1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
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Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity

  1. Xue-Song Zhang  Is a corresponding author
  2. Jackie Li
  3. Kimberly A Krautkramer
  4. Michelle Badri
  5. Thomas Battaglia
  6. Timothy C Borbet
  7. Hyunwook Koh
  8. Sandy Ng
  9. Rachel A Sibley
  10. Yuanyuan Li
  11. Wimal Pathmasiri
  12. Shawn Jindal
  13. Robin R Shields-Cutler
  14. Ben Hillmann
  15. Gabriel A Al-Ghalith
  16. Victoria E Ruiz
  17. Alexandra Livanos
  18. Angelique Wout
  19. Nabeetha Nagalingam
  20. Arlin B Rogers
  21. Susan Jenkins Sumner
  22. Dan Knights
  23. John M Denu
  24. Huilin Li  Is a corresponding author
  25. Kelly V Ruggles
  26. Richard Bonneau
  27. Anthony R Williamson
  28. Marcus Rauch
  29. Martin J Blaser  Is a corresponding author
  1. New York University Langone Medical Center, United States
  2. University of Wisconsin School of Medicine and Public Health, United States
  3. University of North Carolina at Chapel Hill School of Public Health, United States
  4. University of Minnesota, United States
  5. Janssen Pharmaceutical Companies of Johnson and Johnson, United Kingdom
  6. Tufts University, United States
  7. New York University, United States
Research Article
  • Cited 22
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Cite this article as: eLife 2018;7:e37816 doi: 10.7554/eLife.37816

Abstract

The early-life intestinal microbiota plays a key role in shaping host immune system development. We found that a single early-life antibiotic course (1PAT) accelerated type 1 diabetes (T1D) development in male NOD mice. The single course had deep and persistent effects on the intestinal microbiome, leading to altered cecal, hepatic, and serum metabolites. The exposure elicited sex-specific effects on chromatin states in the ileum and liver and perturbed ileal gene expression, altering normal maturational patterns. The global signature changes included specific genes controlling both innate and adaptive immunity. Microbiome analysis revealed four taxa each that potentially protect against or accelerate T1D onset, that were linked in a network model to specific differences in ileal gene expression. This simplified animal model reveals multiple potential pathways to understand pathogenesis by which early-life gut microbiome perturbations alter a global suite of intestinal responses, contributing to the accelerated and enhanced T1D development.

Article and author information

Author details

  1. Xue-Song Zhang

    Department of Medicine, New York University Langone Medical Center, New York, United States
    For correspondence
    xuesong.zhang@nyumc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5080-0098
  2. Jackie Li

    Department of Medicine, New York University Langone Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1376-6692
  3. Kimberly A Krautkramer

    Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Michelle Badri

    Department of Medicine, New York University Langone Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Thomas Battaglia

    Department of Medicine, New York University Langone Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Timothy C Borbet

    Department of Medicine, New York University Langone Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Hyunwook Koh

    Department of Population Health, New York University Langone Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sandy Ng

    Department of Medicine, New York University Langone Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Rachel A Sibley

    Department of Medicine, New York University Langone Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Yuanyuan Li

    Nutrition Research Institute, University of North Carolina at Chapel Hill School of Public Health, Kannapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Wimal Pathmasiri

    Nutrition Research Institute, University of North Carolina at Chapel Hill School of Public Health, Kannapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Shawn Jindal

    Department of Medicine, New York University Langone Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Robin R Shields-Cutler

    BioTechnology Institute, Computer Science and Engineering, University of Minnesota, St Paul, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Ben Hillmann

    BioTechnology Institute, Computer Science and Engineering, University of Minnesota, St Paul, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Gabriel A Al-Ghalith

    BioTechnology Institute, Computer Science and Engineering, University of Minnesota, St Paul, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Victoria E Ruiz

    Department of Medicine, New York University Langone Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Alexandra Livanos

    Department of Medicine, New York University Langone Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Angelique Wout

    Janssen Prevention Center London, Janssen Pharmaceutical Companies of Johnson and Johnson, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  19. Nabeetha Nagalingam

    Janssen Prevention Center London, Janssen Pharmaceutical Companies of Johnson and Johnson, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  20. Arlin B Rogers

    Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Susan Jenkins Sumner

    Nutrition Research Institute, University of North Carolina at Chapel Hill School of Public Health, Kannapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Dan Knights

    BioTechnology Institute, Computer Science and Engineering, University of Minnesota, St Paul, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. John M Denu

    Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Huilin Li

    Department of Population Health, New York University Langone Medical Center, New York, United States
    For correspondence
    Huilin.Li@nyumc.org
    Competing interests
    The authors declare that no competing interests exist.
  25. Kelly V Ruggles

    Department of Medicine, New York University Langone Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  26. Richard Bonneau

    Center for Data Science, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  27. Anthony R Williamson

    Janssen Prevention Center London, Janssen Pharmaceutical Companies of Johnson and Johnson, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  28. Marcus Rauch

    Janssen Prevention Center London, Janssen Pharmaceutical Companies of Johnson and Johnson, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  29. Martin J Blaser

    Department of Medicine, New York University Langone Medical Center, New York, United States
    For correspondence
    Martin.Blaser@nyumc.org
    Competing interests
    The authors declare that no competing interests exist.

Funding

Janssen Labs London (15-A0-00-00-0039-29-01)

  • Martin J Blaser

Fondation Leducq (-33.17CVD01)

  • Martin J Blaser

National Institutes of Health (R01DK110014)

  • Huilin Li

National Institutes of Health (R37GM059785)

  • John M Denu

National Institutes of Health (5T35DK007421)

  • Sandy Ng
  • Rachel A Sibley

National Institutes of Health (F30DK108494)

  • Kimberly A Krautkramer

C & D fund

  • Martin J Blaser

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (160623) of the New York University Langone Medical Center.

Reviewing Editor

  1. Lora V Hooper, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: April 24, 2018
  2. Accepted: July 12, 2018
  3. Accepted Manuscript published: July 24, 2018 (version 1)
  4. Accepted Manuscript updated: July 25, 2018 (version 2)
  5. Version of Record published: August 9, 2018 (version 3)
  6. Version of Record updated: August 13, 2018 (version 4)

Copyright

© 2018, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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