Skip to main content

Advertisement

SpringerLink
Log in

Human Intestinal Microbiota and Type 1 Diabetes

  • Pathogenesis of Type 1 Diabetes (D Dabelea, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

The role of intestinal microbiota in immune-mediated diseases, such as type 1 diabetes, has deservedly received a lot of attention. Evidently, changes in the intestinal microbiota are associated with type 1 diabetes as demonstrated by recent studies. Children with beta-cell autoimmunity have shown low abundance of butyrate-producing bacteria and increase in the abundance of members of the Bacteroidetes phylum in fecal microbiota. These alterations could explain increased gut permeability, subclinical small intestinal inflammation, and dysregulation of oral tolerance in type 1 diabetes. However, these studies do not provide evidence of the causative role of the gut microbiota in the development of beta-cell autoimmunity, yet. In animal models, the composition of gut microbiota modulates the function of both innate and adaptive immunity, and intestinal bacteria are regulators of autoimmune diabetes. Thus, prevention of type 1 diabetes could, in the future, be based on the interventions targeted to the gut microbiota.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

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

  1. Vaarala O, Atkinson MA, Neu J. The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes. 2008;57:2555–62.

    Article  PubMed  CAS  Google Scholar 

  2. Bosi E, Molteni L, Radaelli MG, Folini L, Fermo I, Bazzigaluppi E, et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia. 2006;49:2824–7.

    Article  PubMed  CAS  Google Scholar 

  3. Vaarala O. Leaking gut in type 1 diabetes. Curr Opin Gastroenterol. 2008;24:701–6.

    Article  PubMed  Google Scholar 

  4. Westerholm-Ormio M, Vaarala O, Pihkala P, Ilonen J, Savilahti E. Immunologic activity in the small intestinal mucosa of pediatric patients with type 1 diabetes. Diabetes. 2003;52:2287–95.

    Article  PubMed  CAS  Google Scholar 

  5. Auricchio R, Paparo F, Maglio M, Franzese A, Lombardi F, Valerio G, et al. In vitro-deranged intestinal immune response to gliadin in type 1 diabetes. Diabetes. 2004;53:1680–3.

    Article  PubMed  CAS  Google Scholar 

  6. Tiittanen M, Westerholm-Ormio M, Verkasalo M, Savilahti E, Vaarala O. Infiltration of forkhead box P3-expressing cells in small intestinal mucosa in coeliac disease but not in type 1 diabetes. Clin Exp Immunol. 2008;152:498–507.

    Article  PubMed  CAS  Google Scholar 

  7. Badami E, Sorini C, Coccia M, Usuelli V, Molteni L, Bolla AM, et al. Defective differentiation of regulatory FoxP3+ T cells by small-intestinal dendritic cells in patients with type 1 diabetes. Diabetes. 2011;60:2120–4.

    Article  PubMed  CAS  Google Scholar 

  8. Luopajärvi K, Savilahti E, Virtanen SM, Ilonen J, Knip M, Akerblom HK, et al. Enhanced levels of cow's milk antibodies in infancy in children who develop type 1 diabetes later in childhood. Pediatr Diabetes. 2008;9:434–41.

    Article  PubMed  Google Scholar 

  9. •• 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. The findings of this pilot study including 4 healthy individuals and 4 children who developed type 1 diabetes suggest type 1 diabetes associated differences in the intestinal microbiota.

    Article  PubMed  CAS  Google Scholar 

  10. •• 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;610:e25792. The findings of this pilot study including 4 healthy individuals and 4 children who developed type 1 diabetes suggest that alterations in the metabolic potential of the microbiota is seen in type 1 diabetes.

    Article  Google Scholar 

  11. •• Goffau M, Luopajärvi K, Knip M, Ilonen J, Ruohtula T, Härkönen T, et al. Fecal microbiota composition differs between children with beta-cell autoimmunity and those without. Diabetes. 2013;62:1238–44. This study demonstrates low abundance of butyrate producing bacteria and increased abundance of Bacteroides in prediabetic individuals providing a link to dysregulation of gut immune system and altered microbiota in type 1 diabetes.

    Article  PubMed  Google Scholar 

  12. • 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;107:12204–9. This study describes Bacteroides fragilis and its polysaccharide A as inducer of intestinal regulatory T-cell development and regulator of colitis.

    Article  PubMed  CAS  Google Scholar 

  13. • Ochoa-Repáraz J, Mielcarz DW, Ditrio LE, Burroughs AR, Begum-Haque S, Dasgupta S, et al. Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J Immunol. 2010;185:4101–8. This article provides evidence of extra-intestinal immunological effects of commensals.

    Article  PubMed  Google Scholar 

  14. • Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331:337–41. This study demonstrates the induction of regulatory T-cells by Clostridium species and the long-lasting immunomodulatory effects of the oral administration with these Clostridium species at early life in a mouse model.

    Article  PubMed  CAS  Google Scholar 

  15. Nagano Y, Itoh K, Honda K. The induction of Treg cells by gut-indigenous Clostridium. Curr Opin Immunol. 2012;24:392–7.

    Article  PubMed  CAS  Google Scholar 

  16. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139:485–98.

    Article  PubMed  CAS  Google Scholar 

  17. • Valladares R, Sankar D, Li N, Williams E, Lai KK, Abdelgeliel AS, et al. Inhibition of type 1 diabetes correlated to a Lactobacillus johnsonii N6.2-mediated Th17 bias. PLoS One. 2010;5:e10507. doi:10.1371/journal.pone.0010507. This study identifies Lactobacillus johnsonii as an up-regulator of the intestinal IL-17 expression.

    Article  PubMed  Google Scholar 

  18. Knip M, Virtanen SM, Seppä K, Ilonen J, Savilahti E, Vaarala O, et al. Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med. 2010;363:1900–8.

    Article  PubMed  CAS  Google Scholar 

  19. Vaarala O, Ilonen J, Ruohtula T, Pesola J, Virtanen SM, Härkönen T, et al. Removal of bovine insulin from cow’s milk formula and early initiation of beta-cell autoimmunity in the FINDIA Pilot Study. Arch Pediatr Adolesc Med. 2012;166:608–14.

    Article  PubMed  Google Scholar 

  20. • Human Microbiome Project Consortium. Structure, function, and diversity of the healthy human microbiome. Nature. 2012;486:207–14. The extensive analyses of our microbiome indicate that the composition of gut microbiota also shows significant variation between healthy individuals.

    Article  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. Manichanh C, Rigottier-Gois L, Bonnaud E, Gloux K, Pelletier E, Frangeul L, et al. Reduced diversity of fecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut. 2006;55:205–11.

    Article  PubMed  CAS  Google Scholar 

  23. Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008;134:577–94.

    Article  PubMed  CAS  Google Scholar 

  24. Romond MB, Colavizza M, Mullié C, Kalach N, Kremp O, Mielcarek C, et al. Does the intestinal bifidobacterial colonisation affect bacterial translocation? Anaerobe. 2008;14:43–8.

    Article  PubMed  CAS  Google Scholar 

  25. Brugman S, Klatter FA, Visser JT, et al. Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes? Diabetologia. 2006;49:2105–8.

    Article  PubMed  CAS  Google Scholar 

  26. Roesch LF, Lorca GL, Casella G, et al. Culture-independent identification of gut bacteria correlated with the onset of diabetes in a rat model. ISME J. 2009;3:536–48.

    Article  PubMed  CAS  Google Scholar 

  27. • Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013;339:1084–8. This study indicates that sex hormones modulate gut microbiota and vice versa and provides a novel link to hormone-dependent regulation of autoimmune diseases.

    Article  PubMed  CAS  Google Scholar 

  28. Hague A, Butt AJ, Paraskeva C. The role of butyrate in human colonic epithelial cells: an energy source or inducer of differentiation and apoptosis? Proc Nutr Soc. 1996;55:937–43.

    Article  PubMed  CAS  Google Scholar 

  29. Peng L, Li ZR, 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. J Nutr. 2009;139:1619–25.

    Article  PubMed  CAS  Google Scholar 

  30. Li N, Hatch M, Wasserfall CH, Douglas-Escobar M, Atkinson MA, Schatz DA, et al. Butyrate and type 1 diabetes mellitus : can we fix the intestinal leak? J Pediatr Gastroenterol Nutr. 2010;51:414–7.

    Article  PubMed  CAS  Google Scholar 

  31. Duncan SH, Barcenilla A, Stewart CS, Pryde SE, Flint HJ. Acetate utilization and butyryl coenzyme A (CoA):acetate-CoA transferase in butyrate-producing bacteria from the human large intestine. Appl Environ Microbiol. 2002;68:5186–90.

    Article  PubMed  CAS  Google Scholar 

  32. Duncan SH, Louis P, Flint HJ. Lactate-utilizing bacteria, isolated from human feces, that produce butyrate as a major fermentation product. Appl Environ Microbiol. 2004;70:5810–7.

    Article  PubMed  CAS  Google Scholar 

  33. Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermidez-Humaran LG, Gratadoux JJ, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105:16731–6.

    Article  PubMed  CAS  Google Scholar 

  34. Hansen CH, Krych L, Nielsen DS, Vogensen FK, Hansen LH, Sørensen SJ, et al. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia. 2012;55:2285–94. The findings of this study suggest that Akkermansia muciniphila could provide protection from autoimmune diabetes.

    Article  PubMed  CAS  Google Scholar 

  35. 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.

    Article  PubMed  CAS  Google Scholar 

  36. • Hara N, Alkanani AK, Ir D, Robertson CE, Wagner BD, Frank DN, et al. Prevention of virus-induced type 1 diabetes with antibiotic therapy. J Immunol. 2012;189:3805–14. This paper demonstrates that viral infection caused change in the composition of the intestinal bacteria is a key determinant in the development of “virus induced autoimmune diabetes”.

    Article  PubMed  CAS  Google Scholar 

  37. •• Cadwell K, Patel KK, Maloney NS, Liu T-C, NG ACY, Storer CE, et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell. 2010;141:1135–45. The development of Crohn’s disease resembling pathologies was demonstrated in a mouse model, in which toxin induced intestinal changes were dependent on the interaction of the disease related gene polymorphism, norovirus infection, commensal bacteria and activation of IFN-γ.

    Article  PubMed  CAS  Google Scholar 

  38. Visser JT, Bos NA, Harthoorn LF, Stellaard F, Beijer-Liefers S, Rozing J, et al. Potential mechanisms explaining why hydrolyzed casein-based diets outclass single amino acid-based diets in the prevention of autoimmune diabetes in diabetes-prone BB rats. Diabetes Metab Res Rev. 2012;28:505–13.

    Article  PubMed  CAS  Google Scholar 

  39. Huovinen P. Bacteriotherapy: the time has come. BMJ. 2001;323:353–4.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Research support from the Academy of Finland, Sigrid Juselius Foundation and Päivikki and Sakari Sohlberg Foundation is acknowledged. My thanks to Prof. Pentti Huovinen for the constructive criticism of the manuscript.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Outi Vaarala declares that she has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Vaccination and Immune Protection, National Institute for Health and Welfare, Haartmaninkatu 8, 00290, Helsinki, Finland

    Outi Vaarala

Authors
  1. Outi Vaarala
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Outi Vaarala.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vaarala, O. Human Intestinal Microbiota and Type 1 Diabetes. Curr Diab Rep 13, 601–607 (2013). https://doi.org/10.1007/s11892-013-0409-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-013-0409-5

Keywords

Search

Navigation