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The role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity

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Abstract

Diabetes is a group of metabolic disorders characterized by persistent hyperglycemia and has become a major public health concern. Autoimmune type 1 diabetes (T1D) and insulin resistant type 2 diabetes (T2D) are the two main types. A combination of genetic and environmental factors contributes to the development of these diseases. Gut microbiota have emerged recently as an essential player in the development of T1D, T2D and obesity. Altered gut microbiota have been strongly linked to disease in both rodent models and humans. Both classic 16S rRNA sequencing and shot-gun metagenomic pyrosequencing analysis have been successfully applied to explore the gut microbiota composition and functionality. This review focuses on the association between gut microbiota and diabetes and discusses the potential mechanisms by which gut microbiota regulate disease development in T1D, T2D and obesity.

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References

  1. Kamada N et al. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol. 2013;13(5):321–35.

    Article  CAS  PubMed  Google Scholar 

  2. Geuking MB, et al. The interplay between the gut microbiota and the immune system. Gut Microbes. 2014;5(3).

  3. Vieira SM, Pagovich OE, Kriegel MA. Diet, microbiota and autoimmune diseases. Lupus. 2014;23(6):518–26.

    Article  CAS  PubMed  Google Scholar 

  4. Nielsen DS, et al. Beyond genetics. Influence of dietary factors and gut microbiota on type 1 diabetes. FEBS Lett. 2014.

  5. Vaarala O. Human intestinal microbiota and type 1 diabetes. Curr Diabetes Rep. 2013;13(5):601–7.

    Article  CAS  Google Scholar 

  6. Wen L et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008;455(7216):1109–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Alkanani AK et al. Induction of diabetes in the RIP-B7.1 mouse model is critically dependent on TLR3 and MyD88 pathways and is associated with alterations in the intestinal microbiome. Diabetes. 2014;63(2):619–31.

    Article  CAS  PubMed  Google Scholar 

  8. Roesch LF et al. Culture-independent identification of gut bacteria correlated with the onset of diabetes in a rat model. ISME J. 2009;3(5):536–48.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Hara N et al. Prevention of virus-induced type 1 diabetes with antibiotic therapy. J Immunol. 2012;189(8):3805–14.

    Article  CAS  PubMed  Google Scholar 

  10. Peng J, et al. Long term effect of gut microbiota transfer on diabetes development. J Autoimmun. 2014.

  11. Dahlquist G, Kallen B. Maternal-child blood group incompatibility and other perinatal events increase the risk for early-onset type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1992;35(7):671–5.

    Article  CAS  PubMed  Google Scholar 

  12. Knip M, Simell O. Environmental triggers of type 1 diabetes. Cold Spring Harb Perspect Med. 2012;2(7):a007690.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Rosenbauer J, Herzig P, Giani G. Early infant feeding and risk of type 1 diabetes mellitus-a nationwide population-based case–control study in pre-school children. Diabetes Metab Res Rev. 2008;24(3):211–22.

    Article  CAS  PubMed  Google Scholar 

  14. Funda DP et al. Gluten-free diet prevents diabetes in NOD mice. Diabetes Metab Res Rev. 1999;15(5):323–7.

    Article  CAS  PubMed  Google Scholar 

  15. Lefebvre DE et al. Dietary proteins as environmental modifiers of type 1 diabetes mellitus. Annu Rev Nutr. 2006;26:175–202.

    Article  CAS  PubMed  Google Scholar 

  16. Schmid S et al. Delayed exposure to wheat and barley proteins reduces diabetes incidence in non-obese diabetic mice. Clin Immunol. 2004;111(1):108–18.

    Article  CAS  PubMed  Google Scholar 

  17. Marietta EV et al. Low incidence of spontaneous type 1 diabetes in non-obese diabetic mice raised on gluten-free diets is associated with changes in the intestinal microbiome. PLoS One. 2013;8(11):e78687.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Hansen CH et al. A maternal gluten-free diet reduces inflammation and diabetes incidence in the offspring of NOD mice. Diabetes. 2014;63(8):2821–32.

    Article  CAS  PubMed  Google Scholar 

  19. Ejsing-Duun M et al. Dietary gluten reduces the number of intestinal regulatory T cells in mice. Scand J Immunol. 2008;67(6):553–9.

    Article  CAS  PubMed  Google Scholar 

  20. Adlercreutz EH et al. A gluten-free diet lowers NKG2D and ligand expression in BALB/c and non-obese diabetic (NOD) mice. Clin Exp Immunol. 2014;177(2):391–403.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Larsen J, et al. Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion. Eur J Immunol. 2014.

  22. Gur C et al. The activating receptor NKp46 is essential for the development of type 1 diabetes. Nat Immunol. 2010;11(2):121–8.

    Article  CAS  PubMed  Google Scholar 

  23. Poirot L, Benoist C, Mathis D. Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity. Proc Natl Acad Sci U S A. 2004;101(21):8102–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Scaramuzza AE et al. Type 1 diabetes and celiac disease: the effects of gluten free diet on metabolic control. World J Diabetes. 2013;4(4):130–4.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Abid N et al. Clinical and metabolic effects of gluten free diet in children with type 1 diabetes and coeliac disease. Pediatr Diabetes. 2011;12(4 Pt 1):322–5.

    Article  PubMed  Google Scholar 

  26. Antvorskov JC et al. Dietary gluten and the development of type 1 diabetes. Diabetologia. 2014;57(9):1770–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Hummel S et al. Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care. 2011;34(6):1301–5.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Kaukinen K et al. No effect of gluten-free diet on the metabolic control of type 1 diabetes in patients with diabetes and celiac disease. Retrospective and controlled prospective survey. Diabetes Care. 1999;22(10):1747–8.

    Article  CAS  PubMed  Google Scholar 

  29. Leeds JS et al. High prevalence of microvascular complications in adults with type 1 diabetes and newly diagnosed celiac disease. Diabetes Care. 2011;34(10):2158–63.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Gray JD, Shiner M. Influence of gastric pH on gastric and jejunal flora. Gut. 1967;8(6):574–81.

    Article  CAS  PubMed  Google Scholar 

  31. Sofi MH et al. pH of drinking water influences the composition of gut microbiome and type 1 diabetes incidence. Diabetes. 2014;63(2):632–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Wolf KJ et al. Consumption of acidic water alters the gut microbiome and decreases the risk of diabetes in NOD mice. J Histochem Cytochem. 2014;62(4):237–50.

    Article  CAS  PubMed  Google Scholar 

  33. Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol. 2014;35(3):347–69.

    Article  CAS  PubMed  Google Scholar 

  34. Zandman-Goddard G, Peeva E, Shoenfeld Y. Gender and autoimmunity. Autoimmun Rev. 2007;6(6):366–72.

    Article  CAS  PubMed  Google Scholar 

  35. Yurkovetskiy L et al. Gender bias in autoimmunity is influenced by microbiota. Immunity. 2013;39(2):400–12.

    Article  CAS  PubMed  Google Scholar 

  36. Markle JG et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013;339(6123):1084–8.

    Article  CAS  PubMed  Google Scholar 

  37. Gale EA, Gillespie KM. Diabetes and gender. Diabetologia. 2001;44(1):3–15.

    Article  CAS  PubMed  Google Scholar 

  38. Giongo A et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 2011;5(1):82–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Murri M et al. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case–control study. BMC Med. 2013;11:46.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Brown CT et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One. 2011;6(10):e25792.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. de Goffau MC et al. Fecal microbiota composition differs between children with beta-cell autoimmunity and those without. Diabetes. 2013;62(4):1238–44.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Mejia-Leon ME et al. Fecal microbiota imbalance in Mexican children with type 1 diabetes. Sci Rep. 2014;4:3814.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Ringel-Kulka T et al. Intestinal microbiota in healthy U.S. young children and adults--a high throughput microarray analysis. PLoS One. 2013;8(5):e64315.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. de Goffau MC et al. Aberrant gut microbiota composition at the onset of type 1 diabetes in young children. Diabetologia. 2014;57(8):1569–77.

    Article  PubMed  Google Scholar 

  45. Van den Abbeele P et al. Butyrate-producing clostridium cluster XIVa species specifically colonize mucins in an in vitro gut model. ISME J. 2013;7(5):949–61.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Van Immerseel F et al. Butyric acid-producing anaerobic bacteria as a novel probiotic treatment approach for inflammatory bowel disease. J Med Microbiol. 2010;59(Pt 2):141–3.

    Article  PubMed  Google Scholar 

  47. Endesfelder D et al. Compromised gut microbiota networks in children with anti-islet cell autoimmunity. Diabetes. 2014;63(6):2006–14.

    Article  CAS  PubMed  Google Scholar 

  48. Kriegel MA et al. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc Natl Acad Sci U S A. 2011;108(28):11548–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Yang Y et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature. 2014;510(7503):152–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 2008;453(7195):620–5.

    Article  CAS  PubMed  Google Scholar 

  51. Ochoa-Reparaz J et al. A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol. 2010;3(5):487–95.

    Article  CAS  PubMed  Google Scholar 

  52. Surana NK, Kasper DL. The yin yang of bacterial polysaccharides: lessons learned from B. fragilis PSA. Immunol Rev. 2012;245(1):13–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Ochoa-Reparaz J et al. Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J Immunol. 2010;185(7):4101–8.

    Article  CAS  PubMed  Google Scholar 

  54. Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A. 2010;107(27):12204–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Mazmanian SK et al. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005;122(1):107–18.

    Article  CAS  PubMed  Google Scholar 

  56. Grundy SM. Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab. 2004;89(6):2595–600.

    Article  CAS  PubMed  Google Scholar 

  57. Haslam DW, James WP. Obesity. Lancet. 2005;366(9492):1197–209.

    Article  PubMed  Google Scholar 

  58. Bleich S et al. Why is the developed world obese? Annu Rev Public Health. 2008;29:273–95.

    Article  PubMed  Google Scholar 

  59. Lau DC et al. 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children [summary]. CMAJ. 2007;176(8):S1–13.

    Article  PubMed Central  PubMed  Google Scholar 

  60. Musso G, Gambino R, Cassader M. Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu Rev Med. 2011;62:361–80.

    Article  CAS  PubMed  Google Scholar 

  61. Remely M et al. Effects of short chain fatty acid producing bacteria on epigenetic regulation of FFAR3 in type 2 diabetes and obesity. Gene. 2014;537(1):85–92.

    Article  CAS  PubMed  Google Scholar 

  62. Fava F et al. The type and quantity of dietary fat and carbohydrate alter faecal microbiome and short-chain fatty acid excretion in a metabolic syndrome ‘at-risk’ population. Int J Obes (Lond). 2013;37(2):216–23.

    Article  CAS  Google Scholar 

  63. Karlsson F et al. Assessing the human gut microbiota in metabolic diseases. Diabetes. 2013;62(10):3341–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Kotzampassi K, Giamarellos-Bourboulis EJ, Stavrou G. Obesity as a consequence of gut bacteria and diet interactions. ISRN Obes. 2014;2014:651895.

    PubMed Central  PubMed  Google Scholar 

  65. Moreno-Indias I et al. Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus. Front Microbiol. 2014;5:190.

    Article  PubMed Central  PubMed  Google Scholar 

  66. Turnbaugh PJ et al. A core gut microbiome in obese and lean twins. Nature. 2009;457(7228):480–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Ley RE. Obesity and the human microbiome. Curr Opin Gastroenterol. 2010;26(1):5–11.

    Article  PubMed  Google Scholar 

  68. Zhao L. The gut microbiota and obesity: from correlation to causality. Nat Rev Microbiol. 2013;11(9):639–47.

    Article  CAS  PubMed  Google Scholar 

  69. Armougom F et al. Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and Methanogens in anorexic patients. PLoS One. 2009;4(9):e7125.

    Article  PubMed Central  PubMed  Google Scholar 

  70. Ley RE et al. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444(7122):1022–3.

    Article  CAS  PubMed  Google Scholar 

  71. Duncan SH et al. Human colonic microbiota associated with diet, obesity and weight loss. Int J Obes (Lond). 2008;32(11):1720–4.

    Article  CAS  Google Scholar 

  72. Schwiertz A et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring). 2010;18(1):190–5.

    Article  Google Scholar 

  73. Zhang C et al. Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. ISME J. 2010;4(2):232–41.

    Article  CAS  PubMed  Google Scholar 

  74. Parks BW et al. Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice. Cell Metab. 2013;17(1):141–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116(7):1793–801.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Tang T et al. Uncoupling of inflammation and insulin resistance by NF-kappa B in transgenic mice through elevated energy expenditure. J Biol Chem. 2010;285(7):4637–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Lee YS et al. Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance. Diabetes. 2011;60(10):2474–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Lee JY, Zhao L, Hwang DH. Modulation of pattern recognition receptor-mediated inflammation and risk of chronic diseases by dietary fatty acids. Nutr Rev. 2010;68(1):38–61.

    Article  PubMed  Google Scholar 

  79. Ye J. Mechanisms of insulin resistance in obesity. Front Med. 2013;7(1):14–24.

    Article  PubMed Central  PubMed  Google Scholar 

  80. Vijay-Kumar M et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science. 2010;328(5975):228–31.

    Article  CAS  PubMed  Google Scholar 

  81. Davis JE et al. Absence of Tlr2 protects against high-fat diet-induced inflammation and results in greater insulin-stimulated glucose transport in cultured adipocytes. J Nutr Biochem. 2011;22(2):136–41.

    Article  CAS  PubMed  Google Scholar 

  82. Ehses JA et al. Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet. Diabetologia. 2010;53(8):1795–806.

    Article  CAS  PubMed  Google Scholar 

  83. Caricilli AM et al. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol. 2011;9(12):e1001212.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Ubeda C et al. Familial transmission rather than defective innate immunity shapes the distinct intestinal microbiota of TLR-deficient mice. J Exp Med. 2012;209(8):1445–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Azad MB, et al., Infant antibiotic exposure and the development of childhood overweight and central adiposity. Int J Obes (Lond). 2014.

  86. Million M, Raoult D. The role of the manipulation of the gut microbiota in obesity. Curr Infect Dis Rep. 2013;15(1):25–30.

    Article  PubMed  Google Scholar 

  87. Murphy R, et al. Antibiotic treatment during infancy and increased body mass index in boys: an international cross-sectional study. Int J Obes (Lond). 2013.

  88. Million M et al. Lactobacillus reuteri and Escherichia coli in the human gut microbiota may predict weight gain associated with vancomycin treatment. Nutr Diabetes. 2013;3:e87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Murphy EF et al. Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity. Gut. 2013;62(2):220–6.

    Article  PubMed  Google Scholar 

  90. Liou AP et al. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med. 2013;5(178):178ra41.

    Article  PubMed Central  PubMed  Google Scholar 

  91. Ridaura VK et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013;341(6150):1241214.

    Article  PubMed  Google Scholar 

  92. Duca FA et al. Replication of obesity and associated signaling pathways through transfer of microbiota from obese-prone rats. Diabetes. 2014;63(5):1624–36.

    Article  CAS  PubMed  Google Scholar 

  93. Zhang H et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci U S A. 2009;106(7):2365–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. Brunetti P. The lean patient with type 2 diabetes: characteristics and therapy challenge. Int J Clin Pract Suppl. 2007;153:3–9.

    CAS  Google Scholar 

  95. Camhi SM, Katzmarzyk PT. Differences in body composition between metabolically healthy obese and metabolically abnormal obese adults. Int J Obes (Lond). 2014;38(8):1142–5.

    Article  CAS  Google Scholar 

  96. Karelis AD. Metabolically healthy but obese individuals. Lancet. 2008;372(9646):1281–3.

    Article  PubMed  Google Scholar 

  97. Larsen N et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One. 2010;5(2):e9085.

    Article  PubMed Central  PubMed  Google Scholar 

  98. Zhang X et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One. 2013;8(8):e71108.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Qin J et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55–60.

    Article  CAS  PubMed  Google Scholar 

  100. Karlsson FH et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498(7452):99–103.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Supported by grants from NIH (DK088181, DK09882, DK100500, UL1 RR 024139), JDRF (47-2013-516) and ADA (1-14-BS-222).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, USA

    Ningwen Tai & Li Wen

  2. Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK

    F. Susan Wong

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  1. Ningwen Tai
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  2. F. Susan Wong
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Correspondence to Li Wen.

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Tai, N., Wong, F.S. & Wen, L. The role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity. Rev Endocr Metab Disord 16, 55–65 (2015). https://doi.org/10.1007/s11154-015-9309-0

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