Skip to main content

Guts, Germs, and Meals: The Origin of Type 1 Diabetes

Abstract

Type 1 diabetes mellitus (T1DM) is due, in part, to non-genetically determined factors including environmental factors. The nature of these environmental effects remains unclear but they are important to identify since they may be amenable to therapy. Recently, the gut microbiota, the trillions of microorganisms inhabiting the gut, as well as diet, have been implicated in T1DM pathogenesis. Since dietary changes can reshape this complex gut community, its co-evolution could have been altered by changes to our diet, agriculture, personal hygiene, and antibiotic usage, which coincide with the increased incidence of T1DM. Recent studies demonstrate an association between altered gut microbiota and T1DM in both T1DM patients and animal models of the disease. Further studies should provide new insight into those critical host-microbial interactions, potentially suggesting new diagnostic or therapeutic strategies for disease prevention.

This is a preview of subscription content, access via your institution.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med. 2002;347:911–20. Evidence that infections are relevant to the rising incidence of autoimmune and allergic diseases.

    PubMed  Article  Google Scholar 

  2. Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010;464:1293–300.

    PubMed  Article  CAS  Google Scholar 

  3. Todd JA. Etiology of type 1 diabetes. Immunity. 2010;32:457–67.

    PubMed  Article  CAS  Google Scholar 

  4. Redondo MJ, Yu L, Hawa M, Mackenzie T, Pyke DA, Eisenbarth GS, et al. Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia. 2001;44:354–62.

    PubMed  Article  CAS  Google Scholar 

  5. Ziegler AG, Nepom GT. Prediction and pathogenesis in type 1 diabetes. Immunity. 2010;32:468–78.

    PubMed  Article  CAS  Google Scholar 

  6. Leslie RD, Delli Castelli M. Age-dependent influences on the origins of autoimmune diabetes: evidence and implications. Diabetes. 2004;53:3033–40.

    PubMed  Article  CAS  Google Scholar 

  7. Harron KL, Feltbower RG, McKinney PA, Bodansky HJ, Campbell FM, Parslow RC. Rising rates of all types of diabetes in south Asian and non-south Asian children and young people aged 0–29 years in West Yorkshire, U.K., 1991–2006. Diabetes Care. 2011;34:652–4.

    PubMed  Article  Google Scholar 

  8. Couper JJ, Beresford S, Hirte C, Baghurst PA, Pollard A, Tait BD, et al. Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes. Diabetes Care. 2009;32:94–9.

    PubMed  Article  Google Scholar 

  9. Beyan H, Riese H, Hawa MI, Beretta G, Davidson HW, Hutton JC, et al. Glycotoxin and autoantibodies are additive environmentally determined predictors of type 1 diabetes: a twin and population study. Diabetes. 2012;61:1192–8.

    PubMed  Article  CAS  Google Scholar 

  10. Cooper JD, Smyth DJ, Walker NM, Stevens H, Burren OS, Wallace C, et al. Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes. 2011;60:1624–31.

    PubMed  Article  CAS  Google Scholar 

  11. Heinig M, Petretto E, Wallace C, Bottolo L, Rotival M, Lu H, et al. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature. 2010;467:460–4.

    PubMed  Article  CAS  Google Scholar 

  12. Nejentsev S, Walker N, Riches D, Egholm M, Todd JA. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science. 2009;324:387–9.

    PubMed  Article  CAS  Google Scholar 

  13. Vlassara H, Striker GE. AGE restriction in diabetes mellitus: a paradigm shift. Nat Rev Endocrinol. 2011;7:526–39.

    PubMed  Article  CAS  Google Scholar 

  14. Oresic M, Simell S, Sysi-Aho M, Näntö-Salonen K, Seppänen-Laakso T, Parikka V, et al. Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J Exp Med. 2008;205:2975–84.

    PubMed  Article  CAS  Google Scholar 

  15. Pflueger M, Seppänen-Laakso T, Suortti T, Hyötyläinen T, Achenbach P, Bonifacio E, et al. Age- and islet autoimmunity-associated differences in amino acid and lipid metabolites in children at risk for type 1 diabetes. Diabetes. 2011;60:2740–7.

    PubMed  Article  CAS  Google Scholar 

  16. • Rakyan VK, Beyan H, Down TA, Hawa MI, Maslau S, Aden D, et al. Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis. PLoS Genet. 2011;7:e1002300. The first epigenome-wide association study (EWAS) of a common human disease.

    PubMed  Article  CAS  Google Scholar 

  17. Turnbaugh PJ, Bäckhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3:213–23.

    PubMed  Article  CAS  Google Scholar 

  18. Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med. 2009;1:6ra14.

    PubMed  Article  Google Scholar 

  19. Kosiewicz MM, Zirnheld AL, Alard P. Gut microbiota, immunity, and disease: a complex relationship. Front Microbiol. 2011;2:180.

    PubMed  Google Scholar 

  20. Reading NC, Kasper DL. The starting lineup: key microbial players in intestinal immunity and homeostasis. Front Microbiol. 2011;2:148.

    PubMed  CAS  Google Scholar 

  21. Smith PM, Garrett WS. The gut microbiota and mucosal T cells. Front Microbiol. 2011;2:111.

    PubMed  Google Scholar 

  22. •• Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science. 2012;336:489–93. The first evidence that education of gut mucosal immune cells is associated with protection from immune-mediated diseases.

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  24. de St Groth BF. Regulatory T-cell abnormalities and the global epidemic of immuno-inflammatory disease. Immunol Cell Biol. 2012;90:256–9.

    PubMed  Article  Google Scholar 

  25. • Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 2008;453:620–5. Evidence that a microbial polysaccharide can influence gut immune regulation.

    PubMed  Article  CAS  Google Scholar 

  26. Pfeiffer JK, Sonnenburg JL. The intestinal microbiota and viral susceptibility. Front Microbiol. 2011;2:92.

    PubMed  Google Scholar 

  27. Foxman EF, Iwasaki A. Genome-virome interactions: examining the role of common viral infections in complex disease. Nat Rev Microbiol. 2011;9:254–64.

    PubMed  Article  CAS  Google Scholar 

  28. Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ, Samuel BS, et al. Metagenomic analysis of the human distal gut microbiome. Science. 2006;312:1355–9.

    PubMed  Article  CAS  Google Scholar 

  29. •• Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457:480–4. This paper illustrates the deviations from a core microbiome, at a functional level, are associated with physiology deviations from normality.

    PubMed  Article  CAS  Google Scholar 

  30. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59–65.

    PubMed  Article  CAS  Google Scholar 

  31. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472:57–63.

    PubMed  Article  CAS  Google Scholar 

  32. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449:804–10.

    PubMed  Article  CAS  Google Scholar 

  33. •• Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. Bacterial community variation in human body habitats across space and time. Science. 2009;326:1694–7. Gut microbiota, although personalized, varies across body habitats and time.

    PubMed  Article  CAS  Google Scholar 

  34. 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;444:1027–31.

    PubMed  Article  Google Scholar 

  35. Greenblum S, Turnbaugh PJ, Borenstein E. Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease. Proc Natl Acad Sci U S A. 2012;109:594–9.

    PubMed  Article  CAS  Google Scholar 

  36. Vijay-Kumar M, Carvalho FA, Aitken JD, Fifadara NH, Gewirtz AT. TLR5 or NLRC4 is necessary and sufficient for promotion of humoral immunity by flagellin. Eur J Immunol. 2010;40:3528–34.

    PubMed  Article  CAS  Google Scholar 

  37. •• Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008;455:1109–13. The first evidence that changes in the innate immune response, mediated by the gut microbiome, prevents autoimmune diabetes.

    PubMed  Article  CAS  Google Scholar 

  38. Young VB, Kahn SA, Schmidt TM, Chang EB. Studying the Enteric Microbiome in Inflammatory Bowel Diseases: Getting through the Growing Pains and Moving Forward. Front Microbiol. 2011;2:144.

    PubMed  Google Scholar 

  39. Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH, et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med. 2008;359:2767–77.

    PubMed  Article  CAS  Google Scholar 

  40. Vaarala O. Is the origin of type 1 diabetes in the gut? Immunol Cell Biol. 2012;90:271–6.

    PubMed  Article  CAS  Google Scholar 

  41. •• Mathis D, Benoist C. The influence of the microbiota on type-1 diabetes: on the threshold of a leap forward in our understanding. Immunol Rev. 2012;245:239–49. Comprehensive review of the immune response in the context of the gut microbiota.

    PubMed  Article  CAS  Google Scholar 

  42. Boerner BP, Sarvetnick NE. Type 1 diabetes: role of intestinal microbiome in humans and mice. Ann N Y Acad Sci. 2011;1243:103–18.

    PubMed  Article  CAS  Google Scholar 

  43. Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL, Casella G, et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 2011;5:82–91.

    PubMed  Article  CAS  Google Scholar 

  44. Brown CT, Davis-Richardson AG, Giongo A, Gano KA, Crabb DB, Mukherjee N, et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One. 2011;6:e25792.

    PubMed  Article  CAS  Google Scholar 

  45. Oikarinen M, Tauriainen S, Oikarinen S, Honkanen T, Collin P, Rantala I, et al. Type 1 diabetes is associated with enterovirus infection in gut mucosa. Diabetes. 2012;61:687–91.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgment

The authors thank Peter Turnbaugh, Harvard, for helpful comments.

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R. D. Leslie.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Beyan, H., Wen, L. & Leslie, R.D. Guts, Germs, and Meals: The Origin of Type 1 Diabetes. Curr Diab Rep 12, 456–462 (2012). https://doi.org/10.1007/s11892-012-0298-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-012-0298-z

Keywords

  • Microbiome
  • Virome
  • Enterotypes
  • Type 1 diabetes
  • Autoimmunity
  • Autoimmune disease
  • NOD mice
  • Toll-like receptors
  • Innate immune response
  • Guts
  • Germs
  • Meals