Circulating but not faecal short-chain fatty acids are related to insulin sensitivity, lipolysis and GLP-1 concentrations in humans

Mattea Müller, Manuel A González Hernández, Gijs H Goossens, Dorien Reijnders, Jens J Holst, Johan W E Jocken, Hans van Eijk, Emanuel E Canfora, Ellen E Blaak, Mattea Müller, Manuel A González Hernández, Gijs H Goossens, Dorien Reijnders, Jens J Holst, Johan W E Jocken, Hans van Eijk, Emanuel E Canfora, Ellen E Blaak

Abstract

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/m2, 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.

Conflict of interest statement

The authors declare no competing interests.

References

    1. Macfarlane GT, Macfarlane S. Bacteria, Colonic Fermentation, and Gastrointestinal Health. Journal of AOAC International. 2012;95:50–60. doi: 10.5740/jaoacint.SGE_Macfarlane.
    1. Schwiertz A, et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring, Md.) 2010;18:190–195. doi: 10.1038/oby.2009.167.
    1. Fernandes J, Su W, Rahat-Rozenbloom S, Wolever TMS, Comelli EM. Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans. Nutrition & Diabetes. 2014;4:e121. doi: 10.1038/nutd.2014.23.
    1. Roediger WE. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut. 1980;21:793–798. doi: 10.1136/gut.21.9.793.
    1. Boets E, et al. Systemic availability and metabolism of colonic‐derived short‐chain fatty acids in healthy subjects: a stable isotope study. The Journal of Physiology. 2017;595:541–555. doi: 10.1113/JP272613.
    1. Kroger J, et al. Erythrocyte membrane phospholipid fatty acids, desaturase activity, and dietary fatty acids in relation to risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. The American journal of clinical nutrition. 2011;93:127–142. doi: 10.3945/ajcn.110.005447.
    1. Bloemen JG, et al. Short chain fatty acids exchange across the gut and liver in humans measured at surgery. Clinical Nutrition. 2009;28:657–661. doi: 10.1016/j.clnu.2009.05.011.
    1. Tang Cong, Ahmed Kashan, Gille Andreas, Lu Shun, Gröne Hermann-Josef, Tunaru Sorin, Offermanns Stefan. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nature Medicine. 2015;21(2):173–177. doi: 10.1038/nm.3779.
    1. Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell. 2016;165:1332–1345. doi: 10.1016/j.cell.2016.05.041.
    1. Priyadarshini M, et al. An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion. Molecular Endocrinology. 2015;29:1055–1066. doi: 10.1210/me.2015-1007.
    1. Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol. 2015;11:577–591. doi: 10.1038/nrendo.2015.128.
    1. van der Beek CM, et al. Distal, not proximal, colonic acetate infusions promote fat oxidation and improve metabolic markers in overweight/obese men. Clinical science (London, England: 1979) 2016;130:2073–2082. doi: 10.1042/cs20160263.
    1. Canfora EE, et al. Colonic infusions of short-chain fatty acid mixtures promote energy metabolism in overweight/obese men: a randomized crossover trial. Scientific Reports. 2017;7:2360. doi: 10.1038/s41598-017-02546-x.
    1. Wolever TM, Spadafora P, Eshuis H. Interaction between colonic acetate and propionate in humans. The American journal of clinical nutrition. 1991;53:681–687. doi: 10.1093/ajcn/53.3.681.
    1. Wolever TM, Brighenti F, Royall D, Jenkins AL, Jenkins DJ. Effect of rectal infusion of short chain fatty acids in human subjects. The American journal of gastroenterology. 1989;84:1027–1033.
    1. Chambers ES, et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut. 2015;64:1744–1754. doi: 10.1136/gutjnl-2014-307913.
    1. Perry RJ, et al. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature. 2016;534:213–217. doi: 10.1038/nature18309.
    1. Rahat-Rozenbloom S, Fernandes J, Gloor GB, Wolever TM. Evidence for greater production of colonic short-chain fatty acids in overweight than lean humans. International journal of obesity (2005) 2014;38:1525–1531. doi: 10.1038/ijo.2014.46.
    1. Teixeira TF, et al. Higher level of faecal SCFA in women correlates with metabolic syndrome risk factors. The British journal of nutrition. 2013;109:914–919. doi: 10.1017/s0007114512002723.
    1. Turnbaugh PJ, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031. doi: 10.1038/nature05414.
    1. Murphy EF, et al. Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut. 2010;59:1635–1642. doi: 10.1136/gut.2010.215665.
    1. McNeil NI, Cummings JH, James WP. Short chain fatty acid absorption by the human large intestine. Gut. 1978;19:819–822. doi: 10.1136/gut.19.9.819.
    1. Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiological reviews. 2001;81:1031–1064. doi: 10.1152/physrev.2001.81.3.1031.
    1. Ruppin H, Bar-Meir S, Soergel KH, Wood CM, Schmitt MG., Jr. Absorption of short-chain fatty acids by the colon. Gastroenterology. 1980;78:1500–1507. doi: 10.1016/S0016-5085(19)30508-6.
    1. Rechkemmer G, Rönnau K, Engelhardt WV. Fermentation of polysaccharides and absorption of short chain fatty acids in the mammalian hindgut. Comparative Biochemistry and Physiology Part A: Physiology. 1988;90:563–568. doi: 10.1016/0300-9629(88)90668-8.
    1. de la Cuesta-Zuluaga Jacobo, Mueller Noel, Álvarez-Quintero Rafael, Velásquez-Mejía Eliana, Sierra Jelver, Corrales-Agudelo Vanessa, Carmona Jenny, Abad José, Escobar Juan. Higher Fecal Short-Chain Fatty Acid Levels Are Associated with Gut Microbiome Dysbiosis, Obesity, Hypertension and Cardiometabolic Disease Risk Factors. Nutrients. 2018;11(1):51. doi: 10.3390/nu11010051.
    1. Vogt JA, Wolever TM. Fecal acetate is inversely related to acetate absorption from the human rectum and distal colon. The Journal of nutrition. 2003;133:3145–3148. doi: 10.1093/jn/133.10.3145.
    1. den Besten G, et al. The short-chain fatty acid uptake fluxes by mice on a guar gum supplemented diet associate with amelioration of major biomarkers of the metabolic syndrome. PloS one. 2014;9:e107392–e107392. doi: 10.1371/journal.pone.0107392.
    1. Kaji I, Karaki S, Kuwahara A. Short-chain fatty acid receptor and its contribution to glucagon-like peptide-1 release. Digestion. 2014;89:31–36. doi: 10.1159/000356211.
    1. Freeland KR, Wilson C, Wolever TM. Adaptation of colonic fermentation and glucagon-like peptide-1 secretion with increased wheat fibre intake for 1 year in hyperinsulinaemic human subjects. The British journal of nutrition. 2010;103:82–90. doi: 10.1017/s0007114509991462.
    1. Christiansen CB, et al. The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2018;315:G53–G65. doi: 10.1152/ajpgi.00346.2017.
    1. Chambers AP, et al. The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice. Cell Metabolism. 2017;25:927–934.e923. doi: 10.1016/j.cmet.2017.02.008.
    1. Gromada J, Chabosseau P, Rutter GA. The α-cell in diabetes mellitus. Nature Reviews. Endocrinology. 2018;14:694–704. doi: 10.1038/s41574-018-0097-y.
    1. Canfora EE, Blaak EE. Acetate: a diet-derived key metabolite in energy metabolism: good or bad in context of obesity and glucose homeostasis? Current opinion in clinical nutrition and metabolic care. 2017;20:477–483. doi: 10.1097/mco.0000000000000408.
    1. Larraufie P, et al. SCFAs strongly stimulate PYY production in human enteroendocrine cells. Scientific Reports. 2018;8:74. doi: 10.1038/s41598-017-18259-0.
    1. Ge H, et al. Activation of G Protein-Coupled Receptor 43 in Adipocytes Leads to Inhibition of Lipolysis and Suppression of Plasma Free Fatty Acids. Endocrinology. 2008;149:4519–4526. doi: 10.1210/en.2008-0059.
    1. Fernandes J, Vogt J, Wolever TM. Intravenous acetate elicits a greater free fatty acid rebound in normal than hyperinsulinaemic humans. Eur J Clin Nutr. 2012;66:1029–1034. doi: 10.1038/ejcn.2012.98.
    1. Jocken, J. W. E. et al. Short-Chain Fatty Acids Differentially Affect Intracellular Lipolysis in a Human White Adipocyte Model. Frontiers in Endocrinology8, 10.3389/fendo.2017.00372 (2018).
    1. Girousse A, et al. Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass. PLoS biology. 2013;11:e1001485. doi: 10.1371/journal.pbio.1001485.
    1. Al-Lahham S, et al. Propionic acid affects immune status and metabolism in adipose tissue from overweight subjects. European journal of clinical investigation. 2012;42:357–364. doi: 10.1111/j.1365-2362.2011.02590.x.
    1. Rumberger JM, Arch JRS, Green A. Butyrate and other short-chain fatty acids increase the rate of lipolysis in 3T3-L1 adipocytes. PeerJ. 2014;2:e611–e611. doi: 10.7717/peerj.611.
    1. Khan S, Jena G. Sodium butyrate reduces insulin-resistance, fat accumulation and dyslipidemia in type-2 diabetic rat: A comparative study with metformin. Chemico-biological interactions. 2016;254:124–134. doi: 10.1016/j.cbi.2016.06.007.
    1. Khan S, Jena GB. Protective role of sodium butyrate, a HDAC inhibitor on beta-cell proliferation, function and glucose homeostasis through modulation of p38/ERK MAPK and apoptotic pathways: study in juvenile diabetic rat. Chemico-biological interactions. 2014;213:1–12. doi: 10.1016/j.cbi.2014.02.001.
    1. Qin J, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490:55. doi: 10.1038/nature11450.
    1. Karlsson FH, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498:99. doi: 10.1038/nature12198.
    1. Brahe LK, Astrup A, Larsen LH. Is butyrate the link between diet, intestinal microbiota and obesity-related metabolic diseases? Obesity Reviews. 2013;14:950–959. doi: 10.1111/obr.12068.
    1. Layden BT, Yalamanchi SK, Wolever TM, Dunaif A, Lowe WL., Jr. Negative association of acetate with visceral adipose tissue and insulin levels. Diabetes, metabolic syndrome and obesity: targets and therapy. 2012;5:49–55. doi: 10.2147/dmso.S29244.
    1. Moreno-Navarrete José María, Serino Matteo, Blasco-Baque Vincent, Azalbert Vincent, Barton Richard H., Cardellini Marina, Latorre Jèssica, Ortega Francisco, Sabater-Masdeu Mònica, Burcelin Rémy, Dumas Marc-Emmanuel, Ricart Wifredo, Federici Massimo, Fernández-Real José Manuel. Gut Microbiota Interacts with Markers of Adipose Tissue Browning, Insulin Action and Plasma Acetate in Morbid Obesity. Molecular Nutrition & Food Research. 2017;62(3):1700721. doi: 10.1002/mnfr.201700721.
    1. Fernandes J, Vogt J, Wolever TMS. Inulin increases short-term markers for colonic fermentation similarly in healthy and hyperinsulinaemic humans. European journal of clinical nutrition. 2011;65:1279. doi: 10.1038/ejcn.2011.116.
    1. Fernandes J, Vogt J, Wolever TMS. Kinetic model of acetate metabolism in healthy and hyperinsulinaemic humans. European journal of clinical nutrition. 2014;68:1067–1071. doi: 10.1038/ejcn.2014.136.
    1. Han J-H, et al. The effects of propionate and valerate on insulin responsiveness for glucose uptake in 3T3-L1 adipocytes and C2C12 myotubes via G protein-coupled receptor 41. PloS one. 2014;9:e95268–e95268. doi: 10.1371/journal.pone.0095268.
    1. Weitkunat K, et al. Importance of propionate for the repression of hepatic lipogenesis and improvement of insulin sensitivity in high-fat diet-induced obesity. Mol Nutr Food Res. 2016;60:2611–2621. doi: 10.1002/mnfr.201600305.
    1. Weitkunat K, et al. Odd-chain fatty acids as a biomarker for dietary fiber intake: a novel pathway for endogenous production from propionate. The American journal of clinical nutrition. 2017;105:1544–1551. doi: 10.3945/ajcn.117.152702.
    1. Knowles SE, Jarrett IG, Filsell OH, Ballard FJ. Production and utilization of acetate in mammals. Biochem J. 1974;142:401–411. doi: 10.1042/bj1420401.
    1. Sun EW, et al. Mechanisms Controlling Glucose-Induced GLP-1 Secretion in Human Small Intestine. Diabetes. 2017;66:2144–2149. doi: 10.2337/db17-0058.
    1. American Diabetes, A. Diagnosis and classification of diabetes mellitus. Diabetes care. 2010;33(Suppl 1):S62–S69. doi: 10.2337/dc10-S062.
    1. Canfora EE, et al. Supplementation of Diet With Galacto-oligosaccharides Increases Bifidobacteria, but Not Insulin Sensitivity, in Obese Prediabetic Individuals. Gastroenterology. 2017;153:87–97.e83. doi: 10.1053/j.gastro.2017.03.051.
    1. Reijnders D, et al. Effects of Gut Microbiota Manipulation by Antibiotics on Host Metabolism in Obese Humans: A Randomized Double-Blind Placebo-Controlled Trial. Cell Metab. 2016;24:63–74. doi: 10.1016/j.cmet.2016.06.016.
    1. Müller, M. et al. In European Congress on Obesity Vol. 11 (Obesity Facts, Vienna, 2018).
    1. Frayn KN. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol Respir Environ Exerc Physiol. 1983;55:628–634. doi: 10.1152/jappl.1983.55.2.628.
    1. Weir JBDV. New methods for calculating metabolic rate with special reference to protein metabolism. The Journal of Physiology. 1949;109:1–9. doi: 10.1113/jphysiol.1949.sp004363.
    1. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. The American journal of physiology. 1979;237:E214–223. doi: 10.1152/ajpendo.1979.237.3.E214.
    1. Garcia-Villalba R, et al. Alternative method for gas chromatography-mass spectrometry analysis of short-chain fatty acids in faecal samples. Journal of separation science. 2012;35:1906–1913. doi: 10.1002/jssc.201101121.
    1. van Eijk HM, Bloemen JG, Dejong CH. Application of liquid chromatography-mass spectrometry to measure short chain fatty acids in blood. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. 2009;877:719–724. doi: 10.1016/j.jchromb.2009.01.039.
    1. Orskov C, Rabenhoj L, Wettergren A, Kofod H, Holst JJ. Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes. 1994;43:535–539. doi: 10.2337/diab.43.4.535.
    1. Schols AM, Buurman WA, Staal van den Brekel AJ, Dentener MA, Wouters EF. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax. 1996;51:819–824. doi: 10.1136/thx.51.8.819.
    1. Matthews DR, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419. doi: 10.1007/BF00280883.

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