Gut microbiota dysbiosis exacerbates heart failure by the LPS-TLR4/NF-κB signalling axis: mechanistic insights and therapeutic potential of TLR4 inhibition

作者：Chunlei Zhang, Xiaodong Teng, Qiuhang Cao, Yanyan Deng, Mo Yang, Lei Wang, Daorong Rui, Ling Xiu, Cao Wei, Yue Chen, Dasheng Lu, Hongxiang Zhang · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-06821-8 · 被引用次数：20 · 研究领域：Gut microbiota and health、Cardiac Fibrosis and Remodeling、Clostridium difficile and Clostridium perfringens research

OBJECTIVE: This study aimed to investigate the associations between gut microbiota dysbiosis and alterations in cardiac function and to elucidate the underlying molecular mechanisms involved. METHODS: Eighteen rats were divided into a control group (n = 6), a heart failure (HF) group (n = 6), and a TAK-242 intervention group (n = 6). Cardiac function was assessed using small-animal echocardiography. Serum levels of brain natriuretic peptide (BNP) and inflammatory cytokines were measured by ELISA. Western blotting was used to detect phosphorylated p65 (P-p65) protein expression in myocardial tissue, and 16 S rRNA sequencing was performed to analyse the composition of the faecal gut microbiota. RESULTS: Compared with the control group, the heart failure group presented significant gut microbiota dysbiosis, characterized by increased relative abundance of Bacteroidetes and Spirochaetes and decreased relative abundance of Actinobacteria and Proteobacteria, along with reduced species diversity. The serum levels of lipopolysaccharide (LPS), IL-1β, IL-17, IL-6, and TNF-α were significantly elevated (P < 0.05). Myocardial tissue pathology revealed disordered myocardial fibre arrangement and significant lymphocyte infiltration. TAK-242 intervention normalized the gut microbiota composition; reduced LPS and inflammatory cytokine levels; improved the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS); and decreased the left ventricular end-systol...