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

Background: Fermentation of dietary fiber by the gut microbiota leads to the production of metabolites called short-chain fatty acids, which lower blood pressure and exert cardioprotective effects. Short-chain fatty acids activate host signaling responses via the functionally redundant receptors GPR41 and GPR43, which are highly expressed by immune cells. Whether and how these receptors protect against hypertension or mediate the cardioprotective effects of dietary fiber remains unknown.

Methods: Cardiovascular phenotype was assessed in untreated and Ang II (angiotensin II) treated hypertensive wild-type and GPR41/43 knockout (KO) double knockout male mice fed diets with different levels of fiber content. Some mice received TLR4-antagonist treatment and bone marrow chimeras. Single-nucleotide polymorphisms associated with GPR41 and GPR43 expression were assessed in UK Biobank participants.

Results: Untreated GPR41/43KO mice had unaltered blood pressure but had greater cardiac and renal collagen deposition with higher macrophage numbers in the kidney compared with wild-type mice. Ang II-treated GPR41/43KO mice showed higher systolic blood pressure, cardiorenal weights and collagen deposition, and increased gut permeability, which allows the translocation of gastrointestinal bacterial components such as lipopolysaccharides into the circulation. The use of an antagonist to the lipopolysaccharide receptor, TLR4, a potent proinflammatory signaling molecule, restored the cardiovascular phenotype in GPR41/43KO mice. The lack of GPR41/43 expression in the immune compartment was sufficient to lead to a worsened hypertensive phenotype. We also demonstrate that GPR41/43 is, at least partially, responsible for the blood pressure-lowering and cardioprotective effects of a high-fiber diet. Finally, using the UK Biobank, we provide translational evidence that variants associated with lower expression of both GPR41 and GPR43 are more prevalent in participants with hypertension.

Conclusions: Our findings highlight that lack of short-chain fatty acid-receptor signaling via both GPR41 and GPR43 increases risk of high blood pressure, suggesting treatments that target these receptors could be a novel strategy to prevent or treat hypertension.