High-fat diet-induced obesity-related hypertension via altered gut microbiota-mediated histone butyrylation.

Hypertension is a chronic cardiovascular disease that significantly impacts human quality of life. Gut microbiota and its metabolites have been reported to be involved in lipid metabolism and blood pressure regulation, but the specific alterations and pathogenic mechanisms of gut microbiota in obesity-related hypertension (OrHTN) remain unclear. In this study, we observed a significant proliferation of Desulfobacterota and Proteobacteria, while a decrease in the abundance of several butyrate-producing bacterial genera, accompanied by decreased fecal and plasma butyrate levels in high-fat diet (HFD)-induced OrHTN rats. Histone 3 lysine 9 butyrylation (H3K9bu) modification in the kidney of OrHTN rats was reduced and downregulated the expression of the hypertension-related gene MAS1. Subsequent transplantation of cecal contents from OrHTN rats on HFD into recipient rats on a normal chow diet resulted in hypertension but without obesity. Furthermore, in vitro experiments suggested that sodium butyrate increased H3K9bu modification and the expression of MAS1 in a concentration-dependent manner. In conclusion, our findings suggest that gut microbiota may contribute to the development of OrHTN by altering the expression of hypertension-related genes through butyrate-mediated histone butyrylation. This work may provide new insights into the prevention and treatment of hypertension by targeting the regulation of gut microbiota and metabolites.