Gut Microbiota Metabolites Sensed by Host GPR41/43 Protect Against Hypertension

Area of Science:

• Microbiology
• Immunology
• Cardiovascular Science

Background:

• Gut microbiota ferment dietary fiber into short-chain fatty acids (SCFAs), which have cardioprotective effects.
• SCFAs signal through G-protein-coupled receptors GPR41 and GPR43, primarily on immune cells.
• The role of GPR41 and GPR43 in hypertension and the cardioprotective effects of fiber remains unclear.

Purpose of the Study:

• To investigate the role of GPR41 and GPR43 in hypertension and the cardioprotective effects of dietary fiber.
• To determine if GPR41/43 signaling mediates the cardiovascular benefits of a high-fiber diet.

Main Methods:

• Assessed cardiovascular phenotype in GPR41/43 knockout mice and wild-type mice under varying fiber diets and angiotensin II treatment.
• Utilized toll-like receptor 4 (TLR4) antagonist treatment and bone marrow chimeras.
• Analyzed single-nucleotide polymorphisms (SNPs) associated with GPR41/43 expression in UK Biobank participants.

Main Results:

• GPR41/43 knockout mice exhibited exacerbated hypertension, increased cardiac and renal collagen deposition, and heightened gut permeability.
• TLR4 antagonist treatment ameliorated the hypertensive phenotype in knockout mice.
• Lack of GPR41/43 in immune cells was sufficient to worsen hypertension.
• GPR41/43 receptors are partially responsible for the blood pressure-lowering and cardioprotective effects of a high-fiber diet.
• Hypertension was associated with genetic variants linked to lower GPR41/43 expression in humans.

Conclusions:

• Absence of SCFA signaling through GPR41 and GPR43 increases hypertension risk.
• Targeting GPR41 and GPR43 presents a potential novel therapeutic strategy for hypertension.