Oral sodium butyrate increases daytime systolic blood pressure in hypertensive patients: a double-blind, randomized, placebo-controlled trial

Objective: The microbiota-derived short chain fatty acid (SCFA) butyrate has been shown to modulate blood pressure (BP) in rodent studies, while in humans, plasma butyrate levels have been associated with BP. Nonetheless the net effect of butyrate on hypertension in humans remains uncovered. In this study, we aimed to determine the effect of oral butyrate on BP in hypertensive patients. Design and method: We performed a double-blind randomized placebo-controlled trial including 23 patients with grade I hypertension. Antihypertensive medication was discontinued for the duration of the study with a wash-out period of four weeks before starting the intervention. Participants received either oral sodium butyrate capsules 4 g per day or placebo capsules with an equivalent amount of sodium chloride for four weeks. The primary outcome was daytime 24-hours systolic BP. We also collected data on short-term heart rate variability (HRV) using finger photoplethysmography, and extracellular water percentage using body impedance analyses. We measured plasma renin, aldosterone, and fecal SCFA levels. Gut microbiota composition was determined using 16S rRNA sequencing. Differences between groups over time were assessed using linear mixed models (group*time interaction). Results: Study participants had a mean age of 59.0 ± 3.7 years, 56.5% female and an average baseline office systolic BP of 143.5 ± 14.6 mmHg and diastolic BP of 93.0 ± 8.3 mmHg. Daytime 24-hours systolic and diastolic BP significantly increased over the intervention period in the butyrate compared to the -placebo group, with an effect size of 9.65 (95%CI 3.88 - 17.15) mmHg in daytime 24-hours systolic BP and 5.08 (95%CI 1.89 - 8.76) mmHg in diastolic BP in the linear mixed model. Heart rate and extracellular water percentage changes were not significantly different between the groups. There was a trend towards increasing HRV in the butyrate group (group*time p = 0.078), but no significant changes in renin and aldosterone levels, nor in fecal SCFA levels. Butyrate did not impact gut microbiota composition substantially. Conclusions: Four weeks of oral butyrate treatment increased daytime systolic and diastolic BP in hypertensive subjects. Our findings implicate that not all SCFA have beneficial effects on human cardiovascular health which warrants caution in future prebiotic and butyrate intervention studies.