Microbial Metabolite, Butyrate, Increases Blood Pressure in Rodent Models of Hypertension

Abstract

IntroductionThe emerging link between gut dysbiosis and hypertension is characterized by a significant reduction in butyrate‐producing bacteria in the spontaneously hypertensive rat (SHR) compared with the Wistar Kyoto (WKY) control. Butyrate, a major end product of dietary fiber fermentation by gut microbiota, reportedly produces beneficial effects in multiple dysbiosis‐related diseases. However, butyrate has also been linked with activation of the sympathetic drive, elevated heart rate and release of norepinephrine. Considering the established link between sympathetic drive and hypertension, we investigated the role of butyrate in blood pressure (BP) control in hypertension.MethodsMale SHR (5 wo) were placed on either the fiber‐rich (butyrolytic) diet (SHR‐BD) or control diet (SHR‐CD) for 13 weeks ad libitum. Fecal/cecal butyrate levels were determined using high performance liquid chromatography (HPLC) throughout the study. Following this, fecal matter transplant (FMT) from both groups was performed separately to male WKY recipients (7 wo) with antibiotic‐depleted endogenous gut bacteria, to create two groups: WKY FMT‐BD and WKY FMT‐CD. Five weeks following FMT, both groups were infused with a subpressor dose of angiotensin II (Ang II; 50ng/kg/min) for three weeks. Separate male SHR (9 wo) were administered with daily injections of either saline or butyrate (500mg/kg/day I.P.) for four weeks. BPs were measured in all groups using tailcuff or telemetry throughout the study.ResultsElevated cecal butyrate in SHR‐BD (by 2 fold vs. SHR‐CD; P<0.001) was associated with significantly higher SBP (SHR‐CD: 183.3mmHg vs SHR‐BD: 206.6 mmHg; P<0.01). FMT from SHR‐CD and SHR‐BD caused a similar BP increase in the WKY recipients (ΔSBP=11.5 mmHg, P<0.001), However, a subsequent administration of subpressor Ang II further elevated SBP in the WKY FMT‐BD group only (by 7.7 mmHg vs. WKY FMT‐CD; P=0.06). Finally, chronic IP injection of butyrate in the SHR resulted in significant SBP increase compared to saline‐injected SHR (ΔSBP=14.5 mmHg, P<0.05).ConclusionSHR gut microbiota is pro‐hypertensive in the WKY. Moreover, subpressor Ang II exacerbates this hypertension in the presence of excess butyrate. Thus, elevated butyrate may interact with Ang II in the pathophysiology of hypertension, indicating the disadvantageous role of butyrate in the context of hypertension.Support or Funding Information1. American Heart Association 2. College of Veterinary Medicine, University of Florida