The connection between the gut microbiota and the aetiology of obesity and cardiometabolic disorders is increasingly being recognized by clinicians. Our gut microbiota might affect the cardiometabolic phenotype by fermenting indigestible dietary components and thereby producing short-chain fatty acids (SCFA). These SCFA are not only of importance in gut health and as signalling molecules, but might also enter the systemic circulation and directly affect metabolism or the function of peripheral tissues. In this Review, we discuss the effects of three SCFA (acetate, propionate and butyrate) on energy homeostasis and metabolism, as well as how these SCFA can beneficially modulate adipose tissue, skeletal muscle and liver tissue function. As a result, these SCFA contribute to improved glucose homeostasis and insulin sensitivity. Furthermore, we also summarize the increasing evidence for a potential role of SCFA as metabolic targets to prevent and counteract obesity and its associated disorders in glucose metabolism and insulin resistance. However, most data are derived from animal and in vitro studies, and consequently the importance of SCFA and differential SCFA availability in human energy and substrate metabolism remains to be fully established. Well-controlled human intervention studies investigating the role of SCFA on cardiometabolic health are, therefore, eagerly awaited.

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Evidence is accumulating that short chain fatty acids (SCFA) play an important role in the maintenance of gut and metabolic health. The SCFA acetate, propionate and butyrate are produced from the microbial fermentation of indigestible carbohydrates and appear to be key mediators of the beneficial effects elicited by the gut microbiome. Microbial SCFA production is essential for gut integrity by regulating the luminal pH, mucus production, providing fuel for epithelial cells and effects on mucosal immune function. SCFA also directly modulate host metabolic health through a range of tissue-specific mechanisms related to appetite regulation, energy expenditure, glucose homeostasis and immunomodulation. Therefore, an increased microbial SCFA production can be considered as a health benefit, but data are mainly based on animal studies, whereas well-controlled human studies are limited. In this review an expert group by ILSI Europe’s Prebiotics Task Force discussed the current scientific knowledge on SCFA to consider the relationship between SCFA and gut and metabolic health with a particular focus on human evidence. Overall, the available mechanistic data and limited human data on the metabolic consequences of elevated gut-derived SCFA production strongly suggest that increasing SCFA production could be a valuable strategy in the preventing gastro-intestinal dysfunction, obesity and type 2 diabetes mellitus. Nevertheless, there is an urgent need for well controlled longer term human SCFA intervention studies, including measurement of SCFA fluxes and kinetics, the heterogeneity in response based on metabolic phenotype, the type of dietary fibre and fermentation site in fibre intervention studies and the control for factors that could shape the microbiome like diet, physical activity and use of medication.

The interplay of gut microbiota, host metabolism, and metabolic health has gained increased attention. Gut microbiota may play a regulatory role in gastrointestinal health, substrate metabolism, and peripheral tissues including adipose tissue, skeletal muscle, liver, and pancreas via its metabolites short-chain fatty acids (SCFA). Animal and human data demonstrated that, in particular, acetate beneficially affects host energy and substrate metabolism via secretion of the gut hormones like glucagon-like peptide-1 and peptide YY, which, thereby, affects appetite, via a reduction in whole-body lipolysis, systemic pro-inflammatory cytokine levels, and via an increase in energy expenditure and fat oxidation. Thus, potential therapies to increase gut microbial fermentation and acetate production have been under vigorous scientific scrutiny. In this review, the relevance of the colonically and systemically most abundant SCFA acetate and its effects on the previously mentioned tissues will be discussed in relation to body weight control and glucose homeostasis. We discuss in detail the differential effects of oral acetate administration (vinegar intake), colonic acetate infusions, acetogenic fiber, and acetogenic probiotic administrations as approaches to combat obesity and comorbidities. Notably, human data are scarce, which highlights the necessity for further human research to investigate acetate’s role in host physiology, metabolic, and cardiovascular health.

Short-chain fatty acids (SCFA), formed by microbial fermentation, are believed to be involved in the aetiology of obesity and diabetes. This study investigated the effects of colonic administration of physiologically relevant SCFA mixtures on human substrate and energy metabolism. In this randomized, double-blind, crossover study, twelve normoglycaemic men (BMI 25–35 kg/m2) underwent four investigational days, during which SCFA mixtures (200 mmol/L) high in either acetate (HA), propionate (HP), butyrate (HB) or placebo (PLA) were rectally administered during fasting and postprandial conditions (oral glucose load). Before and for two hours after colonic infusions, indirect calorimetry was performed and blood samples were collected. All three SCFA mixtures increased fasting fat oxidation (P < 0.01), whilst resting energy expenditure increased after HA and HP compared with PLA (P < 0.05). In addition, all three SCFA mixtures increased fasting and postprandial plasma peptide YY (PYY) concentrations, and attenuated fasting free glycerol concentrations versus PLA (P < 0.05). Colonic infusions of SCFA mixtures, in concentrations and ratios reached after fibre intake, increased fat oxidation, energy expenditure and PYY, and decreased lipolysis in overweight/obese men. Human intervention studies are warranted to investigate whether these effects translate into long-term benefits for body weight control and insulin sensitivity in the obese insulin resistant state.

Microbial-derived short-chain fatty acids (SCFA) acetate, propionate and butyrate may provide a link between gut microbiota and whole-body insulin sensitivity (IS). In this cross-sectional study (160 participants, 64% male, BMI: 19.2–41.0 kg/m 2 , normal or impaired glucose metabolism), associations between SCFA (faecal and fasting circulating) and circulating metabolites, substrate oxidation and IS were investigated. In a subgroup (n = 93), IS was determined using a hyperinsulinemic-euglycemic clamp. Data were analyzed using multiple linear regression analysis adjusted for sex, age and BMI. Fasting circulating acetate, propionate and butyrate concentrations were positively associated with fasting GLP-1 concentrations. Additionally, circulating SCFA were negatively related to whole-body lipolysis (glycerol), triacylglycerols and free fatty acids levels (standardized (std) β adjusted (adj) −0.190, P = 0.023; std β adj −0.202, P = 0.010; std β adj −0.306, P = 0.001, respectively). Circulating acetate and propionate were, respectively, negatively and positively correlated with IS (M-value: std β adj −0.294, P < 0.001; std β adj 0.161, P = 0.033, respectively). We show that circulating rather than faecal SCFA were associated with GLP-1 concentrations, whole-body lipolysis and peripheral IS in humans. Therefore, circulating SCFA are more directly linked to metabolic health, which indicates the need to measure circulating SCFA in human prebiotic/probiotic intervention studies as a biomarker/mediator of effects on host metabolism.

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Gut microbial-derived short-chain fatty acids (SCFA) are believed to affect host metabolism and cardiometabolic risk factors. The present study aim was to investigate the effects of proximal and distal colonic infusions with the SCFA acetate on fat oxidation and other metabolic parameters in men. In this randomized, double-blind crossover trial, six overweight/obese men [body mass index (BMI) 25-35 kg/m] underwent two experimental periods: one with distal and one with proximal colonic sodium acetate infusions. A feeding catheter was endoscopically positioned at the beginning of each period and remained in the colon for three consecutive test days, enabling colonic acetate (100 or 180 mmol/l) or placebo infusion during fasting conditions and after an oral glucose load (postprandial). Fat oxidation and energy expenditure were measured using an open-circuit ventilated hood system and blood samples were repeatedly collected for 2 h during fasting and postprandial conditions. Distal colonic 180 mmol/l acetate infusions increased fasting fat oxidation (1.78±0.28 compared with -0.78±0.89 g fat 2 h, P=0.015), fasting peptide YY (PYY, P=0.01) and postprandial glucose and insulin concentrations (P<0.05), and tended to increase fasting plasma acetate (P=0.069) compared with placebo. Distal 100 mmol/l acetate administration tended to decrease fasting tumour necrosis factor-α (TNF-α; P=0.067) compared with placebo. In contrast, proximal colonic acetate infusions showed no effects on substrate metabolism, circulating hormones or inflammatory markers. In conclusion distal colonic acetate infusions affected whole-body substrate metabolism, with a pronounced increase in fasting fat oxidation and plasma PYY. Modulating colonic acetate may be a nutritional target to treat or prevent metabolic disorders.