Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41

Abstract

Short chain fatty acid (SCFA) metabolites are byproducts of gut microbial metabolism that are known to affect host physiology via host G protein-coupled receptor (GPCRs). We previously showed that an acute SCFA bolus decreases blood pressure (BP) in anesthetized mice, an effect mediated primarily via Gpr41. In this study, our aims were to identify the cellular localization of Gpr41 and to determine its role in BP regulation. We localized Gpr41 to the vascular endothelium using RT-PCR: Gpr41 is detected in intact vessels (with endothelium) but is absent from denuded vessels (without endothelium). Furthermore, using pressure myography we confirmed that SCFAs dilate resistance vessels in an endothelium-dependent manner. Since we previously found that Gpr41 mediates a hypotensive response to acute SCFA administration, we hypothesized that Gpr41 knockout (KO) mice would be hypertensive. Here, we report that Gpr41 KO mice have isolated systolic hypertension compared with wild-type (WT) mice; diastolic BP was not different between WT and KO. Older Gpr41 KO mice also exhibited elevated pulse wave velocity, consistent with a phenotype of systolic hypertension; however, there was no increase in ex vivo aorta stiffness (measured by mechanical tensile testing). Plasma renin concentrations were also similar in KO and WT mice. The systolic hypertension in Gpr41 KO is not salt sensitive, as it is not significantly altered on either a high- or low-salt diet. In sum, these studies suggest that endothelial Gpr41 lowers baseline BP, likely by decreasing active vascular tone without altering passive characteristics of the blood vessels, and that Gpr41 KO mice have hypertension of a vascular origin.

Linking gut microbiota to cardiovascular disease and hypertension: Lessons from chronic kidney disease

“…Hence, a growing body of evidence supports that a high blood pressure (BP) is coupled to depressed carbohydrate fermentation [50]. Prescient ex vivo studies using pressure myography applied to rodent and human samples suggested that SCFA induce the vasodilation of resistance vessels in an endothelium-dependent manner [53][54][55]. Binding of SCFAs to the GPCR can activate a variety of intracellular signaling cascades, involving nuclear transcription, enzyme activation, and cell membrane ion transport [56].…”

“…At the mRNA level, Gpr41 is expressed in the vascular endothelium of intact vessels, where it lowers baseline BP by decreasing active vascular tone [54]. Gpr41-null mice present with hypertension of vascular origin: at baseline, plasma renin concentration is similar in Gpr41 KO and WT mice, and the systolic hypertension in Gpr41 KO mice is not salt-sensitive [54].…”

“…Gpr41-null mice present with hypertension of vascular origin: at baseline, plasma renin concentration is similar in Gpr41 KO and WT mice, and the systolic hypertension in Gpr41 KO mice is not salt-sensitive [54]. Gpr41 couples to G i in response to various SCFA, including propionate, formate, acetate, butyrate and isobutyrate (with an EC 50 in the micromolar range) [62].…”

Nutritional approaches for managing obesity-associated metabolic diseases

“…The intestinal microbial community is especially vital to metabolic homeostasis as it participates in nutrient absorption and maintaining the health of the intestinal tract. Specifically, intestinal microbiota aid in the production of bioactive compounds and some essential nutrients and metabolites and, arguably their most beneficial role within the intestinal environment, generate short chain fatty acids (SCFA) (Natarajan and Pluznick 2015). Although pathogenic bacteria are also present, within normal/healthy hosts diseased/inflammatory states are efficiently regulated and do not negatively alter metabolism.…”

FFAR2‐FFAR3 receptor heteromerization modulates short‐chain fatty acid sensing

“…The genetic deletion of either FFAR2 or FFAR3 expression in mice was found to either exacerbate or reduce a number of inflammatory diseases. Studies have implicated FFAR2 in diabetes (3), obesity (4–9), colitis (10–16), colon cancer (17), and arthritis (10); FFAR3 has been implicated in diabetes (3), colitis (14), hypertension (18), and asthma (19). …”