• A Corrigendum to this article was published on 20 September 2016

This article has been updated

Abstract

The effect of alterations in intestinal microbiota on microbial metabolites and on disease processes such as graft-versus-host disease (GVHD) is not known. Here we carried out an unbiased analysis to identify previously unidentified alterations in gastrointestinal microbiota–derived short-chain fatty acids (SCFAs) after allogeneic bone marrow transplant (allo-BMT). Alterations in the amount of only one SCFA, butyrate, were observed only in the intestinal tissue. The reduced butyrate in CD326+ intestinal epithelial cells (IECs) after allo-BMT resulted in decreased histone acetylation, which was restored after local administration of exogenous butyrate. Butyrate restoration improved IEC junctional integrity, decreased apoptosis and mitigated GVHD. Furthermore, alteration of the indigenous microbiota with 17 rationally selected strains of high butyrate–producing Clostridia also decreased GVHD. These data demonstrate a heretofore unrecognized role of microbial metabolites and suggest that local and specific alteration of microbial metabolites has direct salutary effects on GVHD target tissues and can mitigate disease severity.

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Change history

  • 26 August 2016

    In the version of this article initially published, the middle initial (C) for the sixteenth author was incorrect. The correct author name should be Thomas M. Schmidt (and the corresponding initials in the Author Contributions section should be T.M.S.). The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This work was supported by the US National Institutes of Health (NIH) (National Heart, Lung and Blood Institute, grants HL-090775 and HL-128046 (to P.R.); National Cancer Institute, grant CA-173878 (to P.R.)). Metabolomic studies were performed through the Molecular Phenotyping Core, Michigan Nutrition and Obesity Center (grant DK089503 (to S.P.)) and Michigan Regional Metabolomics Resource Core (grant DK097153 (to S.P.)). We acknowledge use of the Microscopy & Image-analysis Laboratory (MIL) of the University of Michigan's Biomedical Research Core Facilities for preparation of samples and images. Support for the MIL core is provided by the University of Michigan Cancer Center (NIH grant CA46592) and the University of Michigan Gut Peptide Research Center (NIH grant DK34933).

Author information

Author notes

    • Nathan D Mathewson
    • , Robert Jenq
    • , Anna V Mathew
    • , Mark Koenigsknecht
    • , Alan Hanash
    • , Vincent B Young
    • , Subramaniam Pennathur
    •  & Marcel van den Brink

    These authors contributed equally to this work.

Affiliations

  1. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA.

    • Nathan D Mathewson
    • , Tomomi Toubai
    • , Katherine Oravecz-Wilson
    • , Shin-Rong Wu
    • , Yaping Sun
    • , Corinne Rossi
    • , Hideaki Fujiwara
    •  & Pavan Reddy
  2. Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

    • Nathan D Mathewson
    •  & Shin-Rong Wu
  3. Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Robert Jenq
    • , Alan Hanash
    • , Yusuke Shono
    • , Caroline Lindemans
    • , Marco Calafiore
    •  & Marcel van den Brink
  4. Division of Nephrology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA.

    • Anna V Mathew
    • , Jaeman Byun
    •  & Subramaniam Pennathur
  5. Division of Infectious Disease, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA.

    • Mark Koenigsknecht
    • , Thomas M Schmidt
    •  & Vincent B Young
  6. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Kenya Honda

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Contributions

N.D.M. designed experiments, performed experiments, analyzed data and wrote the paper. A.V.M. and M.K. performed experiments and analyzed data. R.J. and A.H. designed and performed experiments. T.T., K.O.-W., S.-R.W., Y.S., C.R., H.F., J.B., Y.S., C.L. and M.C. performed experiments. T.M.S., V.B.Y. and M.v.d.B. wrote the paper. K.H. provided reagents and wrote the paper. S.P. analyzed data and wrote the paper. P.R. designed experiments, analyzed data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Pavan Reddy.

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    Supplementary Table 1: qPCR primers

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DOI

https://doi.org/10.1038/ni.3400

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