Iñaki Robles‐Vera1, Marta Toral2,3, Néstor de la Visitación1, Manuel Sánchez1,4, Manuel Gómez‐Guzmán1,4, Raquel Muñoz1, Francesca Algieri1,4, Teresa Vezza1,4, Rosario Jiménez2,1,4, Júlio Gálvez1,4, Miguel Romero1,4, Juan Miguel Redondo2,3, Juan Duarte2,1,4
1Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
2CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
3Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
4Instituto de Investigación Biosanitaria de Granada (Ibs.GRANADA), Granada, Spain
Tóm tắt
Background and PurposeHypertension is associated with gut dysbiosis. Here we have evaluated the effects of the angiotensin receptor antagonist losartan on gut microbiota in spontaneously hypertensive rats (SHR) to assess their contribution to its antihypertensive effects.Experimental ApproachTwenty‐week‐old Wistar Kyoto rats (WKY) and SHR were treated with losartan for 5 weeks (SHR‐losartan). Faecal microbiota transplantation (FMT) was performed from donor SHR‐losartan group to recipient untreated‐SHR. Blood pressure (BP) was measured using tail‐cuff plethysmography. Composition of the gut microbiota was assessed by amplification of the V3‐V4 region of 16S rRNA gene. T cells were analysed in gut/aorta by flow cytometry.Key ResultsFaeces from SHR showed gut dysbiosis, characterised by higher Firmicutes/Bacteroidetes ratios, lower acetate‐ and higher lactate‐producing bacteria, and lower levels of strict anaerobic bacteria, effects which were restored to normal by losartan. Improvement of gut dysbiosis was linked to higher colonic integrity and lower sympathetic drive in the gut. In contrast, hydralazine reduced BP, but it neither restored gut dysbiosis nor colonic integrity. FMT from SHR‐losartan to SHR reduced BP, improved the aortic endothelium‐dependent relaxation to ACh, and reduced NADPH oxidase activity. These vascular changes were accompanied by both increased Treg and decreased Th17 cell populations in the vascular wall.Conclusion and ImplicationsIn SHR, losartan treatment reduced gut dysbiosis and sympathetic drive in the gut, thus improving gut integrity. The changes induced by losartan in gut microbiota contributed, in part, to protecting the vasculature and reducing BP, possibly by modulating the immune system in the gut.
