Microbiota-derived acetate suppresses sympathetic outflow via olfactory receptor 59 in the rostral ventrolateral medulla

Dysbiosis of gut microbiota is closely associated with the development of hypertension, yet the underlying mechanism remains unclear. In this study, we aimed to elucidate the molecular mechanisms through which microbiota-derived acetate regulates sympathetic activity and arterial blood pressure (ABP). Bulk RNA sequencing was used to determine the expression of short-chain fatty acids receptors in the rostral ventrolateral medulla (RVLM). We examined the influence of olfactory receptor 59 (Olr59) on renal sympathetic nerve activity (RSNA) and ABP in anesthetized rats. The effect of Olr59 on the excitability of RVLM neurons was assessed through calcium imaging. Moreover, the 24-hour ambulatory blood pressure of conscious rats was recorded using radiotelemetry. The RNA sequencing results indicated that Olr59 was the most highly expressed short-chain fatty acids receptor in the rat RVLM and was upregulated in spontaneously hypertensive rats (SHR). Injection of the Olr59 agonist acetate or β-ionone into the RVLM reduced ABP and RSNA. However, administration of Olr59 antagonist or the knockdown of Olr59 in RVLM neurons did not significantly alter ABP, but it counteracted the hypotensive effect of acetate within the RVLM. Application of acetate or β-ionone to isolated brain slices mainly inhibited calcium signal in spinally-projecting RVLM neurons. Furthermore, overexpression of Olr59 in RVLM neurons via adeno-associated virus reduced ABP in SHR. Microbiota-derived acetate inhibits sympathetic activity and decreases blood pressure via Olr59 in the RVLM. Thus, Olr59 represents a promising new target for the treatment of hypertension.