DIETARY FIBRE REDUCES INTESTINAL PH AND EXHIBITS CARDIOVASCULAR‐PROTECTIVE EFFECTS THROUGH A PROTON‐SENSING RECEPTOR. (April 2021)

• Record Type: Journal Article
• Authors: Xie, Liang; Dinakis, Evany; Muralitharan, Rikeish; Nakai, Michael; Zhang, Xiaoyue; Jama, Hamdi; Paterson, Madeleine; Robert, Remy; Mackay, Charles; Marques, Francine
• Is Part Of: Journal of hypertension. Volume 39(2021)e-Supplement 1
• Publication Date: 2021-04
• Subjects: Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/01.hjh.0000749052.60458.1a
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : Objective: Dietary fibre lowers blood pressure (BP) and risk of cardiovascular disease and death via production of acidic metabolites by the gut microbiota. The mechanisms involved, however, are still elusive. Here, we aimed to understand the role of intestinal pH and the proton-sensing receptor GPR65 in the cardiovascular protection by dietary fibre. Design and method: Intestinal pH of C57BL/6 (WT) mice was measured after a 7-day dietary intervention with different levels of dietary fibre. The impact of pH and GPR65 on production of an inflammatory cytokine, TNFa, was determined by flow cytometry. We also determined the cardiovascular phenotype of male and female naïve WT and Gpr65-/- mice, including BP, tissue weights, sodium handling and immune cell infiltration. Results: Compared to the control diet, high fibre diet significantly reduced pH in caecum (control 6.84 ± 0.12 vs high fibre 6.03 ± 0.07; P < 0.001) and colon (7.10 ± 0.12 vs 5.95 ± 0.12, P < 0.001), while a diet lacking fibre significantly elevated pH (caecum, 7.37 ± 0.05, P = 0.001; colon, 7.53 ± 0.07, P = 0.030). Acidic pH inhibited the production of the pro-inflammatory TNFa by both CD4+ and CD8+ T cells (pH 6 vs pH 7; P < 0.001). Deletion of GPR65 increased TNFa production, particularly at acidic pH (CD4+, P = 0.002; CD8+, P < 0.001). Compared to WT controls, male and female Gpr65-/- mice had higher BP (mean arterial pressure; males WT 76.57 ± 3.26 vs Gpr65-/- 87.69 ± 2.18, P = 0.013; females WT 73.40 ± 2.41 vs Gpr65-/- 82.27 ± 2.56, P = 0.018; mmHg), and significant cardiac (Males, P < 0.001; Females, P = 0.001), renal (Males, P = 0.003; Females, P = 0.003) and splenic (Males, P = 0.002; Females, P = 0.002) hypertrophies when adjusted to tibia length. Male Gpr65-/- mice exhibited compromised capability in handling sodium (P < 0.001) and water (P = 0.028). Furthermore, male Gpr65-/- mice had increased infiltrations of CD4+ T cells (P = 0.015) and gamma-delta T cells (P = 0.038) in the kidneys, suggesting an increased susceptibility to renal inflammation. Conclusions: We determined that dietary fibre reduces large intestine pH. Low pH inhibits TNFa production in a partially GPR65-dependent way. Gpr65-/- mice exhibited spontaneous cardiovascular disorders including higher BP. This supports that the cardiovascular protection by dietary fibre is likely to be through pH regulation and GPR65. This is a highly novel mechanism that regulates BP.