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Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: a randomised cross-over trial.
Chambers, ES, Byrne, CS, Morrison, DJ, Murphy, KG, Preston, T, Tedford, C, Garcia-Perez, I, Fountana, S, Serrano-Contreras, JI, Holmes, E, et al
Gut. 2019;68(8):1430-1438
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Literature shows that higher intakes of dietary fibre are associated with a reduced risk of type 2 diabetes. The main aim of this study was to elucidate the underlying mechanisms behind improvements in glucose homeostasis following long-term delivery of propionate (a short-chain fatty acid produced by human gut microbiota in response to dietary fibre) to the human colon. The study is a randomised, double-blind, placebo-controlled cross over trial. Fourteen participants randomly received 20 g/day of a low-fermentable fibre control, a high-fermentable fibre control and inulin-propionate ester (IPE) for 42 days each. Results indicate that stool concentrations of short-chain fatty acids were not different following the three supplementation periods. Furthermore, dietary supplementation with 20 g/day IPE promoted no superior impacts on measures of glucose homeostasis compared with inulin (high-fermentable fibre), yet both IPE and inulin improved insulin resistance relative to cellulose (low-fermentable fibre). Authors conclude that manipulating the colonic fermentation profile of a dietary fibre in favour of propionate promotes selective effects on the mechanisms that contribute to metabolic dysregulation.
Abstract
OBJECTIVE 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. DESIGN 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. RESULTS 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. CONCLUSION 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.
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The effects of dietary supplementation with inulin and inulin-propionate ester on hepatic steatosis in adults with non-alcoholic fatty liver disease.
Chambers, ES, Byrne, CS, Rugyendo, A, Morrison, DJ, Preston, T, Tedford, C, Bell, JD, Thomas, L, Akbar, AN, Riddell, NE, et al
Diabetes, obesity & metabolism. 2019;21(2):372-376
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Non-alcoholic fatty liver disease (NAFLD) is characterised by an accumulation of fat within the liver, and is strongly associated with obesity. Recent investigations suggest that diet, the gut microbiota and liver fat storage could be linked through a mechanism involving short chain fatty acids (SCFA), in particular the SCFA propionate, which are produced by the gut bacteria. The aim of this randomised controlled study was to evaluate whether an inulin-propionate ester (IPE) has benefits in patients with NAFLD. Subjects with NAFLD received either 20 g/d of inulin (control) or IPE for 42 days. 18 subjects completed the trial. Intrahepatocellular lipids IHCL (a marker of fat accumulation in the liver) increased post supplementation in both groups with no significant difference between control and IPE group. There was a change in insulin resistance (HOMA-IR) which was significantly different between groups, with a non-significant increase in the inulin-control group and decrease in the IPE group. There were no within- or between-group differences in body composition. The authors discuss these unexpected results and suggest that the SCFA acetate, from inulin fermentation by gut bacteria, may have led to an increase in IHCL which was attenuated by the propionate.
Abstract
The short chain fatty acid (SCFA) propionate, produced through fermentation of dietary fibre by the gut microbiota, has been shown to alter hepatic metabolic processes that reduce lipid storage. We aimed to investigate the impact of raising colonic propionate production on hepatic steatosis in adults with non-alcoholic fatty liver disease (NAFLD). Eighteen adults were randomized to receive 20 g/d of an inulin-propionate ester (IPE), designed to deliver propionate to the colon, or an inulin control for 42 days in a parallel design. The change in intrahepatocellular lipid (IHCL) following the supplementation period was not different between the groups (P = 0.082), however, IHCL significantly increased within the inulin-control group (20.9% ± 2.9% to 26.8% ± 3.9%; P = 0.012; n = 9), which was not observed within the IPE group (22.6% ± 6.9% to 23.5% ± 6.8%; P = 0.635; n = 9). The predominant SCFA from colonic fermentation of inulin is acetate, which, in a background of NAFLD and a hepatic metabolic profile that promotes fat accretion, may provide surplus lipogenic substrate to the liver. The increased colonic delivery of propionate from IPE appears to attenuate this acetate-mediated increase in IHCL.
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A study protocol for a randomised crossover study evaluating the effect of diets differing in carbohydrate quality on ileal content and appetite regulation in healthy humans.
Byrne, CS, Blunt, D, Burn, J, Chambers, E, Dagbasi, A, Franco Becker, G, Gibson, G, Mendoza, L, Murphy, K, Poveda, C, et al
F1000Research. 2019;:258
Abstract
Introduction: A major component of the digesta reaching the colon from the distal ileum is carbohydrate. This carbohydrate is subject to microbial fermentation and can radically change bacterial populations in the colon and the metabolites they produce, particularly short-chain fatty acids (SCFA). However, very little is currently known about the forms and levels of carbohydrate in the ileum and the composition of the ileal microbiota in humans. Most of our current understanding of carbohydrate that is not absorbed by the small intestine comes from ileostomy models, which may not reflect the physiology of an intact gastrointestinal tract. Methods: We will investigate how ileal content changes depending on diet using a randomised crossover study in healthy humans. Participants will be inpatients at the research facility for three separate 4-day visits. During each visit, participants will consume one of three diets, which differ in carbohydrate quality: 1) low-fibre refined diet; 2) high-fibre diet with intact cellular structures; 3) high-fibre diet where the cellular structures have been disrupted (e.g. milling, blending). On day 1, a nasoenteric tube will be placed into the distal ileum and its position confirmed under fluoroscopy. Ileal samples will be collected via the nasoenteric tube and metabolically profiled, which will determine the amount and type of carbohydrate present, and the composition of the ileal microbiota will be measured. Blood samples will be collected to assess circulating hormones and metabolites. Stool samples will be collected to assess faecal microbiota composition. Subjective appetite measures will be collected using visual analogue scales. Breath hydrogen will be measured in real-time as a marker of intestinal fermentation. Finally, an in vitro continuous fermentation model will be inoculated with ileal fluid in order to understand the shift in microbial composition and SCFA produced in the colon following the different diets. Registration: ISRCTN11327221.
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Effects of Inulin Propionate Ester Incorporated into Palatable Food Products on Appetite and Resting Energy Expenditure: A Randomised Crossover Study.
Byrne, CS, Chambers, ES, Preston, T, Tedford, C, Brignardello, J, Garcia-Perez, I, Holmes, E, Wallis, GA, Morrison, DJ, Frost, GS
Nutrients. 2019;(4)
Abstract
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.
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The effect of L-rhamnose on intestinal transit time, short chain fatty acids and appetite regulation: a pilot human study using combined 13CO2/H2 breath tests.
Byrne, CS, Preston, T, Brignardello, J, Garcia-Perez, I, Holmes, E, Frost, GS, Morrison, DJ
Journal of breath research. 2018;(4):046006
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Abstract
BACKGROUND The appetite-regulating effects of non-digestible carbohydrates (NDC) have in part previously been attributed to their effects on intestinal transit rates as well as microbial production of short chain fatty acids (SCFA). Increased colonic production of the SCFA propionate has been shown to reduce energy intake and stimulate gut hormone secretion acutely in humans. OBJECTIVE We investigated the effect of the propiogenic NDC, L-rhamnose, on gastrointestinal transit times using a combined 13CO2/H2 breath test. We hypothesised that L-rhamnose would increase plasma propionate leading to a reduction in appetite, independent of changes in gastrointestinal transit times. DESIGN We used a dual 13C-octanoic acid/lactose 13C-ureide breath test combined with breath H2 to measure intestinal transit times following the consumption of 25 g d-1 L-rhamnose, compared with inulin and cellulose, in 10 healthy humans in a randomised cross-over design pilot study. Gastric emptying (GE) and oro-caecal transit times (OCTTs) were derived from the breath 13C data and compared with breath H2. Plasma SCFA and peptide YY (PYY) were also measured alongside subjective measures of appetite. RESULTS L-rhamnose significantly slowed GE rates (by 19.5 min) but there was no difference in OCTT between treatments. However, breath H2 indicated fermentation of L-rhamnose before it reached the caecum. OCTT was highly correlated with breath H2 for inulin but not for L-rhamnose or cellulose. L-rhamnose consumption significantly increased plasma propionate and PYY but did not significantly reduce subjective appetite measures. CONCLUSIONS The NDCs tested had a minimal effect on intestinal transit time. Our data suggest that L-rhamnose is partially fermented in the small intestine and that breath H2 reflects the site of gastrointestinal fermentation and is only a reliable marker of OCTT for certain NDCs (e.g. inulin). Future studies should focus on investigating the appetite-suppressing potential of L-rhamnose and verifying the findings in a larger cohort.
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Acute oral sodium propionate supplementation raises resting energy expenditure and lipid oxidation in fasted humans.
Chambers, ES, Byrne, CS, Aspey, K, Chen, Y, Khan, S, Morrison, DJ, Frost, G
Diabetes, obesity & metabolism. 2018;(4):1034-1039
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Abstract
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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The role of short chain fatty acids in appetite regulation and energy homeostasis.
Byrne, CS, Chambers, ES, Morrison, DJ, Frost, G
International journal of obesity (2005). 2015;(9):1331-8
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Abstract
Over the last 20 years there has been an increasing interest in the influence of the gastrointestinal tract on appetite regulation. Much of the focus has been on the neuronal and hormonal relationship between the gastrointestinal tract and the brain. There is now mounting evidence that the colonic microbiota and their metabolic activity have a significant role in energy homeostasis. The supply of substrate to the colonic microbiota has a major impact on the microbial population and the metabolites they produce, particularly short chain fatty acids (SCFAs). SCFAs are produced when non-digestible carbohydrates, namely dietary fibres and resistant starch, undergo fermentation by the colonic microbiota. Both the consumption of fermentable carbohydrates and the administration of SCFAs have been reported to result in a wide range of health benefits including improvements in body composition, glucose homeostasis, blood lipid profiles and reduced body weight and colon cancer risk. However, published studies tend to report the effects that fermentable carbohydrates and SCFAs have on specific tissues and metabolic processes, and fail to explain how these local effects translate into systemic effects and the mitigation of disease risk. Moreover, studies tend to investigate SCFAs collectively and neglect to report the effects associated with individual SCFAs. Here, we bring together the recent evidence and suggest an overarching model for the effects of SCFAs on one of their beneficial aspects: appetite regulation and energy homeostasis.