Gut microbiota-derived butyrate prevents aortic dissection via GPR41.

Abstract

Aortic dissection (AD) is a life-threatening condition with high morbidity. Its underlying pathogenesis remains poorly understood, yielding limited therapeutic options. In this study, we investigated the role of gut microbiota and its metabolite, butyrate, in AD development. Experimental AD was established in 3-week-old mice by administering of β-aminopropionitrile monofumarate (BAPN, 1 g·kg^-1·d^-1) in drinking water for 4 weeks. Microbiota composition analysis was conducted on fecal samples from of the mice. AD mice exhibited significant alterations in gut microbiota composition in particular a decrease in butyrate-producing bacteria, accompanied by markedly reduced serum and fecal butyrate levels. Supplementation with exogenous butyrate (200 mg·kg^-1·d^-1, i.g., for 4 weeks) significantly attenuated the progression of AD by enhancing the expression of vascular smooth muscle cell (SMC) contractile markers. Moreover, butyrate alleviated AD-associated SMC phenotypic switching by suppressing NADPH oxidase 4 expression, thereby reducing reactive oxygen species production. Notably, the protective effects of butyrate were abolished in G-protein-coupled receptor 41 (GPR41) knockout mice, but not in GPR109A knockout mice, highlighting the critical role of GPR41 in mediating its therapeutic effects. These results provide new insights into the pathogenesis of AD and suggest that targeting gut microbiota and its metabolites, such as butyrate, may offer a promising strategy.