Hypertension-Linked Pathophysiological Alterations in the Gut

• Published in: Circulation research Vol. 120; no. 2; pp. 312 - 323
• Main Authors: Santisteban, Monica M, Qi, Yanfei, Zubcevic, Jasenka, Kim, Seungbum, Yang, Tao, Shenoy, Vinayak, Cole-Jeffrey, Colleen T, Lobaton, Gilberto O, Stewart, Daniel C, Rubiano, Andres, Simmons, Chelsey S, Garcia-Pereira, Fernando, Johnson, Richard D, Pepine, Carl J, Raizada, Mohan K
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 20.01.2017; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Angiotensin; Angiotensin II; Angiotensin II - toxicity; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Animal models; Animals; Antibiotics; Blood pressure; Digestive system; Dysbacteriosis; Gastrointestinal Microbiome - drug effects; Gastrointestinal Microbiome - physiology; Gastrointestinal tract; Homeostasis; Hypertension; Hypertension - drug therapy; Hypertension - metabolism; Hypertension - physiopathology; Hypothalamus; Inflammation; Innervation; Intestinal microflora; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - physiopathology; Intestine; Male; Microbiota; Paraventricular nucleus; Pathology; Peptidyl-dipeptidase A; Permeability; Permeability - drug effects; Probiotics; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Rats, Wistar; Sympathetic nervous system; microbiota; autonomic nervous system; intestines; inflammation; hypertension; gut
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.116.309006

RATIONALE:Sympathetic nervous system control of inflammation plays a central role in hypertension. The gut receives significant sympathetic innervation, is densely populated with a diverse microbial ecosystem, and contains immune cells that greatly impact overall inflammatory homeostasis. Despite this uniqueness, little is known about the involvement of the gut in hypertension. OBJECTIVE:Test the hypothesis that increased sympathetic drive to the gut is associated with increased gut wall permeability, increased inflammatory status, and microbial dysbiosis and that these gut pathological changes are linked to hypertension. METHODS AND RESULTS:Gut epithelial integrity and wall pathology were examined in spontaneously hypertensive rat and chronic angiotensin II infusion rat models. The increase in blood pressure in spontaneously hypertensive rat was associated with gut pathology that included increased intestinal permeability and decreased tight junction proteins. These changes in gut pathology in hypertension were associated with alterations in microbial communities relevant in blood pressure control. We also observed enhanced gut–neuronal communication in hypertension originating from paraventricular nucleus of the hypothalamus and presenting as increased sympathetic drive to the gut. Finally, angiotensin-converting enzyme inhibition (captopril) normalized blood pressure and was associated with reversal of gut pathology. CONCLUSIONS:A dysfunctional sympathetic–gut communication is associated with gut pathology, dysbiosis, and inflammation and plays a key role in hypertension. Thus, targeting of gut microbiota by innovative probiotics, antibiotics, and fecal transplant, in combination with the current pharmacotherapy, may be a novel strategy for hypertension treatment.