Cholic Acid Attenuates Systemic Hypertension in Spontaneously Hypertensive Rats

Abstract

Gut dysbiosis, defined as a pathological imbalance of the gut microbiota, is associated with hypertension in humans and animal models. Recent studies have demonstrated a cause and effect relationship between gut dysbiosis and 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). BAs, which serve to emulsify fats, are derived from the liver, released into the gut, and further modified by bacteria into a variety of primary and secondary BAs species. These primary and secondary BAs diffuse into the systemic circulation, disperse throughout the body, and act as hormones by stimulating BA receptors. BA signaling has been shown to influence many pathways involved in BP regulation, including systemic inflammation and vascular function. Thus, we hypothesized that gut dysbiosis contributes to the development of hypertension by reducing bile acid signaling. By comparing 16s rRNA sequencing data from normotensive WKY and spontaneously hypertensive stroke prone rat (SHRSP) cecal content, we found that SHRSP had a significant increase in the genus Lactobacillus, known to sequester BAs within its cytosol and reduce systemic BAs availability, when compared to WKY (p<.05). Additionally, we observed a significant reduction in 9 of 18 plasma BAs in SHRSPs, as compared to WKY. This included a 77% reduction in cholic acid (CA), a primary BA. We next examined the effects of CA supplementation on systolic BP (SBP) in WKY and SHRSP. Starting at 6 weeks old, WKY and SHRSP were fed control or control + 0.5% CA diet for 16 weeks. SBP was measured weekly. At 22 wks, rats were euthanized, and the thoracic aorta was isolated to examine endothelial function by aortic ring assay. Cecal content was collected for 16s rRNA sequencing and BA measurements. CA treatment restored CA and hyocholic acid 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 (p<.05) but had no effect on SBP in WKY rats. Acetylcholine‐induced vasodilation of the aorta was significantly impaired in SHRSP control as compared to WKY control. Interestingly, CA supplementation significantly improved endothelium‐dependent vasodilation in the aorta of SHRSP rats similar to that in WKY rats (p<.0005). Beta‐diversity analysis of the cecal microbiota showed that CA treatment significantly altered the community makeup in WKY and SHRSPs. Of interest, CA treatment restored relative abundance of Lactobacillus in SHRSP to the level of WKY controls. We conclude that reduced BA signaling contribute 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.Support or Funding InformationNational Heart, Lung, and Blood In stitute R01HL134838 (D.J. Durgan), and by National Institute of Neurological Disorders and Stroke R01NS080531 (R.M. Bryan)