pH-sensor GPR68 plays a role in how dietary fibre lowers blood pressure in a preclinical model of hypertension

Abstract

Dietary fibre lowers blood pressure (BP) via short-chain fatty acids, acidic metabolites released from fibre fermentation by bacteria in the large intestine. This acidic microenvironment may activate the pH-sensing receptor GPR68, primarily expressed in immune cells. Here, we aimed to investigate whether GPR68 confers the BP-lowering effects of a high-fibre diet in hypertension by regulating inflammatory responses. Baseline BP parameters were measured using telemetry in C57BL/6J wildtype (WT) and GPR68-deficient (Gpr68-/-) male and female mice. Moreover, male mice were fed a control or high-fibre diet following minipump implantation with saline or angiotensin II (Ang II), where BP was measured weekly by tail-cuff. Cardiac ultrasounds, histological, flow cytometric and gut microbiome (16S) analyses were performed. No BP differences were detected in untreated male and female mice, irrespective of genotype. Similarly to WT mice, Gpr68-/- male mice were susceptible to Ang II-induced hypertension. High-fibre-fed WT mice exhibited blunted elevations in BP and improved cardiac collagen deposition and aortic elastin content compared with control-fed WT mice. These were not observed in high-fibre-fed Gpr68-/- mice. A high-fibre diet decreased pro-inflammatory renal and aortic immune cell counts independently of GPR68. Dietary fibre, rather than GPR68 or Ang II, was the primary factor influencing differences in the gut microbiota. This study provides novel insight into how the pH-sensing receptor GPR68 may be implicated in the protective effects of a high-fibre diet. However, these effects are likely immune-independent.

Keywords: G protein-coupled receptor; blood pressure; diet; hypertension; immune cells; microbiome; pH.