Hypertension as a Metabolic Disorder and the Novel Role of the Gut

Abstract

Purpose of review: Hypertension is related to impaired metabolic homeostasis and can be regarded as a metabolic disorder. This review presents possible mechanisms by which metabolic disorders increase blood pressure (BP) and discusses the importance of the gut as a novel modulator of BP.

Recent findings: Obesity and high salt intake are major risk factors for hypertension. There is a hypothesis of "salt-induced obesity"; i.e., high salt intake may tie to obesity. Heightened sympathetic nervous system (SNS) activity, especially in the kidney and brain, increases BP in obese patients. Adipokines, including adiponectin and leptin, and renin-angiotensin-aldosterone system (RAAS) contribute to hypertension. Adiponectin induced by a high-salt diet may decrease sodium/glucose cotransporter (SGLT) 2 expression in the kidney, which results in reducing BP. High salt can change secretions of adipokines and RAAS-related components. Evidence has been accumulating linking the gastrointestinal tract to BP. Glucagon-like peptide-1 (GLP-1) and ghrelin decrease BP in both rodents and humans. The sweet taste receptor in enteroendocrine cells increases SGLT1 expression and stimulates sodium/glucose absorption. Roux-en-Y gastric bypass improves glycemic and BP control due to reducing the activity of SGLT1. Na/H exchanger isoform 3 (NHE3) increases BP by stimulating the intestinal absorption of sodium. Gastrin functions as an intestinal sodium taste sensor and inhibits NHE3 activity. Intestinal mineralocorticoid receptors also regulate sodium absorption and BP due to changing ENaC activity. Gastric sensing of sodium induces natriuresis, and gastric distension increases BP. Changes in the composition and function of gut microbiota contribute to hypertension. A high-salt/fat diet may disrupt the gut barrier, which results in systemic inflammation, insulin resistance, and increased BP. Gut microbiota regulates BP by secreting vasoactive hormones and short-chain fatty acids. BP-lowering effects of probiotics and antibiotics have been reported. Bariatric surgery improves metabolic disorders and hypertension due to increasing GLP-1 secretion, decreasing leptin secretion and SNS activity, and changing gut microbiome composition. Strategies targeting the gastrointestinal system may be therapeutic options for improving metabolic abnormalities and reducing BP in humans. SNS, brain, adipocytes, RAAS, the kidney, the gastrointestinal tract, and microbiota play important roles in regulating BP. Most notably, the gut could be a novel target for treatment of hypertension as a metabolic disorder.

Keywords: Adipokines; Gastrointestinal tract; Hypertension; Microbiota; Obesity; Renin-angiotensin-aldosterone system; Salt; Sodium/glucose cotransporter; Sympathetic nervous activity.

Fig. 1

The gut, brain, and kidney play important roles in regulating blood pressure. Enhanced renal SNS induces sodium retention, increases renin secretion, and impairs pressure natriuresis. Central SNS is enhanced through increased microglial activation and neuroinflammation. Leptin acts on the hypothalamus and regulates energy metabolism by decreasing appetite and increasing energy expenditure. Adiponectin is induced by a high-salt diet and decreases the expression of SGLT2. AT1 in the brain stimulates thermogenic SNS activity, energy expenditure, and RMR. Low-pressure gastric distention raises blood pressure. Ghrelin exerts an orexigenic effect and increases taste sensitivity. Gastrin, whose secretion is stimulated by oral sodium intake, is reabsorbed by renal proximal tubules and inhibits NHE3 activity. T1R3 and gustducin act as sweet taste receptors in the intestine. When they sense sugar/sweetener, they increase the expression of SGLT1. Intestinal MR modulates ENaC activity and regulates sodium absorption. Sodium in the bile is required for the proper function of SGLT1 in the intestine. Gut microbiota produces both pro-inflammatory mediators, such as uremic toxin, and anti-inflammatory mediators, such as SCFA. SCFA stimulates the secretion of anti-inflammatory gut hormones, such as GLP-1 from the enteroendocrine cells. High-salt and high-fat diets alter the microbial composition and induce intestinal inflammation and gut barrier disruption, leading to the leaky gut mucosa. AgRP agouti-related peptide, AngII angiotensin II, ARC arcuate nucleus, AT1 angiotensin II type-1 receptor, BP blood pressure, ENaC epithelial sodium channel, GLP glucagon-like peptide, Glu glucose, IL interleukin, Lepr leptin receptor, MR mineralocorticoid receptor, Na sodium, NHE3 Na/H exchanger isoform 3, NO nitric oxide, POMC preproopiomelanocortin, PVN paraventricular nucleus, PYY peptide YY, RMR resting metabolic rate, SCFA short-chain fatty acid, SGLT sodium/glucose cotransporter, SNS sympathetic nervous system, TGF transforming growth factor, TNF tumor necrosis factor

Fig. 2

The effect of intestinal mineralocorticoid receptor knockout on fecal sodium, γ-ENaC expression, and blood pressure. *P < 0.05 versus control. Adapted from [•]. DOCA deoxycorticosterone, ENaC epithelial sodium channel, IEC-MR KO intestinal epithelial cell-specific mineralocorticoid receptor knockout, W weeks