Project Summary Metabolites produced by the gut microbiota play critical roles in host physiology and pathophysiology. We have previously shown that one class of microbial metabolites, short chain fatty acids (SCFAs), bind to host G protein-coupled receptors (GPCRs) to modulate blood pressure. We have found that SCFAs activate Olfactory Receptor 78 (Olfr78) to modulate renin release, and activate Gpr41 to modulate vascular tone. Recently, we have identified two other GPCRs (Gpr43 and Olfr558) which respond to SCFAs and are expressed in the vasculature, and thus are well-positioned to also influence blood pressure. In this proposal, we Aim to investigate how SCFA-GPCR signaling pathways modulate – and are modulated by – hypertension. In Specific Aim 1, we will examine how components of the SCFA signaling pathway (SCFAs, as well as SCFA GPCRs) are modulated in two different models of hypertension (Angiotensin II, and DOCA/Salt). Plasma SCFAs increase in hypertension; here, we will test our novel hypothesis that altered host handling of SCFAs, not increased microbial production, is key in determining plasma levels. To achieve this, we will measure microbial production, intestinal reabsorption, and renal clearance of SCFAs in normotension and in two hypertension models. To examine SCFA GPCRs in hypertension, we will determine how the expression of Olfr78, Olfr558, Gpr41, and Gpr43 is altered in normotension versus hypertension. In Specific Aim 2 of this proposal, we will determine how each of these components of the SCFA-GPCR signaling pathway can modulate the course of hypertension. We have extensively studied Olfr78 and Gpr41 in the past, therefore, we will focus on uncovering novel roles for Olfr558 and Gpr43 in blood pressure regulation under basal conditions and in hypertension. In a separate experiment, we will test our novel hypothesis that low doses of SCFAs are protective but higher doses of SCFAs are detrimental, thereby resolving a conflict in the literature. To do this, we will treat normotensive and hypertensive mice with varying doses of exogenous SCFAs. In sum, these studies will advance the field by illuminating how SCFAs and SCFA GPCRs are modulated in hypertension, and by determining how modulation of this pathway can alter the course of hypertension.

Public Health Relevance Recent studies have found that metabolites produced by your gut bacteria can influence many aspects of how your body functions. We have recently found that one type of gut bacterial metabolite, short chain fatty acids, plays a role in blood pressure regulation by binding to host receptors. In this proposal, we will explore how the various parts of this signaling pathway are altered in hypertension, and, determine how this pathway itself can modulate hypertension.