Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes

Alessandra Puddu, Roberta Sanguineti, Fabrizio Montecucco, Giorgio Luciano Viviani, Alessandra Puddu, Roberta Sanguineti, Fabrizio Montecucco, Giorgio Luciano Viviani

Abstract

In type 2 diabetes, hyperglycemia, insulin resistance, increased inflammation, and oxidative stress were shown to be associated with the progressive deterioration of beta-cell function and mass. Short-chain fatty acids (SCFAs) are organic fatty acids produced in the distal gut by bacterial fermentation of macrofibrous material that might improve type 2 diabetes features. Their main beneficial activities were identified in the decrease of serum levels of glucose, insulin resistance as well as inflammation, and increase in protective Glucagon-like peptide-1 (GLP-1) secretion. In this review, we updated evidence on the effects of SCFAs potentially improving metabolic control in type 2 diabetes.

Figures

Figure 1
Figure 1
SCFAs improve metabolic functions in T2D. SCFAs were shown to affect pancreatic beta-cell function by directly acting as HDAC inhibitors (promoting β-cell development, proliferation, and differentiation) or by indirectly increasing GLP-1 secretion from enteroendocrine L-cells (leading to insulin release). Furthermore, SCFAs reduce the release of proinflammatory cytokines by adipose tissue and weaken leukocyte activation. These anti-inflammatory effects improve insulin resistance, tissue glucose uptake, and blood glucose levels.

References

    1. Stumvoll M, Goldstein BJ, Van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. The Lancet. 2005;365(9467):1333–1346.
    1. Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nature Reviews Genetics. 2012;13(4):260–270.
    1. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489:220–230.
    1. de Vos WM, de Vos EAJ. Role of the intestinal microbiome in health and disease: from correlation to causation. Nutrition Reviews. 2012;70(supplement 1):S45–S56.
    1. Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498:99–103.
    1. Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55–60.
    1. Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012;143(4):e913–e917.
    1. Mortensen PB, Clausen MR. Short-chain fatty acids in the human colon: relation to gastrointestinal health and disease. Scandinavian Journal of Gastroenterology, Supplement. 1996;216:132–148.
    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 Letters. 2010;584(11):2381–2386.
    1. Zhang X, Zhao Y, Zhang M, et al. Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PLoS ONE. 2012;7(8)e42529
    1. Xiong Y, Miyamoto N, Shibata K, et al. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(4):1045–1050.
    1. Scheppach W, Bartram P, Richter A, et al. Effect of short-chain fatty acids on the human colonic mucosa in vitro. Journal of Parenteral and Enteral Nutrition. 1992;16(1):43–48.
    1. Al-Lahham SH, Roelofsen H, Priebe M, et al. Regulation of adipokine production in human adipose tissue by propionic acid. European Journal of Clinical Investigation. 2010;40(5):401–407.
    1. Udayappan SD, Hartstra AV, Dallinga-Thie GM, Nieuwdorp M. Intestinal microbiota and faecal transplantation as treatment modality for insulin resistance and type 2 diabetes mellitus. Clinical and Experimental Immunology. 2014;177(1):24–29.
    1. Remely M, Aumueller E, Merold C, et al. Effects of short chain fatty acid producing bacteria on epigenetic regulation of FFAR3 in type 2 diabetes and obesity. Gene. 2014;537:85–92.
    1. Duranton B, Keith G, Gossé F, Bergmann C, Schleiffer R, Raul F. Concomitant changes in polyamine pools and DNA methylation during growth inhibition of human colonic cancer cells. Experimental Cell Research. 1998;243(2):319–325.
    1. Wieser M, Bonifer R, Oster W, Lindemann A, Mertelsmann R, Herrmann F. Interleukin-4 induces secretion of CSF for granulocytes and CSF for macrophages by peripheral blood monocytes. Blood. 1989;73(5):1105–1108.
    1. Cummings JH, Macfarlane GT. The control and consequences of bacterial fermentation in the human colon. Journal of Applied Bacteriology. 1991;70(6):443–459.
    1. Miller TL, Wolin MJ. Fermentations by saccharolytic intestinal bacteria. American Journal of Clinical Nutrition. 1979;32(1):164–172.
    1. Cummings JH, Englyst HN, Wiggins HS. The role of carbohydrates in lower gut function. Nutrition Reviews. 1986;44(2):50–54.
    1. Cummings JH, Englyst HN. Fermentation in the human large intestine and the available substrates. American Journal of Clinical Nutrition. 1987;45(5):1243–1255.
    1. Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiological Reviews. 1990;70(2):567–590.
    1. Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiological Reviews. 2001;81(3):1031–1064.
    1. Fleming SE, Fitch MD, DeVries S, Liu ML, Kight C. Nutrient utilization by cells isolated from rat jejunum, cecum and colon. Journal of Nutrition. 1991;121(6):869–878.
    1. Pouteau E, Meirim I, Métairon S, Fay L. Acetate, propionate and butyrate in plasma: determination of the concentration and isotopic enrichment by gas chromatography/mass spectrometry with positive chemical ionization. Journal of Mass Spectrometry. 2001;36(7):798–805.
    1. Mascord D, Smith J, Starmer GA, Whitfield JB. Effects of increasing the rate of alcohol metabolism on plasma acetate concentration. Alcohol and Alcoholism. 1992;27(1):25–28.
    1. Goncalves P, Martel F. Butyrate and colorectal cancer: the role of butyrate transport. Current Drug Metabolism. 2013;14:994–1008.
    1. Gupta N, Martin PM, Prasad PD, Ganapathy V. SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sciences. 2006;78(21):2419–2425.
    1. McNeil NI. The contribution of the large intestine to energy supplies in man. American Journal of Clinical Nutrition. 1984;39(2):338–342.
    1. Looijer-van Langen MAC, Dieleman LA. Prebiotics in chronic intestinal inflammation. Inflammatory Bowel Diseases. 2009;15(3):454–462.
    1. Canani RB, Costanzo MD, Leone L, Pedata M, Meli R, Calignano A. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World Journal of Gastroenterology. 2011;17(12):1519–1528.
    1. Scott KP, Gratz SW, Sheridan PO, Flint HJ, Duncan SH. The influence of diet on the gut microbiota. Pharmacological Research. 2013;69(1):52–60.
    1. Jakobsdottir G, Xu J, Molin G, Ahrne S, Nyman M. High-fat diet reduces the formation of butyrate, but increases succinate, inflammation, liver fat and cholesterol in rats, while dietary fibre counteracts these effects. PLoS ONE. 2013;8e80476
    1. Freeland KR, Wilson C, Wolever TMS. Adaptation of colonic fermentation and glucagon-like peptide-1 secretion with increased wheat fibre intake for 1 year in hyperinsulinaemic human subjects. British Journal of Nutrition. 2010;103(1):82–90.
    1. Mattace Raso G, Simeoli R, Russo R, et al. Effects of sodium butyrate and its synthetic amide derivative on liver inflammation and glucose tolerance in an animal model of steatosis induced by high fat diet. PLoS ONE. 2013;8(7)e68626
    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.
    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. Journal of Biological Chemistry. 2003;278(13):11312–11319.
    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. The Journal of Biological Chemistry. 2003;278(28):25481–25489.
    1. Nilsson NE, Kotarsky K, Owman C, Olde B. Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochemical and Biophysical Research Communications. 2003;303(4):1047–1052.
    1. Stoddart LA, Smith NJ, Milligan G. International union of pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions. Pharmacological Reviews. 2008;60(4):405–417.
    1. Wang A, Gu Z, Heid B, Akers RM, Jiang H. Identification and characterization of the bovine G protein-coupled receptor GPR41 and GPR43 genes. Journal of Dairy Science. 2009;92(6):2696–2705.
    1. Tazoe H, Otomo Y, Karaki S, et al. Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomedical Research. 2009;30(3):149–156.
    1. Karaki S, Mitsui R, Hayashi H, et al. Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell and Tissue Research. 2006;324(3):353–360.
    1. Karaki S, Tazoe H, Hayashi H, et al. Expression of the short-chain fatty acid receptor, GPR43, in the human colon. Journal of Molecular Histology. 2008;39(2):135–142.
    1. Senga T, Iwamoto S, Yoshida T, et al. LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3. Blood. 2003;101(3):1185–1187.
    1. Hirasawa A, Hara T, Katsuma S, Adachi T, Tsujimoto G. Free fatty acid receptors and drug discovery. Biological and Pharmaceutical Bulletin. 2008;31(10):1847–1851.
    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. Nature Communications. 2013;4, article 1829
    1. Maslowski KM, Vieira AT, Ng A, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461(7268):1282–1286.
    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(2):364–371.
    1. Samuel BS, Shaito A, Motoike T, et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(43):16767–16772.
    1. Lin HV, Frassetto A, Kowalik EJ, Jr., et al. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS ONE. 2012;7(4)e35240
    1. Holst JJ. The physiology of glucagon-like peptide 1. Physiological Reviews. 2007;87(4):1409–1439.
    1. Ross SA, Ekoé J. Incretin agents in type 2 diabetes. Canadian Family Physician. 2010;56(7):639–648.
    1. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocrine Reviews. 1999;20(6):876–913.
    1. Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V. Glucagon-like peptide-1(7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns. Journal of Endocrinology. 1993;138(1):159–166.
    1. Herrmann C, Goke R, Richter G, Fehmann HC, Arnold R, Goke B. Glucagon-like peptide-1 and glucose-dependent insulin releasing polypeptide plasma levels in response to nutrients. Digestion. 1995;56(2):117–126.
    1. Yadav H, Lee JH, Lloyd J, Walter P, Rane SG. Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion. The Journal of Biological Chemistry. 2013;288(35):25088–25097.
    1. Regmi PR, van Kempen TATG, Matte JJ, Zijlstra RT. Starch with high amylose and low in vitro digestibility increases short-chain fatty acid absorption, reduces peak insulin secretion, and modulates incretin secretion in pigs. The Journal of Nutrition. 2011;141(3):398–405.
    1. Fukumori R, Mita T, Sugino T, Obitsu T, Taniguchi K. Plasma concentrations and effects of glucagon-like peptide-1 (7–36) amide in calves before and after weaning. Domestic Animal Endocrinology. 2012;43(4):299–306.
    1. Freeland KR, Wolever TMS. Acute effects of intravenous and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, adiponectin and tumour necrosis factor-α. British Journal of Nutrition. 2010;103(3):460–466.
    1. Hartvigsen ML, Laerke HN, Overgaard A, Holst JJ, Bach Knudsen KE, Hermansen K. Postprandial effects of test meals including concentrated arabinoxylan and whole grain rye in subjects with the metabolic syndrome: a randomised study. European Journal of Clinical Nutrition. 2014;68(5):567–574.
    1. Bodinham CL, Al-Mana NM, Smith L, Robertson MD. Endogenous plasma glucagon-like peptide-1 following acute dietary fibre consumption. British Journal of Nutrition. 2013;110:1429–1433.
    1. Nilsson A, Johansson E, Ekström L, Björck I. Effects of a brown beans evening meal on metabolic risk markers and appetite regulating hormones at a subsequent standardized breakfast: a randomized cross-over study. PLoS ONE. 2013;8(4)e59985
    1. Herr NR, Park J, McElligott ZA, Belle AM, Carelli RM, Mark Wightman R. In vivo voltammetry monitoring of electrically evoked extracellular norepinephrine in subregions of the bed nucleus of the stria terminalis. Journal of Neurophysiology. 2012;107(6):1731–1737.
    1. Dumoulin V, Moro F, Barcelo A, Dakka T, Cuber JC. Peptide YY, glucagon-like peptide-1, and neurotensin responses to luminal factors in the isolated vascularly perfused rat ileum. Endocrinology. 1998;139(9):3780–3786.
    1. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444(7122):1027–1031.
    1. Gao Z, Yin J, Zhang J, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. 2009;58(7):1509–1517.
    1. Bjursell M, Admyre T, Göransson M, et al. Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. American Journal of Physiology. Endocrinology and Metabolism. 2011;300(1):E211–E220.
    1. Regard JB, Kataoka H, Cano DA, et al. Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. The Journal of Clinical Investigation. 2007;117(12):4034–4043.
    1. Goicoa S, Álvarez S, Ricordi C, Inverardi L, Domínguez-Bendala J. Sodium butyrate activates genes of early pancreatic development in embryonic stem cells. Cloning and Stem Cells. 2006;8(3):140–149.
    1. Li L, Lili R, Hui Q, et al. Combination of GLP-1 and sodium butyrate promote differentiation of pancreatic progenitor cells into insulin-producing cells. Tissue and Cell. 2008;40(6):437–445.
    1. Christensen DP, Dahllöf M, Lundh M, et al. Histone deacetylase (HDAC) inhibition as a novel treatment for diabetes mellitus. Molecular Medicine. 2011;17(5-6):378–390.
    1. Pickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia. 1998;41(10):1241–1248.
    1. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860–867.
    1. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. Journal of Clinical Investigation. 2006;116(7):1793–1801.
    1. Musso G, Gambino R, Cassader M. Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded? Diabetes Care. 2010;33(10):2277–2284.
    1. Zhang C, Zhang M, Wang S, et al. Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. ISME Journal. 2010;4(2):232–241.
    1. Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334(6052):105–108.
    1. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–563.
    1. Amar J, Burcelin R, Ruidavets JB, et al. Energy intake is associated with endotoxemia in apparently healthy men. The American Journal of Clinical Nutrition. 2008;87(5):1219–1223.
    1. Manco M, Putignani L, Bottazzo GF. Gut microbiota, lipopolysaccharides, and innate immunity in the pathogenesis of obesity and cardiovascular risk. Endocrine Reviews. 2010;31(6):817–844.
    1. Mariadason JM, Barkla DH, Gibson PR. Effect of short-chain fatty acids on paracellular permeability in Caco- 2 intestinal epithelium model. American Journal of Physiology. 1997;272(4):G705–G712.
    1. Peng L, Li Z, Green RS, Holzman IR, Lin J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. Journal of Nutrition. 2009;139(9):1619–1625.
    1. Cucak H, Mayer C, Tonnesen M, Thomsen LH, Grunnet LG, Rosendahl A. Macrophage contact dependent and independent TLR4 mechanisms induce beta-cell dysfunction and apoptosis in a mouse model of type 2 diabetes. PLoS ONE. 2014;9(3)e90685
    1. Garay-Malpartida HM, Mourão RF, Mantovani M, Santos IA, Sogayar MC, Goldberg AC. Toll-like receptor 4 (TLR4) expression in human and murine pancreatic beta-cells affects cell viability and insulin homeostasis. BMC Immunology. 2011;12, article 18
    1. Vives-Pi M, Somoza N, Fernández-Alvarez J, et al. Evidence of expression of endotoxin receptors CD14, toll-like receptors TLR4 and TLR2 and associated molecule MD-2 and of sensitivity to endotoxin (LPS) in islet beta cells. Clinical and Experimental Immunology. 2003;133(2):208–218.
    1. Chung S, LaPoint K, Martinez K, Kennedy A, Sandberg MB, McIntosh MK. Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes. Endocrinology. 2006;147(11):5340–5351.
    1. Ding S, Chi MM, Scull BP, et al. High-fat diet: bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. PLoS ONE. 2010;5e12191
    1. Roelofsen H, Priebe MG, Vonk RJ. The interaction of short-chain fatty acids with adipose tissue: relevance for prevention of type 2 diabetes. Beneficial Microbes. 2010;1(4):433–437.
    1. Säemann MD, Böhmig GA, Osterreicher CH, et al. Anti-inflammatory effects of sodium butyrate on human monocytes: potent inhibition of IL-12 and up-regulation of IL-10 production. The FASEB Journal. 2000;14(15):2380–2382.
    1. Gomez J, Bloom JW, Yamamura HI, Halonen M. Characterization of receptors for platelet-activating factor in guinea pig lung membranes. The American Journal of Respiratory Cell and Molecular Biology. 1990;3(3):259–264.
    1. Maslowski KM, MacKay CR. Diet, gut microbiota and immune responses. Nature Immunology. 2011;12(1):5–9.
    1. Tedelind S, Westberg F, Kjerrulf M, Vidal A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: A study with relevance to inflammatory bowel disease. World Journal of Gastroenterology. 2007;13(20):2826–2832.
    1. Al-Lahham S, Roelofsen H, Rezaee F, et al. Propionic acid affects immune status and metabolism in adipose tissue from overweight subjects. European Journal of Clinical Investigation. 2012;42(4):357–364.
    1. Vinolo MAR, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3(10):858–876.
    1. Brunkhorst BA, Kraus E, Coppi M, Budnick M, Niederman R. Propionate induces polymorphonuclear leukocyte activation and inhibits formylmethionyl-leucyl-phenylalanine-stimulated activation. Infection and Immunity. 1992;60(7):2957–2968.
    1. Eftimiadi C, Buzzi E, Tonetti M, et al. Short-chain fatty acids produced by anaerobic bacteria alter the physiological responses of human neutrophils to chemotactic peptide. Journal of Infection. 1987;14(1):43–53.
    1. Yuli I, Oplatka A. Cytosolic acidification as an early transductory signal of human neutrophil chemotaxis. Science. 1987;235(4786):340–342.
    1. Maa M, Chang MY, Hsieh M, et al. Butyrate reduced lipopolysaccharide-mediated macrophage migration by suppression of Src enhancement and focal adhesion kinase activity. Journal of Nutritional Biochemistry. 2010;21(12):1186–1192.
    1. Meijer K, de Vos P, Priebe MG. Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health? Current Opinion in Clinical Nutrition and Metabolic Care. 2010;13(6):715–721.

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