supporting a functional contribution of fecally transferable gut-associated factors. QLQX ameliorated post-MI HF in association with remodeling of the gut microbial ecosystem, alterations in fecal SCFA profiles, and coordinated myocardial metabolic, epigenetic, and stress-signaling responses. The antibiotic and FMT experiments suggest that gut-associated factors partly contribute to the cardioprotective effects of QLQX. Butyrate and isobutyrate emerged as prioritized candidate metabolites, with SPR providing direct binding evidence for the isobutyrate-JNK1 interaction, although their broader causal roles and myocardial exposure require further validation.

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