Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults

Edward S Chambers, Alexander Viardot, Arianna Psichas, Douglas J Morrison, Kevin G Murphy, Sagen E K Zac-Varghese, Kenneth MacDougall, Tom Preston, Catriona Tedford, Graham S Finlayson, John E Blundell, Jimmy D Bell, E Louise Thomas, Shahrul Mt-Isa, Deborah Ashby, Glen R Gibson, Sofia Kolida, Waljit S Dhillo, Stephen R Bloom, Wayne Morley, Stuart Clegg, Gary Frost, Edward S Chambers, Alexander Viardot, Arianna Psichas, Douglas J Morrison, Kevin G Murphy, Sagen E K Zac-Varghese, Kenneth MacDougall, Tom Preston, Catriona Tedford, Graham S Finlayson, John E Blundell, Jimmy D Bell, E Louise Thomas, Shahrul Mt-Isa, Deborah Ashby, Glen R Gibson, Sofia Kolida, Waljit S Dhillo, Stephen R Bloom, Wayne Morley, Stuart Clegg, Gary Frost

Abstract

Objective: 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.

Design: 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.

Results: 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.

Conclusions: These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.

Trial registration number: NCT00750438.

Keywords: APPETITE; COLONIC FERMENTATION; GUT HORMONES; NUTRITIONAL SUPPLEMENTATION; OBESITY.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Figure 1
Figure 1
Propionate increases peptide YY (PYY) and glucagon like peptide-1 (GLP-1) release from primary human colonic cells and inulin-propionate ester supplementation delivers propionate to the colon in vivo. Cells isolated from human colonic tissue were incubated with increasing concentrations of propionate. (A) PYY and (B) GLP-1 levels were measured in the supernatants and lysed cells by radioimmunoassay. Percentage gut hormone release per well is expressed relative to the basal release measured (n=4–6). (C) The increase in breath H2 at 240 min suggests that >80% of the labelled propionate entered the colon. (D) Plasma acetate and propionate 13C enrichment (δ13C per mil) at baseline and 360 min. Plasma propionate was significantly more enriched at 360 min whereas no difference was seen in acetate enrichment. Total plasma propionate (E) and acetate (F) concentrations (µmol/L) at baseline and 360 min. Data are presented as mean±SEM, *p<0.05, ***p<0.001.
Figure 2
Figure 2
Acute inulin-propionate ester supplementation increases plasma peptide YY (PYY) and glucagon like peptide-1 (GLP-1) levels and reduces energy intake in humans. (A) The mean reduction in energy intake following inulin-control versus inulin-propionate ester. (B) A reduction in energy intake occurred in 16 of the 20 volunteers. (C–F) Plasma gut hormone levels following acute supplementation of inulin-control versus inulin-propionate ester. Arrows indicate standardised meals. Dotted lines signify the time point after which >80% inulin-propionate ester enters the colon as determined by the enrichment of 13C in expired air and breath H2 methodology (figure 1C). Data are presented as mean±SEM, *p<0.05, **p<0.01. AUC, area under the curve.
Figure 3
Figure 3
The effect of 24 weeks inulin-control and inulin-propionate ester supplementation on weight gain, liver fat content and gut hormone response. (A) The proportion of subjects who gained 3% or more and 5% or more of their baseline weight at 24 weeks. (B) Intrahepatocellular lipid (IHCL) content at baseline and following 24 weeks of inulin-control and inulin-propionate ester supplementation in subjects with non-alcoholic fatty liver disease (NAFLD). Subjects were identified as having NAFLD on the basis of an IHCL content >5.5% at baseline. Postprandial plasma (C) peptide YY (PYY) and (D) GLP-1 release at baseline and following 24 weeks of inulin-control and inulin-propionate ester supplementation. Data are presented as mean±SEM, *p

Figure 4

The effect of inulin-propionate ester…

Figure 4

The effect of inulin-propionate ester on the gut microbiota. Bacterial concentrations expressed in…

Figure 4
The effect of inulin-propionate ester on the gut microbiota. Bacterial concentrations expressed in Log10 cells/mL culture fluid enumerated using fluorescent in situ hybridisation (FISH) targeting (A) Bifidobacterium spp (Bif164), (B) Bacteroides/Prevotella (Bac303), (C) Atopobium cluster (Ato291), (D) Lactobacillus/Enterococcus (Lab158), (E) Clostridium histolyticum (Chis150) and (F) Eubacterium rectale/Clostridium coccoides (Erec482) at 0 h, 10 h, 24 h, 34 h and 48 h anaerobic, pH controlled faecal batch culture fermentation with control (no substrate), inulin-control and inulin-propionate ester. Data are presented as mean±SEM (n=3), *<0.05, †<0.001, ‡<0.0001 with respect to the 0 h sample.
Figure 4
Figure 4
The effect of inulin-propionate ester on the gut microbiota. Bacterial concentrations expressed in Log10 cells/mL culture fluid enumerated using fluorescent in situ hybridisation (FISH) targeting (A) Bifidobacterium spp (Bif164), (B) Bacteroides/Prevotella (Bac303), (C) Atopobium cluster (Ato291), (D) Lactobacillus/Enterococcus (Lab158), (E) Clostridium histolyticum (Chis150) and (F) Eubacterium rectale/Clostridium coccoides (Erec482) at 0 h, 10 h, 24 h, 34 h and 48 h anaerobic, pH controlled faecal batch culture fermentation with control (no substrate), inulin-control and inulin-propionate ester. Data are presented as mean±SEM (n=3), *<0.05, †<0.001, ‡<0.0001 with respect to the 0 h sample.

References

    1. Hussain SS, Bloom SR. The regulation of food intake by the gut-brain axis: implications for obesity. Int J Obes (Lond) 2013;37:625–33.
    1. Zhao L. The gut microbiota and obesity: from correlation to causality. Nat Rev Microbiol 2013;11:639–47.
    1. Cani PD. Metabolism in 2013: the gut microbiota manages host metabolism. Nat Rev Endocrinol 2014;10:74–6.
    1. Ridaura VK, Faith JJ, Rey FE, et al. . Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013;341:1241214.
    1. Liou AP, Paziuk M, Luevano JM Jr, et al. . Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med 2013;5:178ra41.
    1. Williamson DF, Kahn HS, Remington PL, et al. . The 10-year incidence of overweight and major weight gain in US adults. Arch Intern Med 1990;150:665–72.
    1. Mozaffarian D, Hao T, Rimm EB, et al. . Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med 2011;364:2392–404.
    1. Peeters A, Magliano DJ, Backholer K, et al. . Changes in the rates of weight and waist circumference gain in Australian adults over time: a longitudinal cohort study. BMJ Open 2014;4:e003667.
    1. Heitmann BL, Garby L. Patterns of long-term weight changes in overweight developing Danish men and women aged between 30 and 60 years. Int J Obes Relat Metab Disord 1999;23:1074–8.
    1. Zhai F, Wang H, Wang Z, et al. . Closing the energy gap to prevent weight gain in China. Obes Rev 2008;9(Suppl 1):107–12.
    1. Liu S, Willett WC, Manson JE, et al. . Relation between changes in intakes of dietary fiber and grain products and changes in weight and development of obesity among middle-aged women. Am J Clin Nutr 2003;78:920–7.
    1. Ludwig DS, Pereira MA, Kroenke CH, et al. . Dietary fiber, weight gain, and cardiovascular disease risk factors in young adults. JAMA 1999;282:1539–46.
    1. Maskarinec G, Takata Y, Pagano I, et al. . Trends and dietary determinants of overweight and obesity in a multiethnic population. Obesity (Silver Spring) 2006;14:717–26.
    1. Wanders AJ, van den Borne JJ, de Graaf C, et al. . Effects of dietary fibre on subjective appetite, energy intake and body weight: a systematic review of randomized controlled trials. Obes Rev 2011;12:724–39.
    1. Cani PD, Neyrinck AM, Maton N, et al. . Oligofructose promotes satiety in rats fed a high-fat diet: involvement of glucagon-like Peptide-1. Obes Res 2005;13:1000–7.
    1. Anastasovska J, Arora T, Sanchez Canon GJ, et al. . Fermentable carbohydrate alters hypothalamic neuronal activity and protects against the obesogenic environment. Obesity (Silver Spring) 2012;20:1016–23.
    1. Cani PD, Joly E, Horsmans Y, et al. . Oligofructose promotes satiety in healthy human: a pilot study. Eur J Clin Nutr 2006;60:567–72.
    1. Rigaud D, Ryttig KR, Angel LA, et al. . Overweight treated with energy restriction and a dietary fibre supplement: a 6-month randomized, double-blind, placebo-controlled trial. Int J Obes 1990;14:763–9.
    1. Howarth NC, Saltzman E, Roberts SB. Dietary fiber and weight regulation. Nutr Rev 2001;59:129–39.
    1. Howarth NC, Saltzman E, McCrory MA, et al. . Fermentable and nonfermentable fiber supplements did not alter hunger, satiety or body weight in a pilot study of men and women consuming self-selected diets. J Nutr 2003;133:3141–4.
    1. Tolhurst G, Heffron H, Lam YS, et al. . Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein-Coupled Receptor FFAR2. Diabetes 2012;61:364–71.
    1. Cherbut C, Ferrier L, Roze C, et al. . Short-chain fatty acids modify colonic motility through nerves and polypeptide YY release in the rat. Am J Physiol 1998;275(6 Pt 1):G1415–22.
    1. Anini Y, Fu-Cheng X, Cuber JC, et al. . Comparison of the postprandial release of peptide YY and proglucagon-derived peptides in the rat. Pflugers Arch 1999;438:299–306.
    1. Murphy KG, Bloom SR. Gut hormones and the regulation of energy homeostasis. Nature 2006;444:854–9.
    1. Batterham RL, Cohen MA, Ellis SM, et al. . Inhibition of food intake in obese subjects by peptide YY3–36. N Engl J Med 2003;349:941–8.
    1. Turton MD, O'Shea D, Gunn I, et al. . A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996;379:69–72.
    1. Batterham RL, Cowley MA, Small CJ, et al. . Gut hormone PYY(3–36) physiologically inhibits food intake. Nature 2002;418:650–4.
    1. Brown AJ, Goldsworthy SM, Barnes AA, et al. . The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 2003;278:11312–19.
    1. Le Poul E, Loison C, Struyf S, et al. . Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem 2003;278:25481–9.
    1. Morrison DJ, Mackay WG, Edwards CA, et al. . Butyrate production from oligofructose fermentation by the human faecal flora: what is the contribution of extracellular acetate and lactate? Br J Nutr 2006;96:570–7.
    1. Cummings JH, Pomare EW, Branch WJ, et al. . Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 1987;28:1221–7.
    1. Reimann F, Habib AM, Tolhurst G, et al. . Glucose sensing in L cells: a primary cell study. Cell Metab 2008;8:532–9.
    1. Thomas EL, Parkinson JR, Frost GS, et al. . The missing risk: MRI and MRS phenotyping of abdominal adiposity and ectopic fat. Obesity (Silver Spring) 2012;20:76–87.
    1. Adrian TE, Ferri GL, Bacarese-Hamilton AJ, et al. . Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 1985;89:1070–7.
    1. Kreymann B, Williams G, Ghatei MA, et al. . Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 1987;2:1300–4.
    1. Flint A, Raben A, Blundell JE, et al. . Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab Disord 2000;24:38–48.
    1. Papke LE, Wooldridge JM. Econometric methods for fractional response variables with an application to 401(k) plan participation rates. Journal of Applied Econometrics 1996;11:619–32.
    1. Szczepaniak LS, Nurenberg P, Leonard D, et al. . Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005;288:E462–8.
    1. le Roux CW, Batterham RL, Aylwin SJ, et al. . Attenuated peptide YY release in obese subjects is associated with reduced satiety. Endocrinology 2006;147:3–8.
    1. Pedersen C, Lefevre S, Peters V, et al. . Gut hormone release and appetite regulation in healthy non-obese participants following oligofructose intake. A dose-escalation study. Appetite 2013;66:44–53.
    1. David LA, Maurice CF, Carmody RN, et al. . Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014;505:559–63.
    1. James WP. Treatment of obesity: the constraints on success. Clin Endocrinol Metab 1984;13:635–59.
    1. Daubioul C, Rousseau N, Demeure R, et al. . Dietary fructans, but not cellulose, decrease triglyceride accumulation in the liver of obese Zucker fa/fa rats. J Nutr 2002;132:967–73.
    1. Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006;444:881–7.
    1. Zaibi MS, Stocker CJ, O'Dowd J, et al. . Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS Lett 2010;584:2381–6.
    1. Kimura I, Inoue D, Maeda T, et al. . Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci U S A 2011;108:8030–5.
    1. Kimura I, Ozawa K, Inoue D, et al. . The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun 2013;4:1829.
    1. De Vadder F, Kovatcheva-Datchary P, Goncalves D, et al. . Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits. Cell 2014;156:84–96.
    1. Daud NM, Ismail NA, Thomas EL, et al. . The impact of oligofructose on stimulation of gut hormones, appetite regulation and adiposity. Obesity (Silver Spring) 2014;22:1430–8.
    1. Beylot M. Effects of inulin-type fructans on lipid metabolism in man and in animal models. Br J Nutr 2005;93(Suppl 1):S163–8.

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