Dietary fibre controls blood pressure and cardiovascular risk by lowering large intestinal pH and activating the proton-sensing receptor GPR65

Dietary fibre regulates blood pressure (BP) through gut microbial production of acidic metabolites known as short-chain fatty acids (SCFAs). The specific mechanisms of how SCFAs regulate BP are still emerging. We hypothesised that acidic metabolites that are abundant in the large intestine may activate proton-sensing G-protein coupled receptors, such as GPR65, thus conferring BP regulating effects. Using mouse models, we found that dietary fibre levels determined the luminal pH in the large intestine, through production of SCFAs by the gut microbiota. We then investigated a new mouse model lacking GPR65, which spontaneously developed higher BP, cardiac and renal hypertrophy and fibrosis. We identified that low pH, acting via GPR65 signalling, increased cAMP production and phosphorylation of CREB, and regulated inflammatory cytokine production involved in hypertension. We showed that the benefits of diets high in fibre, which usually prevent hypertension and its associated phenotypes, were decreased in mice lacking GPR65. Finally, we provided proof-of-concept evidence that the luminal pH profile in the colon of hypertensive participants is higher than that of normotensive participants. Colonic pH was further associated with dietary fibre, particularly in the colonic regions where fibre is fermented by the gut microbiota. Together, we show that pH sensing by GPR65 underlies at least some of the cardiovascular benefits of dietary fibre.