Article | Published:

NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth

Nature Immunology volume 18, pages 541551 (2017) | Download Citation

  • An Erratum to this article was published on 19 July 2017
  • A Corrigendum to this article was published on 18 October 2017

This article has been updated

Abstract

Inflammatory bowel diseases involve the dynamic interaction of host genetics, the microbiome and inflammatory responses. Here we found lower expression of NLRP12 (which encodes a negative regulator of innate immunity) in human ulcerative colitis, by comparing monozygotic twins and other patient cohorts. In parallel, Nlrp12 deficiency in mice caused increased basal colonic inflammation, which led to a less-diverse microbiome and loss of protective gut commensal strains (of the family Lachnospiraceae) and a greater abundance of colitogenic strains (of the family Erysipelotrichaceae). Dysbiosis and susceptibility to colitis associated with Nlrp12 deficency were reversed equally by treatment with antibodies targeting inflammatory cytokines and by the administration of beneficial commensal Lachnospiraceae isolates. Fecal transplants from mice reared in specific-pathogen-free conditions into germ-free Nlrp12-deficient mice showed that NLRP12 and the microbiome each contributed to immunological signaling that culminated in colon inflammation. These findings reveal a feed-forward loop in which NLRP12 promotes specific commensals that can reverse gut inflammation, while cytokine blockade during NLRP12 deficiency can reverse dysbiosis.

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Change history

  • 17 April 2017

    In the version of this article initially published, the second sentence in the first subsection of Results incorrectly described an experimental group as "...seven additional patients with UC...". The correct description is "...seven additional UC patient cohorts...". The error has been corrected in the HTML and PDF versions of the article.

  • 18 May 2017

    In the version of this article initially published, the vertical axis of Figure 5j was incorrectly labeled 'PC1 (22.56%)'. The correct label is 'PC3 (6.47%)'. The error has been corrected in the HTML and PDF versions of this article.

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European Nucleotide Archive

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Acknowledgements

We thank the following for core and technical support: the University of North Carolina (UNC)–North Carolina State University Center for Gastrointestinal Biology and Disease; the UNC Microbiome Core Facility; S.L. Tonkonogy and the Gnotobiotic Core at North Carolina State University; M.A. Bower and J.W. Herzog at the National Gnotobiotic Rodent Resource Center and Crohn's and Colitis Foundation of America Gnotobiotic Animal Facility at UNC; the UNC Lineberger Comprehensive Cancer Center Animal Histopathology Core Facility and Animal Studies Core Facility; and the UNC Flow Cytometry Core Facility. Supported by the US National Institute of Health (RO1-CA156330 to J.P.-Y.T. (National Cancer Institute); P01 DK094779 to J.P.-Y.T., P30 DK034987 to R.B.S., F32-DK088417-01 to J.E.W. and F32-DK098916 to A.D.T. (National Institute of Diabetes and Digestive and Kidney Diseases); U19-AI067798 and R37 AI029564 to J.P.-Y.T. and U19 AI090871 to V.B.Y. (National Institute of Allergy and Infectious Disease); and P40 OD010995 to R.B.S. (Office of the Director)), the American Cancer Society (PF-13-401-01-TBE to J.E.W.), the Crohn's and Colitis Foundation of America (R.B.S.) and the National Multiple Sclerosis Society (FG 1968-A-1 to W-C.C.).

Author information

Author notes

    • Liang Chen
    •  & Justin E Wilson

    These authors contributed equally to this work.

Affiliations

  1. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Liang Chen
    • , W June Brickey
    • , Glenn K Matsushima
    •  & Jenny P-Y Ting
  2. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Liang Chen
    • , Justin E Wilson
    • , Stephanie A Montgomery
    • , Agnieszka D Truax
    • , W June Brickey
    •  & Jenny P-Y Ting
  3. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Justin E Wilson
    • , Wei-Chun Chou
    • , Agnieszka D Truax
    •  & Jenny P-Y Ting
  4. Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA.

    • Mark J Koenigsknecht
    •  & Vincent B Young
  5. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Stephanie A Montgomery
  6. Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York, USA.

    • Christopher D Packey
  7. Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

    • Nitsan Maharshak
  8. UNC Neuroscience Center and Integrative Program for Biological Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Glenn K Matsushima
  9. Immunology Research and Development, Janssen Pharmaceuticals, Spring House, Pennsylvania, USA.

    • Scott E Plevy
  10. Center for Gastrointestinal Biology and Disease and the Departments of Medicine, of Microbiology and of Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.

    • R Balfour Sartor

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Contributions

L.C., J.E.W. and J.P.-Y.T. designed the experiments and wrote the manuscript, with critical input from V.B.Y. and R.B.S.; M.J.K. and V.B.Y. generated the purified Lachnospiraceae strains; W.-C.C. contributed to the immunoblot analysis, cytokine measurement and flow cytometry; S.A.M. performed the histopathological scoring; A.D.T., W.J.B. and G.K.M. generated the radiation-bone-marrow chimeras; C.D.P., N.M., S.E.P. and R.B.S. contributed to the isolation of fecal DNA and 16S rRNA gene-sequencing experiments; and R.B.S. generated the GF mice.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jenny P-Y Ting.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7

Excel files

  1. 1.

    Supplementary Table 1

    Microbiome sequencing of fecal DNA from Wild Type and Nlrp12–/– mice housed in vivarium #1

  2. 2.

    Supplementary Table 2

    Microbiome sequencing of fecal DNA from Wild Type and Nlrp12–/– mice housed in vivarium #2.

  3. 3.

    Supplementary Table 3

  4. 4.

    Supplementary Table 4

    Nlrp12–/– mice and IBD patients share similar reduction of specific microbiota.

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    Supplementary Table 5

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    Supplementary Table 6

    The specificity and coverage of the primers used to identify the 23 Lachnospiraceae strains

  7. 7.

    Supplementary Table 7

    List of isolation conditions and classification of 23 Lachnospiraceae strains

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DOI

https://doi.org/10.1038/ni.3690

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