Gut microbiota dysbiosis exacerbates heart failure by the LPS-TLR4/NF-κB signalling axis: mechanistic insights and therapeutic potential of TLR4 inhibition
Chunlei Zhang, Xiaodong Teng, Qiuhang Cao, Yanyan Deng, Mo Yang, Lei Wang, Daorong Rui, Ling Xiu, Cao Wei, Yue Chen, Dasheng Lu, Hongxiang Zhang
Abstract
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-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), and BNP levels. Myocardial tissue pathology also improved. Western blot analysis revealed increased TLR4 、P-IKBα/ IKBα and P-p65/p65 expressions in the heart failure group, which were significantly inhibited by TAK-242 (P < 0.05). CONCLUSION: Gut microbiota dysbiosis exacerbates heart failure by activating myocardial inflammation through the LPS-TLR4/NF-κB signalling pathway. By modulating this pathway, TAK-242 improves cardiac function, suggesting its potential as a therapeutic target for heart failure. CLINICAL TRIAL NUMBER: Not applicable.