The Role of Short-Chain Fatty Acids of Gut Microbiota Origin in Hypertension

Abstract

Hypertension is a significant risk factor for cardiovascular and cerebrovascular diseases, and its development involves multiple mechanisms. Gut microbiota has been reported to be closely linked to hypertension. Short-chain fatty acids (SCFAs)-the metabolites of gut microbiota-participate in hypertension development through various pathways, including specific receptors, immune system, autonomic nervous system, metabolic regulation and gene transcription. This article reviews the possible mechanisms of SCFAs in regulating blood pressure and the prospects of SCFAs as a target to prevent and treat hypertension.

Keywords: blood pressure; gut microbiota; hypertension; mechanism; short-chain fatty acids; treatment.

Figure 1

SCFAs can directly regulate blood pressure by binding to their receptors. Basal concentration of SCFAs could activate GPR41/GPR43, which triggers Gαi and/or Gαo to decrease cAMP, thereby inducing vasodilation and lowering the blood pressure level. A higher concentration of SCFAs could activate Olfr78, which triggers AC3 and Golf in the olfactory signalling pathway to induce cAMP production, thereby increasing renin release and inducing vasoconstriction. AC3, adenylate cyclase type 3; cAMP, cyclic adenosine monophosphate; GPR, G-protein-coupled receptor; Olfr, olfactory receptor; and SCFA, short-chain fatty acid.

Figure 2

SCFAs play a local protective role in blood pressure regulation by regulating the intestinal barrier and immune response. FOXO3a, forkhead box O-3; GLP-2, glucagon-like peptide 2; HDAC, histone deacetylase; IL, interleukin; MT2, metallothionein-2; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; SCFA, short-chain fatty acid, TH17, T helper cell 17; TNF-α, tumour necrosis factor-α; and Treg, regulatory T cell.

Figure 3

SCFAs can regulate blood pressure through the nervous system. By acting on the receptors expressed in the sympathetic ganglia, SCFAs can directly regulate the sympathetic nervous system. They can also significantly activate vagal afferent neurons, which facilitate SCFAs to regulate blood pressure. Furthermore, SCFAs can directly act on the central nervous system to reduce the blood pressure. GPR, G-protein-coupled receptors; Olfr, olfactory receptor; and SCFA, short-chain fatty acid.

Figure 4

SCFAs indirectly regulate blood pressure by affecting the metabolism. SCFAs can activate IGN, which is involved in maintaining normal blood glucose levels and energy homeostasis. SCFAs enter the liver and muscles to improve glycolipid metabolism. SCFAs can also directly enter the blood–brain barrier and act on the hypothalamus to inhibit appetite. Furthermore, SCFAs promote the secretion of intestinal hormones, such as GLP-1 and PYY, which can slow down gastric emptying and reduce food energy absorption. SCFAs can also increase fat oxidation and promote the secretion of leptin from adipocytes; leptin is a typical metabolic hormone that reduces food intake, increases energy release and reduces body mass. GLP-1, glucagon-like peptide 1; IGN, intestinal gluconeogenesis; PYY, peptide tyrosine tyrosine; and SCFA, short-chain fatty acid.

Figure 5

BHB protects the body against hypertension by delaying vascular stiffness associated with endothelial cell senescence. BHB indirectly increases the lamin B1 level by enhancing the expression of OCT4 and increases p53 acetylation by HDAC inhibition, thereby attenuating cellular apoptosis and delaying endothelial cell senescence. BHB, β-hydroxybutyrate; HDAC, histone deacetylase; and OCT4, octamer-binding transcriptional factor 4.

Figure 6

SCFAs protectively regulate the transcription of genes associated with hypertension. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; Egr-1, early growth response-1; MAPK, mitogen-activated protein kinase; RAAS, renin–angiotensin–aldosterone system; and SCFA, short-chain fatty acid.

Figure 7

Current methods used to intervene and regulate SCFA production for blood pressure normalisation. Dietary fibre, oral probiotics, exercise and FMT can increase the production of SCFAs, which are absorbed into the blood circulation and subsequently lower blood pressure levels. FMT, faecal microflora transplantation; SCFA, short-chain fatty acid.