1. Developmental Biology and Stem Cells
  2. Microbiology and Infectious Disease
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Bacterial colonization stimulates a complex physiological response in the immature human intestinal epithelium

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Cite as: eLife 2017;6:e29132 doi: 10.7554/eLife.29132

Abstract

The human gastrointestinal tract is immature at birth, yet must adapt to dramatic changes such as oral nutrition and microbial colonization. The confluence of these factors can lead to severe inflammatory disease in premature infants; however, investigating complex environment-host interactions is difficult due to limited access to immature human tissue. Here, we demonstrate that the epithelium of human pluripotent stem cell-derived human intestinal organoids is globally similar to the immature human epithelium and we utilize HIOs to investigate complex host-microbe interactions in this naïve epithelium. Our findings demonstrate that the immature epithelium is intrinsically capable of establishing a stable host-microbe symbiosis. Microbial colonization leads to complex contact and hypoxia driven responses resulting in increased antimicrobial peptide production, maturation of the mucus layer, and improved barrier function. These studies lay the groundwork for an improved mechanistic understanding of how colonization influences development of the immature human intestine.

Article and author information

Author details

  1. David R Hill

    Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-1626-6079
  2. Sha Huang

    Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Melinda S Nagy

    Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Veda K Yadagiri

    Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Courtney Fields

    Department of Internal Medicine, Division of Infectious Disease, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Dishari Mukherjee

    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Brooke Bons

    Department of Internal Medicine, Division of Infectious Disease, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Priya H Dedhia

    Department of Surgery, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Alana M Chin

    Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-9567-6825
  10. Yu-Hwai Tsai

    Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Shrikar Thodla

    Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Thomas M Schmidt

    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Seth Walk

    Department of Microbiology and Immunology, Montana State University, Bozeman, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Vincent B Young

    Department of Internal Medicine, Division of Infectious Disease, University of Michigan, Ann Arbor, United States
    For correspondence
    youngvi@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
  15. Jason R Spence

    Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, United States
    For correspondence
    spencejr@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0001-7869-3992

Funding

National Institutes of Health (U19AI116482)

  • Vincent B Young

National Institutes of Health (U01DK103141)

  • Jason R Spence

National Institutes of Health (T32AI007528)

  • David R Hill

National Institutes of Health (UL1TR000433)

  • David R Hill

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 animal experiments were approved by the University of Michigan Institutional Animal Care and Use Committee (IACUC; protocol # PRO00006609).

Human subjects: Normal, de-identified human fetal intestinal tissue was obtained from the University of Washington Laboratory of Developmental Biology. Normal, de-identified human adult intestinal issue was obtained from deceased organ donors through the Gift of Life, Michigan. All human tissue used in this work was obtained from non-living donors, was de-identified and was conducted with approval from the University of Michigan IRB (protocol # HUM00093465 and HUM00105750).

Reviewing Editor

  1. Andrew J MacPherson, Reviewing Editor, University of Bern, Switzerland

Publication history

  1. Received: May 31, 2017
  2. Accepted: October 29, 2017
  3. Accepted Manuscript published: November 7, 2017 (version 1)

Copyright

© 2017, Hill 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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