Abstract
Introduction: Emerging evidence implicates the involvement of intestinal microbiota in overall physiological homeostasis. Altered microbial composition is associated with metabolic, cardiovascular, and neurological diseases. However, the role of intestinal microbiota in blood pressure control and hypertension (HTN) remains unexplored. The present study was designed to evaluate the hypothesis that both intestinal dysbiosis and altered intestinal function are critical pathophysiological events in HTN. Methods: 16S ribosomal DNA from fecal samples from SHR and chronic angiotensin II (Ang II, 200ng/kg/min) rat models was utilized to compare gut microbial communities between normotensive and hypertensive animals. Gut permeability was assessed by accumulation of FITC-dextran (44mg/100g BW) in the plasma 4 hours following oral feeding. Ex vivo atomic force microscopy was used to determine small intestine and colon stiffness (a measure of permeability). Tight junction gene expression was quantified by qPCR. Results: We observed a significant decrease in microbial richness (20%), diversity (12%), and evenness (10%) in SHR vs WKY. This was associated with an increased Firmicutes (F)/Bacteroidetes (B) ratio (4±1 vs 24±5), a hallmark of gut dysbiosis. Additionally, we observed a 95% increase in plasma FITC-dextran in SHRs (1777±428 vs 3514±563 ng/ml, p<0.05), which correlated with decreased mRNA of several tight junction genes throughout the intestine, including Ocln , Tjp1 , and Cldn4 . In addition, we found increased stiffness of both small intestine and colonic tissue, as evidenced by increased elastic modulus in SHR (small intestine: 21.2±3 vs 53.7±8 kPa, colon: 15.7±2 vs 53.4±14 kPa, p<0.05). Similar decreased microbial richness and increased F/B ratio (~2 fold) were observed in the Ang II rat model at 4 weeks. Plasma FITC-dextran began to rise by day 14 (SBP=160 mmHg), and reached maximal increase of 65% by day 21 (SBP=185 mmHg). Furthermore, colon wall stiffness was significantly increased by day 21 of Ang II infusion. Conclusions: These observations show that increased gut permeability/leakiness and dysbiosis is associated with HTN. They are the first to demonstrate a profound intestinal pathophysiology and microbial dysbiosis in HTN.
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