A novel SCFA receptor, the microbiota, and blood pressure regulation

Abstract

T he maintenance of blood pressure homeostasis is a complex process which is carefully regulated by a variety of inputs. We recently identified two sensory receptors (Olfactory receptor 78 and G protein couple receptor 41) as novel regulators of blood pressure. Both Olfr78 and Gpr41 are receptors for short chain fatty acids (SCFAs), and we showed that propionate (a SCFA) modifies blood pressure in a manner which is differentially modulated by the absence of either Olfr78 or Gpr41. In addition, propionate modifies renin release in an Olfr78-dependent manner. Our study also demonstrated that antibiotic treatment modulates blood pressure in Olfr78 null mice, indicating that SCFAs produced by the gut microbiota likely influence blood pressure regulation. In this addendum, we summarize the findings of our recent study and provide a perspective on the implications of the interactions between the gut microbiota and blood pressure control. IntroductionA recent paradigm in sensory physiology suggests that "sensory" receptors (taste receptors, olfactory receptors, and many other G-protein coupled receptors) play important roles in non-sensory tissues, where they serve as selective and sensitive chemoreceptors. For example, sour taste receptors function in the tongue to sense changes in pH as an indicator of sour taste 1,2 -in addition, these receptors are also found in neurons which contact the central canal of the spinal column, where they function to detect changes in pH in cerebrospinal fluid.1 In addition, olfactory receptors (ORs) participate in muscle cell migration 3 and sperm chemotaxis, 4 sweet taste receptors are found in the bladder, 5 and bitter taste receptors mediate both bronchodilation and ciliary beat frequency in airways.6,7 G-protein coupled receptors of the GPR gene family are also known to act as sensors of metabolites. [8][9][10][11][12] Intriguingly, ligands for these sensory receptors are often generated by physiological processes or metabolic pathways, 1,8,12,13 suggesting that known metabolites or chemicals may have signaling functions beyond their traditional roles. 8,12,13 Furthermore, sensory receptors such as ORs are expressed in a variety of tissues in mice, humans, and other primates, where their functional role has not yet been defined. 14-16 Localization of Renal Olfactory Receptor Olfr78We previously identified Olfactory Receptor 78 (Olfr78) as a "renal" olfactory receptor (OR), 17 and in a recent study 18 we set out to localize and to identify the ligand for this OR. We took advantage of a β-galactosidase reporter mouse model in order to localize Olfr78, and determined that Olfr78 is found in vascular resistance beds in a variety of tissues, as well in the renal afferent arteriole. The renal afferent arteriole is an incredibly specialized vessel: blood enters the renal glomerulus for filtration via the afferent arteriole, and this arteriole is the site where renin (the initial, rate-limiting step in the renin-angiotensin-aldosterone pathway) is stored for eventual release into the blood...

Evidence for a link between gut microbiota and hypertension in the Dahl rat

“…2, estimated from data analyzed by the Rat Genome Database; http:// www.rgd.mcw.edu). Since there are no variants in the homologous rat genes for Olfr78 and Gpr41, the two mouse genes reported for gut microbial links to hypertension (38), it is reasonable to conclude that variation within host genomic factors, which are not within Olfr78 and Gpr41, are likely influencing microbiotal compositions of S and R rats.…”

“…Evidence for the gut microbiota to influence BP is limited. To date, there are two studies reported (38,41), which were specifically focused on data obtained from an olfactory G protein-coupled receptor (Olfr78) and G protein-coupled receptor (Gpr41) knockout mice. To our knowledge, there are no gut microbiotal studies reported in genetic models of hypertension.…”

Hypertension as an autoimmune and inflammatory disease

“…61,62 In addition, the production of short-chain fatty acids by the gut microbiota can affect blood pressure by interaction with renal sensory nerves and an increase in renin secretion. 63,64 Perhaps, more importantly, gut microbiota, particularly with regard to intestinal wall inflammation, has been linked to the presence and severity of systemic inflammation. Several studies have shown that the level of Gram-negative bacteria endotoxin and bacterial DNA fragments in the systemic circulation are correlated with increased plasma CRP, IL-6 and D-lactate.…”

Gut Microbiota, a Rising Star in Hypertension

“…Propionate, one of the SCFA, activate the Gpr41 leads to a hypotensive response and enable the Olfr78 favors a hypertensive response via renin release mediated by cAMP production. However, these effects are abolished in Olfr78 and Gpr41-deficient mice, as well as an antibiotic-treated mice [38]. H 2 S is also a microbiota metabolite, an important biological mediator involved in the various process include hypertension [39].…”