Role of Gut Microbiota-Generated Short-Chain Fatty Acids in Metabolic and Cardiovascular Health

Abstract

Purpose of this review: This review assesses the latest evidence linking short-chain fatty acids (SCFA) with host metabolic health and cardiovascular disease (CVD) risk and presents the latest evidence on possible biological mechanisms.

Recent findings: SCFA have a range of effects locally in the gut and at both splanchnic and peripheral tissues which together appear to induce improved metabolic regulation and have direct and indirect effects on markers of CVD risk. SCFA produced primarily from the microbial fermentation of dietary fibre appear to be key mediators of the beneficial effects elicited by the gut microbiome. Not only does dietary fibre fermentation regulate microbial activity in the gut, SCFA also directly modulate host health through a range of tissue-specific mechanisms related to gut barrier function, glucose homeostasis, immunomodulation, appetite regulation and obesity. With the increasing burden of obesity worldwide, the role for gut microbiota-generated SCFA in protecting against the effects of energy dense diets offers an intriguing new avenue for regulating metabolic health and CVD risk.

Keywords: Appetite regulation; Blood pressure; Cardiovascular disease; Fermentation; Glucose homeostasis; Gut microbiome; Inflammation; Metabolic health; Obesity; Short-chain fatty acids.

Fig. 1

Overview of the mechanisms of action of SCFA in metabolic health and CVD. Acetate produced in microbial fermentation in the gut largely escapes first-pass metabolism in the liver. It can contribute acetyl units to lipogenesis in the cytosol of hepatocytes and adipocytes but its primary site of oxidation is peripheral muscle. It can also regulate adipose tissue lipolysis and can act on central appetite regulation. Propionate acts locally in the gut on enteroendocrine L-cells to stimulate release of the anorexigenic gut hormones PYY and GLP-1. Propionate is largely absorbed across the intestine and sequestrated primarily in the liver where it can be oxidised or used in gluconeogenesis. Butyrate is largely oxidised at the gut epithelium where it plays a central role in orchestrating the tight junction protein complexes to control gut barrier function. It also plays role in regulating inflammatory cell populations and function through receptor-mediated and histone deacetylation mechanisms. All three SCFA potentially play a role in blood pressure regulation; acetate and propionate through a complex interplay involving renin production mediated through Olfr78 and counter-regulation through FFAR3 and butyrate through attenuation of angiotensin II-induced expression of renal prorenin receptors and renin