Abstract 13: Cholic Acid Supplementation Attenuates Hypertension In Spontaneously Hypertensive Stroke Prone Rats

Abstract

Recent studies have demonstrated a causal role of gut dysbiosis in the development of hypertension in several animal models. However, our understanding of the mechanisms linking gut dysbiosis to blood pressure (BP) regulation of the host is still lacking. One key mechanism by which the microbiota influences the host is through the generation/modification of metabolites, such as bile acids (BAs). BA signaling has been shown to influence many pathways involved in BP regulation, including systemic inflammation and vascular function. We previously observed that spontaneously hypertensive stroke prone rat (SHRSP) exhibited dysbiotic cecal microbiome, which included a significant increase in the genus Lactobacillus , known to sequester BAs within its cytosol and reduce BAs availability, when compared to WKY. Thus, we hypothesized that gut dysbiosis contributes to the development of hypertension by reducing bile acid signaling. We observed a significant reduction in 9 of 18 plasma BAs in SHRSPs, as compared to WKY. This included a 72% reduction in cholic acid (CA), a primary BA (n=7-8, p<0.05). We next examined the effects of CA supplementation (0.5% CA diet for 16 weeks) on systolic BP (SBP) in WKY and SHRSP. Within the 9 BAs that were reduced in SHRSP, CA and hyocholic acid were restored by CA treatment in SHRSP plasma to similar levels of that observed in WKY control plasma. Furthermore, CA treatment decreased SBP by 18 ±7mmHg at 20 weeks in SHRSP (n=7-8, p<0.05), but had no effect on SBP in WKY rats. Acetylcholine-induced vasodilation of the aorta was significantly impaired in SHRSP control by 40% (10 -6 μM ACh, 59.5% vs. 99.3%) as compared to WKY control (n=3-4, p<0.01). CA treatment significantly improved endothelium-dependent vasodilation in the aorta of SHRSP rats similar to that in WKY rats (n=3-4, p<0.05). CA treatment also altered a number of bacteria in the gut including restoration of relative abundance of Lactobacillus in SHRSP to the level of WKY controls. We conclude that reduced BA signaling contributes to the development of hypertension in SHRSP, and that CA treatment may be a potential therapeutic approach to attenuate vascular endothelial dysfunction and associated hypertension.