Background: High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Amongst key Western lifestyle factors, a diet poor in fibre is associated with prevalence of high BP. The impact of lack of prebiotic fibre and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fibre leads to the development of a hypertensinogenic gut microbiome, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites. Methods: 179 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/d). Mice were fed diets lacking prebiotic fibre with or without addition of gut metabolites called short-chain fatty acids (SCFAs; produced during fermentation of prebiotic fibre in the large intestine), or high prebiotic fibre 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 fibre predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodelling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebioticdeprived hypertensive phenotype, including cardiac manifestations. Re-introduction of SCFAs to fibre-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy and fibrosis. The cardio-protective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-DOPA levels and the abundance of T regulatory (Treg) cells regulated by DNA methylation. Conclusions: The detrimental effects of low fibre Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signalling. Maintaining a healthy, SCFA-producing microbiome is important for cardiovascular health.
David M Kaye, Waled Shihata, Hamdi A Jama, Kirill Tsyganov, Mark Ziemann, Helen Kiriazis, Duncan Horlock, Amrita Vijay, Beverly Giam, Antony Vinh, Chad Johnson, April Fiedler, Daniel Donner, Matthew Snelson, Melinda T Coughlan, Sarah Phillips, Xiao-Jun Du, Assam El-Osta, Grant Drummond, Gavin W Lambert, Tim Spector, Ana M Valdes, Charles R Mackay, Francine Z Marques, Deficiency of Prebiotic Fibre and Insufficient Signalling Through Gut Metabolite Sensing Receptors Leads to Cardiovascular Disease, Circulation, 2020 (epub ahead of print)