Targeting gut microbiotasu-derived butyrate for Ferroptosis inhibition in Sepsis-induced myocardial dysfunction

Sepsis-induced myocardial dysfunction (SIMD) is a critical complication of sepsis, and ferroptosis has been identified as a key contributor to its pathogenesis. Emerging evidence suggests that sepsis profoundly disrupts the gut microbiota composition, leading to dysbiosis. Butyrate, a short-chain fatty acid produced by gut microbiota, has been implicated in ferroptosis regulation; however, its role in SIMD remains controversial. This study aims to elucidate the protective effects of gut microbiota-derived butyrate against SIMD through ferroptosis modulation.

This study assessed cardiac function using echocardiography and quantified myocardial injury biomarkers via ELISA. Myocardial iron deposition was evaluated using Prussian blue staining. The gut microbiota composition was analyzed using 16S rRNA gene sequencing. Ferroptosis-related protein expression in SIMD heart tissues and H9C2 cardiomyocytes was examined via western blotting to determine the regulatory role of butyrate.

Sepsis-induced gut microbiota dysbiosis was characterized by a significant reduction in butyrate-producing bacteria. Echocardiographic assessments (CO, EF), myocardial injury markers (BNP, cTnI), histopathological analysis (H&E staining), and cardiomyocyte ultrastructure (TEM) demonstrated that butyrate administration significantly alleviated myocardial injury in SIMD. Mechanistically, butyrate mitigated oxidative stress by increasing GSH levels and reducing MDA levels. Furthermore, butyrate treatment reversed the sepsis-induced downregulation of GPX4 and suppressed the upregulation of ACSL4 and PTGS2, thereby inhibiting ferroptosis.

These findings highlight the protective role of butyrate in SIMD, with ferroptosis inhibition serving as a key cardioprotective mechanism. Targeting gut microbiota-derived butyrate may represent a promising therapeutic strategy for sepsis-induced myocardial injury.