Abstract

Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell–dependent autoimmune diseases.

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Change history

  • Corrected online 05 April 2017

    In the version of this article initially published online, the callout for Figure 4g was incorrectly attributed, and Figure 5d was displayed incorrectly. The errors have been corrected in the print, PDF and HTML versions of the article.

  • Corrected online 08 May 2017

    In the version of this article initially published, the graph curves in Figure 2b were displayed incorrectly. The error has been corrected in the HTML and PDF versions of the article.

  • Corrected online 20 September 2017

    In the supplementary information originally posted online, Supplementary Tables 2 and 3 were missing titles and legends. The error has been corrected in this file as of 20 September 2017.

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Gene Expression Omnibus

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Acknowledgements

We thank S. Akira (Osaka University) for Myd88−/− mice; D.R. Powell, S. Archer, Deltagen, B. Scherer, H. Thomas, G. Jhala, L. Mason, H.Y. Goh, M. Udugama, F. Lim, Y.A. Leong, C. Ang Kim Lian, C. McKenzie and Monash Animal Services for assistance; the NIH Tetramer Facility for the IGRP and BDC2.5 tetramers; and the Monash Histology Platform of Monash University. Supported by the Juvenile Diabetes Research Foundation (3-2013-94), the Diabetes Australia Research Trust (Y14M1-MARE), and the Australian National Health and Medical Research Council (program grant 1016953 and Australia Fellowship 606947).

Author information

Affiliations

  1. Infection and Immunity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia.

    • Eliana Mariño
    • , James L Richards
    • , Keiran H McLeod
    • , Yu Anne Yap
    • , Jacinta Knight
    • , Craig McKenzie
    • , Laurence Macia
    • , Alison Thorburn
    • , Lee H Wong
    •  & Charles R Mackay
  2. Central Queensland University, School of Medical and Applied Sciences, Rockhampton, Australia.

    • Dragana Stanley
  3. Institute for Immunology, Ludwig Maximilians University, Munich, Munich, Germany.

    • Jan Kranich
  4. Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

    • Ana Carolina Oliveira
  5. Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.

    • Fernando J Rossello
    • , Christian M Nefzger
    •  & Jose M Polo
  6. Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, Australia.

    • Fernando J Rossello
    • , Christian M Nefzger
    •  & Jose M Polo
  7. Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.

    • Fernando J Rossello
    • , Christian M Nefzger
    •  & Jose M Polo
  8. Islet Biology Laboratory, St Vincent's Institute, Fitzroy, Australia.

    • Balasubramanian Krishnamurthy
  9. Nutritional Immunometabolism Node Laboratory, Charles Perkins Centre, University of Sydney, Sydney, Australia.

    • Laurence Macia
  10. School of Medical Sciences, University of Sydney, Sydney, Australia.

    • Laurence Macia
  11. Comparative Genomics Centre, Molecular Sciences, James Cook University, Townsville, Australia.

    • Alan G Baxter
  12. Harry Perkins Institute for Medical Research, Nedlands, Australia.

    • Grant Morahan
  13. Infection and Immunity Program, Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Australia.

    • Robert J Moore
  14. School of Science, RMIT University, Bundoora West Campus, Bundoora, Australia.

    • Robert J Moore
  15. CSIRO Health and Biosecurity, North Ryde, Australia.

    • Trevor J Lockett
  16. CSIRO Health and Biosecurity, Adelaide, Australia.

    • Julie M Clarke
    •  & David L Topping
  17. Walter & Eliza Hall Institute of Medical Research, Parkville, Australia.

    • Leonard C Harrison

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Contributions

E.M. and C.R.M. formulated different elements of the study and wrote the manuscript; E.M. supervised the experimental work and performed flow cytometry, adoptive-transfer experiments and sorting of cells; J.L.R. performed flow cytometry, disease-incidence studies, analysis of pancreata histology and assignment of insulitis scores; K.H.M. performed adoptive-transfer studies, single-sorting experiments, qPCR and GF disease-incidence studies and assisted D.S. in microbiota studies; Y.A.Y. performed flow cytometry of colon samples, in vitro experiments and extraction of fecal DNA; J. Knight. performed flow cytometry; J. Knight and J. Kranich performed disease-incidence studies; C.M. and L.H.W. performed chromatin-immunoprecipitation studies; A.C.O. performed ELISA; F.J.R. did bioinformatics; B.K. provided NOD.Foxp3-GFP mice; C.M.N. performed real-time PCR analysis and Treg cell single-cell expression analysis; L.M. and A.T. edited the manuscript; A.G.B. provided Myd88−/− mice; G.M. performed and assisted with genome-wide studies of single-nucleotide polymorphisms; J.M.P. did bioinformatics and gene-expression analysis; R.J.M. sequenced fecal bacteria DNA; T.J.L., J.M.C. and D.L.T. provided the diets and assisted with intellectual input; L.C.H. performed GF studies and manuscript editing; C.R.M. conceived of and initiated the overall project and provided the overarching hypothesis; and all authors provided specialized technical or intellectual support to the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Eliana Mariño or Charles R Mackay.

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    Supplementary Text and Figures

    Supplementary Figures 1–7 and Supplementary Tables 1–3