Reduced Bile Acid Signaling Contributes to Hypertension Development in Spontaneously Hypertensive Stroke‐Prone Rats

Abstract

Exciting recent findings have identified that gut microbiota plays an essential role in blood pressure (BP) regulation. Studies from our lab and others have shown a causal role of gut dysbiosis in hypertension development in the spontaneously hypertensive stroke-prone (SHRSP) rat and several other animal models. One key mechanism by which the microbiota influences the host is through the generation/modification of metabolites. Among these metabolites, bile acids (BAs), are derived from the liver and modified by gut bacteria. Many BA species cross the gut epithelial barrier into the host circulation and influence inflammation, metabolism, and vascular function through the binding and activation of BA receptors, including TGR5. We hypothesized that disrupted BA signaling, as a result of gut dysbiosis, contributes to the development of hypertension. We observed a significant reduction of several BAs in systemic plasma of SHRSP as compared to WKY, including the TGR5 agonists, cholic acid (CA), hyocholic acid (HCA), hyodeoxycholic acid (HDCA), and tauro-lithocholic acid (TLCA) (p<.05). We next supplemented WKY and SHRSP rats with 0.5% CA in the diet and measured systolic blood pressure (SBP) bi-weekly. After 15 weeks of treatment, systemic plasma was collected for BA analysis and endothelium-dependent dilation was assessed in the isolated aorta. We observed that CA supplementation significantly increased CA, HCA, HDCA, and TLCA in systemic plasma of SHRSP (p<.0001). CA supplementation also significantly reduced SBP of SHRSPs, with an average decrease of 23 mmHg over the final 6 weeks of treatment (p<.05) compared to SHRSP controls. Chronic CA treatment also significantly improved vasodilatory response to increasing doses of acetylcholine (ACh) in the isolated aorta of SHRSPs (p<.05). Next, we determined if BAs had their beneficial effects through activation of the BA receptor TGR5. Beginning at 6 weeks of age, SHRSPs were randomized into vehicle control or oleanolic acid (OA, 10 mg/kg IP daily), a selective TGR5 agonist, treatment groups. OA significantly decreased SBP by an average of 15 mmHg over the final 6 weeks of the treatment, compared to controls (p<.05). Furthermore, 15 weeks of OA treatment significantly improved vasodilatory response to increasing doses of ACh in isolated mesenteric arteries of SHRSPs (p<.05). Because systemic and neuronal inflammation also contributes to the development of hypertension, we examined the effects of TGR5 activation by OA treatment on inflammation in the gut and brain of SHRSPs. Using flow cytometry, we determined that OA treatment increased the percentage of anti-inflammatory Tregs and decreased pro-inflammatory T helper 17 cells in both cecum and brain of SHRSP (p<.05). OA treatment also significantly reduced interferon-γ+ T cells in the cecum of SHRSP. These data suggest an anti-inflammatory role of TGR5 signaling in the gut and brain. We conclude that reduced BA-mediated TGR5 signaling contributes to the development of hypertension in SHRSPs, and that activating TGR5 may be a potential therapeutic approach to attenuate vascular endothelial dysfunction and associated hypertension.