Dinakis, EvanyXu, ChudanMuralitharan, Rikeish R.Jama, HamdiXie, LiangLeung, Kwan CharmaineMirabito Colafella, Katrina M.McArdle, ZoeSalimova, EkaterinaTavares, Leticia CamargoSnelson, MatthewJohnson, ChadGaspari, TraceyMackay, Charles R.O’Donnell, Joanne A.Marques, Francine Z.2026-06-112026-06-110143-5221PubMed:40560060WOS:001608684600002ORCID:/0000-0001-7278-0999/work/219172343https://hdl.handle.net/1885/733810237Dietary 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.This study was supported by a National Heart Foundation Vanguard Grant (102927) and a National Health & Medical Research Council of Australia (NHMRC) Ideas Grant (GTN2017382). F.Z.M. is supported by a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Charitable Foundation, a National Heart Foundation Future Leader Fellowship (105663), and NHMRC Emerging Leader Fellowship (GNT2017382). J.A.O. is supported by an NHMRC Fellowship (GNT 1124288). M.S. is supported by a National Heart Foundation Postdoctoral Fellowship (106698). This study was supported by a National Heart Foundation Vanguard Grant (102927) and a National Health & Medical Research Council of Australia (NHMRC) Ideas Grant (GTN2017382). F.Z.M. is supported by a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Charitable Foundation, a National Heart Foundation Future Leader Fellowship (105663), and NHMRC Emerging Leader Fellowship (GNT2017382). J.A.O. is supported by an NHMRC Fellowship (GNT 1124288). M.S. is supported by a National Heart Foundation Postdoctoral Fellowship (106698). The authors thank the Monash University Animal Research Platform, Monash University Genomic Modification Platform, Monash University Histology Platform, Monash University FlowCore, Monash University Biomedical Imaging, Monash eResearch capabilities for the access to the M3 server, Monash University Biomedicine Learning and Teaching Building & Media Services Facility and the Australian Genome Research Facility.21en©2025 The authors202510.1042/CS20243009105020430567