Butyric acid, a gut bacteria metabolite, lowers arterial blood pressure via colon-vagus nerve signaling and GPR41/43 receptors

Abstract

Butyric acid (BA) is a short-chain fatty acid (SCFA) produced by gut bacteria in the colon. We hypothesized that colon-derived BA may affect hemodynamics. Arterial blood pressure (BP) and heart rate (HR) were recorded in anesthetized, male, 14-week-old Wistar rats. A vehicle, BA, or 3-hydroxybutyrate, an antagonist of SCFA receptors GPR41/43 (ANT) were administered intravenously (IV) or into the colon (IC). Reactivity of mesenteric (MA) and gracilis muscle (GMA) arteries was tested ex vivo. The concentration of BA in stools, urine, portal, and systemic blood was measured with liquid chromatography coupled with mass spectrometry. BA administered IV decreased BP with no significant effect on HR. The ANT reduced, whereas L-NAME, a nitric oxide synthase inhibitor, did not affect the hypotensive effect of BA. In comparison to BA administered intravenously, BA administered into the colon produced a significantly longer decrease in BP and a decrease in HR, which was associated with a 2-3-fold increase in BA colon content. Subphrenic vagotomy and IC pretreatment with the ANT significantly reduced the hypotensive effect. Ex vivo, BA dilated MA and GMA. In conclusion, an increase in the concentration of BA in the colon produces a significant hypotensive effect which depends on the afferent colonic vagus nerve signaling and GPR41/43 receptors. BA seems to be one of mediators between gut microbiota and the circulatory system.

Keywords: Bacterial metabolites; Blood pressure; Butyric acid; SCFA.

Fig. 1

a Changes in mean arterial blood pressure (ΔMABP, mmHg) and b heart rate (ΔHR, beats/min) in Wistar rats after the intravenous administration (IV) of either a vehicle (0.9% NaCl) or butyric acid (BA) at a dose of 0.14, 1.4, 2.8, and 5.6 mmol/kg; *p < 0.05 vs baseline, ^#p < 0.05: 1.4, 2.8, and 5.6 mmol/kg BA series vs the vehicle, ^$p < 0.05: 0.14 mmol/kg BA series vs 2.8 and 5.6 mmol/kg BA series. c, d ΔMABP and ΔHR after the intravenous infusions of BA at a dose of 1.4 mmol/kg, (BA) or 3-hydroxybutyrate, a non-specific antagonist of GPR41/43 receptors at a dose of 1.4 mmol/kg (ANT), or BA after the pretreatment with ANT (ANT + BA) or a non-specific nitric oxide synthase inhibitor at a dose of 0.3 mmol/kg (L-NAME) or the administration of BA after the pretreatment with L-NAME (L-NAME + BA), or the vehicle. *p < 0.05 vs baseline, ^p < 0.05 vs BA series. Means ± SE are presented

Fig. 2

a Changes in mean arterial blood pressure (ΔMABP, mmHg) and b heart rate (ΔHR, beats/min) in Wistar rats after the intracolonic administration (IC) of either a vehicle (0.9% NaCl) or butyric acid (BA) at a dose of 1.4, 2.8, and 5.6 mmol/kg. *p < 0.05 vs baseline, ^#p < 0.05 - 2.8 and 5.6 mmol/kg BA series vs the vehicle. c, d ΔMABP and ΔHR after the IC administration of BA at a dose of 5.6 mmol/kg (BA), or 3-hydroxybutyrate, a non-specific antagonist of GPR41/43 receptors at a dose of 5.6 mmol/kg (ANT) or BA after the pretreatment with ANT (ANT + BA), or the administration of BA after the sham vagotomy (SHAM + BA) or the administration of BA after the vagotomy (VAG + BA), or the vehicle. *p < 0.05 vs baseline, ^p < 0.05 vs BA series, ^$p < 0.05 vs SHAM + BA series. Means ± SE are presented

Fig. 3

Response of the pre-constricted with PE mesenteric artery branches and gracilis muscle arteries to a increasing concentration of butyric acid (BA, from 5 μM up to 1 mM, n = 10); b increasing concentration of 3-hydroxybutyrate (ANT, from 5 μM to 1 mM, n = 10) administered concurrently with BA (5 μM), and c the effect of 3-hydroxybutyrate (ANT, 1 mM) administered concurrently with BA on vasorelaxant responses of mesenteric artery branches (n = 5) and gracilis muscle artery (n = 5) to BA (1 mM). Dilation is expressed as a percentage of maximum diameter (0 Ca²⁺, EGTA 3 mM). Values are means ± SE of n arteries. *p < 0.05, **p < 0.01, ***p, p < 0.001: a significant vasorelaxation; ##p < 0.01, ###p < 0.001: a significant difference between the MA vs GMA response to the BA or ANT ; †††p < 0.001 a significant effect of ANT (1 mM) on the vasodilation evoked by BA (1 mM)

Fig. 4

Postulated mechanisms involved in the hypotensive effect of colon-derived butyric acid (BA). 1 BA stimulates the sensory fibers of the vagus nerve that project to the brain centers controlling the circulatory system. This results in decreased tonic sympathetic activity producing a decrease in arterial blood pressure due to a decrease in HR and vasodilation. 2 BA crosses the gut-blood barrier, enters the bloodstream, and produces a direct vasodilation