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.
Summary
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.
A key metabolic activity of the gut microbiota is the fermentation of non-digestible carbohydrate, which generates short-chain fatty acids (SCFAs) as the principal end products. SCFAs are absorbed ...from the gut lumen and modulate host metabolic responses at different organ sites. Evidence suggests that these organ sites include skeletal muscle, the largest organ in humans, which plays a pivotal role in whole-body energy metabolism. In this Review, we evaluate the evidence indicating that SCFAs mediate metabolic cross-talk between the gut microbiota and skeletal muscle. We discuss the effects of three primary SCFAs (acetate, propionate and butyrate) on lipid, carbohydrate and protein metabolism in skeletal muscle, and we consider the potential mechanisms involved. Furthermore, we highlight the emerging roles of these gut-derived metabolites in skeletal muscle function and exercise capacity, present limitations in current knowledge and provide suggestions for future work.
In recent years, there has been a renewed interest in the role of dietary fibre in obesity management. Much of this interest stems from animal and human studies which suggest that an increased intake ...of fermentable fibre can suppress appetite and improve weight management. A growing number of reports have demonstrated that the principal products of colonic fermentation of dietary fibre, SCFA, contribute to energy homeostasis via effects on multiple cellular metabolic pathways and receptor-mediated mechanisms. In particular, over the past decade it has been identified that a widespread receptor system exists for SCFA. These G-protein-coupled receptors, free fatty acid receptor (FFAR) 2 and FFAR3 are expressed in numerous tissue sites, including the gut epithelium and adipose tissue. Investigations using FFAR2- or FFAR3-deficient animal models suggest that SCFA-mediated stimulation of these receptors enhances the release of the anorectic hormones peptide tyrosine tyrosine and glucagon-like peptide-1 from colonic L cells and leptin from adipocytes. In addition, the SCFA acetate has recently been shown to have a direct role in central appetite regulation. Furthermore, the SCFA propionate is a known precursor for hepatic glucose production, which has been reported to suppress feeding behaviour in ruminant studies through the stimulation of hepatic vagal afferents. The present review therefore proposes that an elevated colonic production of SCFA could stimulate numerous hormonal and neural signals at different organ and tissue sites that would cumulatively suppress short-term appetite and energy intake.
The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite ...regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.
To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.
Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.
These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.
NCT00750438.
Background
Skeletal muscle mass begins to decline from 40 years of age. Limited data suggest that dietary fibre may modify lean body mass (BM), of which skeletal muscle is the largest and most ...malleable component. We investigated the relationship between dietary fibre intake, skeletal muscle mass and associated metabolic and functional parameters in adults aged 40 years and older.
Methods
We analysed cross‐sectional data from the US National Health and Nutrition Examination Survey between 2011 and 2018 from adults aged 40 years and older. Covariate‐adjusted multiple linear regression analyses were used to evaluate the association between dietary fibre intake and BM components (BM, body mass index BMI, total lean mass, appendicular lean mass, bone mineral content, total fat, trunk fat; n = 6454), glucose homeostasis (fasting glucose, fasting insulin, HOMA2‐IR; n = 5032) and skeletal muscle strength (combined grip strength; n = 5326). BM components and skeletal muscle strength were expressed relative to BM (per kg of BM).
Results
Higher intakes of dietary fibre were significantly associated with increased relative total lean mass (β: 0.69 g/kg BM; 95% CI, 0.48–0.89 g/kg BM; P < 0.001), relative appendicular lean mass (β: 0.34 g/kg BM; 95% CI, 0.23–0.45 g/kg BM; P < 0.001), relative bone mineral content (β: 0.05 g/kg BM; 95% CI, 0.02–0.07 g/kg BM; P < 0.001) and relative combined grip strength (β: 0.002 kg/kg BM; 95% CI, 0.001–0.003 kg/kg BM; P < 0.001).
Conversely, higher dietary fibre intakes were significantly associated with a lower BM (β: −0.20; 95% CI, −0.28 to −0.11 kg; P < 0.001), BMI (β: −0.08 kg/m2; 95%CI, −0.10 to −0.05 kg/m2), relative total fat (β: −0.68 g/kg BM; 95% CI, −0.89 to −0.47 g/kg BM; P < 0.001), relative trunk fat (β: −0.48 g/kg BM; 95%CI, −0.63 to −0.33 g/kg; P < 0.001), fasting glucose (β: −0.01 mmol/L; 95% CI, −0.02 to −0.00 mmol/L; P = 0.017), fasting insulin (β: −0.71 pmol/L; 95% CI, −1.01 to −0.41 pmol/L; P < 0.001) and HOMA2‐IR (β: −0.02 AU; 95% CI, −0.02 to −0.01 AU; P < 0.001).
Conclusions
Higher dietary fibre intakes are associated with a lower BM and enhanced body composition, characterized by a reduction in fat mass and an increase in lean mass. Higher dietary fibre intakes were also associated with improvements in glucose homeostasis and skeletal muscle strength. Increasing dietary fibre intake may be a viable strategy to prevent age‐associated declines in skeletal muscle mass.
Aims
Diet‐derived short chain fatty acids (SCFAs) improve glucose homeostasis in vivo, but the role of individual SCFAs and their mechanisms of action have not been defined. This study evaluated the ...effects of increasing colonic delivery of the SCFA propionate on β‐cell function in humans and the direct effects of propionate on isolated human islets in vitro.
Materials and methods
For 24 weeks human subjects ingested an inulin‐propionate ester that delivers propionate to the colon. Acute insulin, GLP‐1 and non‐esterified fatty acid (NEFA) levels were quantified pre‐ and post‐supplementation in response to a mixed meal test. Expression of the SCFA receptor FFAR2 in human islets was determined by western blotting and immunohistochemistry. Dynamic insulin secretion from perifused human islets was quantified by radioimmunoassay and islet apoptosis was determined by quantification of caspase 3/7 activities.
Results
Colonic propionate delivery in vivo was associated with improved β‐cell function with increased insulin secretion that was independent of changes in GLP‐1 levels. Human islet β‐cells expressed FFAR2 and propionate potentiated dynamic glucose‐stimulated insulin secretion in vitro, an effect that was dependent on signalling via protein kinase C. Propionate also protected human islets from apoptosis induced by the NEFA sodium palmitate and inflammatory cytokines.
Conclusions
Our results indicate that propionate has beneficial effects on β‐cell function in vivo, and in vitro analyses demonstrated that it has direct effects to potentiate glucose‐stimulated insulin release and maintain β‐cell mass through inhibition of apoptosis. These observations support ingestion of propiogenic dietary fibres to maintain healthy glucose homeostasis.
Short-chain fatty acids (SCFAs), metabolites produced through the microbial fermentation of nondigestible dietary components, have key roles in energy homeostasis. Animal research suggests that ...colon-derived SCFAs modulate feeding behavior via central mechanisms. In humans, increased colonic production of the SCFA propionate acutely reduces energy intake. However, evidence of an effect of colonic propionate on the human brain or reward-based eating behavior is currently unavailable.
We investigated the effect of increased colonic propionate production on brain anticipatory reward responses during food picture evaluation. We hypothesized that elevated colonic propionate would reduce both reward responses and ad libitum energy intake via stimulation of anorexigenic gut hormone secretion.
In a randomized crossover design, 20 healthy nonobese men completed a functional magnetic resonance imaging (fMRI) food picture evaluation task after consumption of control inulin or inulin-propionate ester, a unique dietary compound that selectively augments colonic propionate production. The blood oxygen level-dependent (BOLD) signal was measured in a priori brain regions involved in reward processing, including the caudate, nucleus accumbens, amygdala, anterior insula, and orbitofrontal cortex (n = 18 had analyzable fMRI data).
Increasing colonic propionate production reduced BOLD signal during food picture evaluation in the caudate and nucleus accumbens. In the caudate, the reduction in BOLD signal was driven specifically by a lowering of the response to high-energy food. These central effects were partnered with a decrease in subjective appeal of high-energy food pictures and reduced energy intake during an ad libitum meal. These observations were not related to changes in blood peptide YY (PYY), glucagon-like peptide 1 (GLP-1), glucose, or insulin concentrations.
Our results suggest that colonic propionate production may play an important role in attenuating reward-based eating behavior via striatal pathways, independent of changes in plasma PYY and GLP-1. This trial was registered at clinicaltrials.gov as NCT00750438.
To investigate the underlying mechanisms behind changes in glucose homeostasis with delivery of propionate to the human colon by comprehensive and coordinated analysis of gut bacterial composition, ...plasma metabolome and immune responses.
Twelve non-diabetic adults with overweight and obesity received 20 g/day of inulin-propionate ester (IPE), designed to selectively deliver propionate to the colon, a high-fermentable fibre control (inulin) and a low-fermentable fibre control (cellulose) in a randomised, double-blind, placebo-controlled, cross-over design. Outcome measurements of metabolic responses, inflammatory markers and gut bacterial composition were analysed at the end of each 42-day supplementation period.
Both IPE and inulin supplementation improved insulin resistance compared with cellulose supplementation, measured by homeostatic model assessment 2 (mean±SEM 1.23±0.17 IPE vs 1.59±0.17 cellulose, p=0.001; 1.17±0.15 inulin vs 1.59±0.17 cellulose, p=0.009), with no differences between IPE and inulin (p=0.272). Fasting insulin was only associated positively with plasma tyrosine and negatively with plasma glycine following inulin supplementation. IPE supplementation decreased proinflammatory interleukin-8 levels compared with cellulose, while inulin had no impact on the systemic inflammatory markers studied. Inulin promoted changes in gut bacterial populations at the class level (increased Actinobacteria and decreased Clostridia) and order level (decreased Clostridiales) compared with cellulose, with small differences at the species level observed between IPE and cellulose.
These data demonstrate a distinctive physiological impact of raising colonic propionate delivery in humans, as improvements in insulin sensitivity promoted by IPE and inulin were accompanied with different effects on the plasma metabolome, gut bacterial populations and markers of systemic inflammation.
Accurate monitoring of changes in dietary patterns in response to food policy implementation is challenging. Metabolic profiling allows simultaneous measurement of hundreds of metabolites in urine, ...the concentrations of which can be affected by food intake. We hypothesised that metabolic profiles of urine samples developed under controlled feeding conditions reflect dietary intake and can be used to model and classify dietary patterns of free-living populations.
In this randomised, controlled, crossover trial, we recruited healthy volunteers (aged 21–65 years, BMI 20–35 kg/m2) from a database of a clinical research unit in the UK. We developed four dietary interventions with a stepwise variance in concordance with the WHO healthy eating guidelines that aim to prevent non-communicable diseases (increase fruits, vegetables, whole grains, and dietary fibre; decrease fats, sugars, and salt). Participants attended four inpatient stays (72 h each, separated by at least 5 days), during which they were given one dietary intervention. The order of diets was randomly assigned across study visits. Randomisation was done by an independent investigator, with the use of opaque, sealed, sequentially numbered envelopes that each contained one of the four dietary interventions in a random order. Participants and investigators were not masked from the dietary intervention, but investigators analysing the data were masked from the randomisation order. During each inpatient period, urine was collected daily over three timed periods: morning (0900–1300 h), afternoon (1300–1800 h), and evening and overnight (1800–0900 h); 24 h urine samples were obtained by pooling these samples. Urine samples were assessed by proton nuclear magnetic resonance (1H-NMR) spectroscopy, and diet-discriminatory metabolites were identified. We developed urinary metabolite models for each diet and identified the associated metabolic profiles, and then validated the models using data and samples from the INTERMAP UK cohort (n=225) and a healthy-eating Danish cohort (n=66). This study is registered with ISRCTN, number ISRCTN43087333.
Between Aug 13, 2013, and May 18, 2014, we contacted 300 people with a letter of invitation. 78 responded, of whom 26 were eligible and invited to attend a health screening. Of 20 eligible participants who were randomised, 19 completed all four 72 h study stays between Oct 2, 2013, and July 29, 2014, and consumed all the food provided. Analysis of 1H-NMR spectroscopy data indicated that urinary metabolic profiles of the four diets were distinct. Significant stepwise differences in metabolite concentrations were seen between diets with the lowest and highest metabolic risks. Application of the derived metabolite models to the validation datasets confirmed the association between urinary metabolic and dietary profiles in the INTERMAP UK cohort (p<0·0001) and the Danish cohort (p<0·0001).
Urinary metabolite models developed in a highly controlled environment can classify groups of free-living people into consumers of diets associated with lower or higher non-communicable disease risk on the basis of multivariate metabolite patterns. This approach enables objective monitoring of dietary patterns in population settings and enhances the validity of dietary reporting.
UK National Institute for Health Research and UK Medical Research Council.
Short‐chain fatty acids (SCFAs), produced from fermentation of dietary fibre by the gut microbiota, have been suggested to modulate energy metabolism. Previous work using rodent models has ...demonstrated that oral supplementation of the SCFA propionate raises resting energy expenditure (REE) by promoting lipid oxidation. The objective of the present study was to investigate the effects of oral sodium propionate on REE and substrate metabolism in humans. Eighteen healthy volunteers (9 women and 9 men; age 25 ± 1 years; body mass index 24.1 ± 1.2 kg/m2) completed 2 study visits following an overnight fast. Tablets containing a total of 6845 mg sodium propionate or 4164 mg sodium chloride were provided over the 180‐minute study period in random order. REE and substrate oxidation were assessed by indirect calorimetry. Oral sodium propionate administration increased REE (0.045 ± 0.020 kcal/min; P = .036); this was accompanied by elevated rates of whole‐body lipid oxidation (0.012 ± 0.006 g/min; P = .048) and was independent of changes in glucose and insulin concentrations. Future studies are warranted to determine whether the acute effects of oral sodium propionate on REE translate into positive improvements in long‐term energy balance in humans.
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