Role of gut microbiota-generated short chain fatty acids in metabolic and cardiovascular health

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

Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods

Background: 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. Objectives: 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. Design: 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). Results: 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. Conclusion: 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

The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro

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

Effects of inulin propionate ester incorporated into palatable food products on appetite and resting energy expenditure: a randomised crossover study

Supplementation with inulin-propionate ester (IPE), which delivers propionate to the colon, suppresses ad libitum energy intake and stimulates the release of satiety hormones acutely in humans, and prevents weight gain. In order to determine whether IPE remains effective when incorporated into food products (FP), IPE needs to be added to a widely accepted food system. A bread roll and fruit smoothie were produced. Twenty-one healthy overweight and obese humans participated. Participants attended an acclimatisation visit and a control visit where they consumed un-supplemented food products (FP). Participants then consumed supplemented-FP, containing 10 g/d inulin or IPE for six days followed by a post-supplementation visit in a randomised crossover design. On study visits, supplemented-FP were consumed for the seventh time and ad libitum energy intake was assessed 420 min later. Blood samples were collected to assess hormones and metabolites. Resting energy expenditure (REE) was measured using indirect calorimetry. Taste and appearance ratings were similar between FP. Ad libitum energy intake was significantly different between treatments, due to a decreased intake following IPE-FP. These observations were not related to changes in blood hormones and metabolites. There was an increase in REE following IPE-FP. However, this effect was lost after correcting for changes in fat free mass. Our results suggest that IPE suppresses appetite and may alter REE following its incorporation into palatable food products

Postprandial ghrelin suppression is exaggerated following major surgery; implications for nutritional recovery

Meeting patients' nutritional requirements and preventing malnutrition is a challenge following major surgical procedures. The role of ghrelin in nutritional recovery after non-gastrointestinal major surgery is unknown. We used coronary artery bypass grafting (CABG) as an example of anticipated good recovery post major surgery

Impacts of plant-based foods in ancestral hominin diets on the metabolism and function of gut microbiota in vitro

Ancestral human populations had diets containing more indigestible plant material than present-day diets in industrialized countries. One hypothesis for the rise in prevalence of obesity is that physiological mechanisms for controlling appetite evolved to match a diet with plant fiber content higher than that of present-day diets. We investigated how diet affects gut microbiota and colon cells by comparing human microbial communities with those from a primate that has an extreme plant-based diet, namely, the gelada baboon, which is a grazer. The effects of potato (high starch) versus grass (high lignin and cellulose) diets on human-derived versus gelada-derived fecal communities were compared in vitro. We especially focused on the production of short-chain fatty acids, which are hypothesized to be key metabolites influencing appetite regulation pathways. The results confirmed that diet has a major effect on bacterial numbers, short-chain fatty acid production, and the release of hormones involved in appetite suppression. The potato diet yielded greater production of short-chain fatty acids and hormone release than the grass diet, even in the gelada cultures, which we had expected should be better adapted to the grass diet. The strong effects of diet on hormone release could not be explained, however, solely by short-chain fatty acid concentrations. Nuclear magnetic resonance spectroscopy found changes in additional metabolites, including betaine and isoleucine, that might play key roles in inhibiting and stimulating appetite suppression pathways. Our study results indicate that a broader array of metabolites might be involved in triggering gut hormone release in humans than previously thought. IMPORTANCE: One theory for rising levels of obesity in western populations is that the body's mechanisms for controlling appetite evolved to match ancestral diets with more low-energy plant foods. We investigated this idea by comparing the effects of diet on appetite suppression pathways via the use of gut bacterial communities from humans and gelada baboons, which are modern-day primates with an extreme diet of low-energy plant food, namely, grass. We found that diet does play a major role in affecting gut bacteria and the production of a hormone that suppresses appetite but not in the direction predicted by the ancestral diet hypothesis. Also, bacterial products were correlated with hormone release that were different from those normally thought to play this role. By comparing microbiota and diets outside the natural range for modern humans, we found a relationship between diet and appetite pathways that was more complex than previously hypothesized on the basis of more-controlled studies of the effects of single compounds

Changes in appetite related gut hormones in intensive care unit patients: a pilot cohort study

INTRODUCTION: The nutritional status of patients in the intensive care unit (ICU) appears to decline not only during their stay in the ICU but also after discharge from the ICU. Recent evidence suggests that gut released peptides, such as ghrelin and peptide YY (PYY) regulate the initiation and termination of meals and could play a role in the altered eating behaviour of sick patients. The aim of this study was to assess the patterns of ghrelin and PYY levels during the stay of ICU patients in hospital. METHODS: Sixteen ICU patients (60 ± 4.7 years, body mass index (BMI) 28.1 ± 1.7 kg/m(2 )(mean ± standard error of the mean)) underwent fasting blood sample collections on days 1, 3, 5, 14, 21 and 28 of their stay at Hammersmith and Charing Cross Hospitals. Changes in appetite and biochemical and anthropometric markers of nutritional status were recorded. A comparison was made to a group of 36 healthy volunteers matched for age and BMI (54.3 ± 2.9 years, p = 0.3; BMI 25.8 ± 0.8 kg/m(2 )p = 0.2). RESULTS: Compared to healthy subjects, ICU patients exhibited a significantly lower level of ghrelin (day one 297.8 ± 76.3 versus 827.2 ± 78.7 pmol/l, p < 0.001) during their stay in the ICU. This tended to rise to the normal level during the last three weeks of hospital stay. Conversely, ICU patients showed a significantly higher level of PYY (day one 31.5 ± 9.6 versus 11.3 ± 1.0 pmol/l, p < 0.05) throughout their stay in the ICU and on the ward, with a downward trend to the normal level during the last three weeks of stay. CONCLUSIONS: Results from our study show high levels of PYY and low levels of ghrelin in ICU patients compared to healthy controls. There appears to be a relationship between the level of these gut hormones and nutritional intake

APOE4 genotype exerts greater benefit in lowering plasma cholesterol and apolipoprotein B than wild type (E3/E3), after replacement of dietary saturated fats with low glycaemic index carbohydrates

We examined the impact of APOE genotype on plasma lipids and glucose in a secondary analysis of data from a five-arm, randomised controlled, parallel dietary intervention trial ('RISCK' study), to investigate the impact of replacing saturated fatty acids (SFA) with either monounsaturated fat (MUFA) or carbohydrate of high or low glycaemic index (GI) on CVD risk factors and insulin sensitivity. We tested the impact of APOE genotype (carriage of E2 and E4 alleles versus E3/E3), determined retrospectively, on plasma lipids, lipoproteins and glucose homeostasis at baseline (n = 469), and on the change in these variables after 24 weeks of dietary intervention (n = 389). At baseline, carriers of E2 (n = 70), E4 (n = 125) and E3/E3 (n = 274) expressed marked differences in total plasma cholesterol (TC, p = 0.001), low density lipoprotein cholesterol (LDL-C, p E3/E3 > E2. Following intervention, there was evidence of a significant diet x genotype interaction with significantly greater decreases in TC (p = 0.02) and apo B (p = 0.006) among carriers of E4 when SFA was replaced with low GI carbohydrate on a lower fat diet (TC -0.28 mmol/L p = 0.03; apo B -0.1 g/L p = 0.02), and a relative increase in TC (in comparison to E3/E3) when SFA was replaced with MUFA and high GI carbohydrates (TC 0.3 mmol/L, p = 0.03). Among carriers of E2 (compared with E3/E3) there was an increase in triacylglycerol (TAG) when SFA was replaced with MUFA and low GI carbohydrates 0.46 mmol/L p = 0.001). There were no significant interactions between APOE genotype and diet for changes in indices of glucose homeostasis. In conclusion, variations in APOE genotype led to differential effects on the lipid response to the replacement of SFA with MUFA and low GI carbohydrates

Spot and Cumulative Urine Samples Are Suitable Replacements for 24-Hour Urine Collections for Objective Measures of Dietary Exposure in Adults Using Metabolite Biomarkers

BACKGROUND: Measurement of multiple food intake exposure biomarkers in urine may offer an objective method for monitoring diet. The potential of spot and cumulative urine samples that have reduced burden on participants as replacements for 24-h urine collections has not been evaluated. OBJECTIVE: The aim of this study was to determine the utility of spot and cumulative urine samples for classifying the metabolic profiles of people according to dietary intake when compared with 24-h urine collections in a controlled dietary intervention study. METHODS: Nineteen healthy individuals (10 male, 9 female, aged 21-65 y, BMI 20-35 kg/m2) each consumed 4 distinctly different diets, each for 1 wk. Spot urine samples were collected ∼2 h post meals on 3 intervention days/wk. Cumulative urine samples were collected daily over 3 separate temporal periods. A 24-h urine collection was created by combining the 3 cumulative urine samples. Urine samples were analyzed with metabolite fingerprinting by both high-resolution flow infusion electrospray mass spectrometry (FIE-HRMS) and proton nuclear magnetic resonance spectroscopy (1H-NMR). Concentrations of dietary intake biomarkers were measured with liquid chromatography triple quadrupole mass spectrometry and by integration of 1H-NMR data. RESULTS: Cross-validation modeling with 1H-NMR and FIE-HRMS data demonstrated the power of spot and cumulative urine samples in predicting dietary patterns in 24-h urine collections. Particularly, there was no significant loss of information when post-dinner (PD) spot or overnight cumulative samples were substituted for 24-h urine collections (classification accuracies of 0.891 and 0.938, respectively). Quantitative analysis of urine samples also demonstrated the relation between PD spot samples and 24-h urines for dietary exposure biomarkers. CONCLUSIONS: We conclude that PD spot urine samples are suitable replacements for 24-h urine collections. Alternatively, cumulative samples collected overnight predict similarly to 24-h urine samples and have a lower collection burden for participants

An Analytical Pipeline for Quantitative Characterization of Dietary Intake:Application To Assess Grape Intake

Lack of accurate dietary assessment in free-living populations requires discovery of new biomarkers reflecting food intake qualitatively and quantitatively to objectively evaluate effects of diet on health. We provide a proof-of-principle for an analytical pipeline to identify quantitative dietary biomarkers. Tartaric acid was identified by nuclear magnetic resonance spectroscopy as a dose-responsive urinary biomarker of grape intake and subsequently quantified in volunteers following a series of 4-day dietary interventions incorporating 0 g/day, 50 g/day, 100 g/day, and 150 g/day of grapes in standardized diets from a randomized controlled clinical trial. Most accurate quantitative predictions of grape intake were obtained in 24 h urine samples which have the strongest linear relationship between grape intake and tartaric acid excretion (r² = 0.90). This new methodological pipeline for estimating nutritional intake based on coupling dietary intake information and quantified nutritional biomarkers was developed and validated in a controlled dietary intervention study, showing that this approach can improve the accuracy of estimating nutritional intakes