Article

Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites

  • Nature Communications 6, Article number: 7320 (2015)
  • doi:10.1038/ncomms8320
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Abstract

Asthma is prevalent in Western countries, and recent explanations have evoked the actions of the gut microbiota. Here we show that feeding mice a high-fibre diet yields a distinctive gut microbiota, which increases the levels of the short-chain fatty acid, acetate. High-fibre or acetate-feeding led to marked suppression of allergic airways disease (AAD, a model for human asthma), by enhancing T-regulatory cell numbers and function. Acetate increases acetylation at the Foxp3 promoter, likely through HDAC9 inhibition. Epigenetic effects of fibre/acetate in adult mice led us to examine the influence of maternal intake of fibre/acetate. High-fibre/acetate feeding of pregnant mice imparts on their adult offspring an inability to develop robust AAD. High fibre/acetate suppresses expression of certain genes in the mouse fetal lung linked to both human asthma and mouse AAD. Thus, diet acting on the gut microbiota profoundly influences airway responses, and may represent an approach to prevent asthma, including during pregnancy.

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Acknowledgements

We thank Monash animal facilities, Histology Platform and FlowCore. We acknowledge Vicki Clifton, Philippa Talbot, Kelly Steel, Penelope McLernon and Karen McLaughlin for human sample and data collection, Phillipe Collas for assistance with ChIP, Andreas Suhrbier for IPA, Magdalena Hubalewska and Marcin Surmiak for qPCR and western blot, Ashlee Burt and Laurent Juglair for general assistance and Pat Holt for critically reviewing this manuscript. Jason Bell provided High Performance Computing support. This work was supported by NHMRC, CRC for Asthma and airways, The University of Newcastle, Asthma Foundation NSW, HMRI, Port Waratah Coal Services and Hunter Children’s Research Foundation.

Author information

Affiliations

  1. Department of Immunology, Monash University, Clayton, Victoria 3800, Australia

    • Alison N. Thorburn
    • , Craig I. McKenzie
    • , Sj Shen
    • , Laurence Macia
    • , Linda J. Mason
    • , Laura K. Roberts
    • , Connie H. Y. Wong
    • , Raymond Shim
    • , Remy Robert
    • , Nina Chevalier
    • , Jian K. Tan
    • , Eliana Mariño
    •  & Charles R. Mackay
  2. School of Medical and Applied Sciences, Central Queensland University, Rockhampton, Queensland 4702, Australia

    • Dragana Stanley
  3. Department of Rheumatology and Clinical Immunology, University Medical Center, 79106 Freiburg, Germany

    • Nina Chevalier
  4. CSIRO Animal, Food, and Health Sciences, Geelong, Victoria 3220, Australia

    • Rob J. Moore
  5. Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia

    • Rob J. Moore
  6. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia

    • Lee Wong
  7. Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Melbourne, Victoria 3010, Australia

    • Malcolm J. McConville
  8. Metabolomics Australia, Bio21 Institute of Molecular Sciences and Biotechnology, University of Melbourne, Melbourne, Victoria 3010, Australia

    • Malcolm J. McConville
    •  & Dedreia L. Tull
  9. Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales 2300, Australia

    • Lisa G. Wood
    • , Vanessa E. Murphy
    • , Joerg Mattes
    •  & Peter G. Gibson
  10. Charles Perkins Centre, Sydney University Medical School, University of Sydney, Sydney, New South Wales 2006, Australia

    • Charles R. Mackay

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Contributions

A.N.T. conceived and initiated the project, planned and performed the experiments, analysed the data and wrote the manuscript. C.I.M. and S.S. planned and performed the experiments and analysed the data. D.S. performed the microbiota analysis. L.M. determined diets for use and provided general support. L.J.M. planned and performed experiments. L.E.R, C.H.Y.W, R.S., R.R., N.C. performed and/or assisted with experiments. J.K.T. and E.M. provided general support. R.J.M. contributed to microbiota analysis. L.W. performed/assisted with the ChIP experiments. M.J.M. and D.L.T. were involved in metabolite analysis. L.G.W. and V.E.M. were involved in clinical outcome data collection and analysis. J.M. and P.G.G. provided patient samples and clinical outcome data. C.R.M. established the overarching hypothesis for the study, supervised the study and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Charles R. Mackay.

Supplementary information

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  1. 1.

    Supplementary Information

    Supplementary Figures 1-19, Supplementary Tables 1-8

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