Differing contributions of the gut microbiota to the blood pressure lowering effects induced by first-line antihypertensive drugs González Correa, Cristina Moleón Moya, Javier Miñano, Sofía Robles Vera, Iñaki Toral Jiménez, Marta Barranco, Antonio Manuel Martín Morales, Natividad O´Valle, Francisco Guerra Hernández, Eduardo Jesús Sánchez, Manuel Gómez Guzmán, Manuel Jiménez Moleón, Rosario Romero Pérez, Miguel Duarte Pérez, Juan Manuel Amlodipine Captopril Endothelial dysfunction Gut dysbiosis Hydrochlorothiazide Hypertension Immune system https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.16410 This work was supported by Grants from Agencia Estatal de Investigación (AEI), Ministerio de Ciencia e Innovación (MCIN) (PID2020-116347RB-I00 funded by MCIN/AEI/10.13039/501100011033) and Junta de Andalucía (CTS 164, P20_00193 and A-CTS-318-UGR20) with funds from the European Union and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain. M.T. and I.R.-V. are postdoctoral fellow of Spanish Ministerio de Ciencia e Innovación (Juan de la Cierva Incorporación Program, IJC2020-044581-I, and Juan de la Cierva Formación Program, respectively). J. M. is a predoctoral fellow of MCIN, and C. G.-C. and S. M. are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, ‘FEDER una manera de hacer Europa’). Background and Purpose: This study analyses whether first-line antihypertensive drugs ameliorate the dysbiosis state in hypertension, and to test if this modification contributes to their blood pressure (BP) lowering properties in a genetic model of neurogenic hypertension. Experimental Approach: Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were untreated or treated with captopril, amlodipine or hydrochlorothiazide. A faecal microbiota transplantation (FMT) experiment was also performed by gavage of faecal content from donor SHR-treated groups to SHR recipients for 3 weeks. Key results: Faeces from SHR showed gut dysbiosis, characterized by lower acetate- and higher lactate-producing bacteria and lower strict anaerobic bacteria. All three drugs increased the anaerobic bacteria proportion, captopril and amlodipine restored the proportion of acetate-producing bacterial populations to WKY levels, whereas hydrochlorothiazide decreased butyrate-producing bacteria. Captopril and amlodipine decreased gut pathology and permeability and attenuated sympathetic drive in the gut. Both drugs decreased neuroinflammation and oxidative stress in the hypothalamic paraventricular nuclei. Hydrochlorothiazide was unable to reduce neuroinflammation, gut sympathetic tone and gut integrity. FMT from SHR-amlodipine to SHR decreased BP, ameliorated aortic endothelium-dependent relaxation to acetylcholine, lowered NADPH oxidase activity, aortic Th17 infiltration and reduced neuroinflammation, whereas FMT from SHR-hydrochlorothiazide did not have these effects. Conclusions and Implications: First-line antihypertensive drugs induced different modifications of gut integrity and gut dysbiosis in SHR, which result in no contribution of microbiota in the BP lowering effects of hydrochlorothiazide, whereas the vasculo-protective effect induced by amlodipine involves gut microbiota reshaping and gut-immune system communication. 2024-05-22T06:47:27Z 2024-05-22T06:47:27Z 2024-05-21 journal article González-Correa, C. et al. Differing contributions of the gut microbiota to the blood pressure lowering effects induced by first-line antihypertensive drugs. British Journal of Pharmacology, 1–25. (2024) https://doi.org/10.1111/bph.16410 https://hdl.handle.net/10481/91942 10.1111/bph.16410 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional Wiley