David M Kaye1,2,3, Waled A Shihata1, Hamdi A Jama1,4, Kirill Tsyganov4,5, Mark Ziemann6,7, Helen Kiriazis8, Duncan Horlock1, Amrita Vijay9, Beverly Giam1, Antony Vinh10, Chad Johnson11, April Fiedler10, Daniel Donner8, Matthew Snelson12, Melinda T Coughlan12, Sarah Phillips, Xiao-Jun Du8, Assam El-Osta6,13, Grant Drummond10, Gavin W Lambert14, Tim D Spector9, Ana M Valdes9,15, Charles R Mackay16,17, Francine Z Marques1,4. 1. Heart Failure Research Group (D.M.K., W.A.S., H.A.J., D.H., B.G., A.F., F.Z.M.), Baker Heart and Diabetes Institute, Melbourne, Australia. 2. Central Clinical School, Faculty of Medicine Nursing and Health Sciences (D.M.K.). 3. Department of Cardiology, Alfred Hospital, Melbourne, Australia (D.M.K.). 4. Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science (H.A.J., K.T., F.Z.M.). 5. Monash Bioinformatics Platform (K.T.). 6. Epigenetics in Human Health and Disease (M.Z., A.E-O.). 7. School of Life and Environmental Sciences, Deakin University, Geelong, Australia (M.Z.). 8. Mouse Cardiology Research Platform (H.K., D.D., X-J.D.), Baker Heart and Diabetes Institute, Melbourne, Australia. 9. Department for Twin Research and Genetic Epidemiology, King's College London, UK (A.Vijay, T.D.S., A.M.V.). 10. Centre for Cardiovascular Biology and Disease Research, and Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Australia (A.Vinh, G.D.). 11. Monash Micro Imaging (C.J.). 12. Department of Diabetes, Central Clinical School (M.S., M.T.C.). 13. Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories (A.E-O.). 14. Iverson Health Innovation Research Institute and School of Health Sciences, Swinburne University of Technology, Melbourne, Australia (G.W.L.). 15. School of Medicine, University of Nottingham, UK; NIHR Nottingham Biomedical Research Centre, UK (A.M.V.). 16. Infection and Immunity Program, Monash Biomedicine Discovery Institute (C.R.M.). 17. Department of Biochemistry and Molecular Biology (C.R.M.), Monash University, Melbourne, Australia.
Abstract
BACKGROUND: High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites. METHODS: One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg-1·d-1). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids ([SCFA)] produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined. RESULTS: Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation. CONCLUSIONS: The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.
BACKGROUND: High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites. METHODS: One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg-1·d-1). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids ([SCFA)] produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined. RESULTS: Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation. CONCLUSIONS: The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.
Authors: Sepiso K Masenga; Benson Hamooya; Joy Hangoma; Valerie Hayumbu; Lale A Ertuglu; Jeanne Ishimwe; Sharla Rahman; Mohammad Saleem; Cheryl L Laffer; Fernando Elijovich; Annet Kirabo Journal: J Hum Hypertens Date: 2022-04-25 Impact factor: 3.012