Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease

Nathan D. Mathewson, Robert Jenq, Anna V. Mathew, Mark Koenigsknecht, Alan Hanash, Tomomi Toubai, Katherine Oravecz-Wilson, Shin Rong Wu, Yaping Sun, Corinne Rossi, Hideaki Fujiwara, Jaeman Byun, Yusuke Shono, Caroline Lindemans, Marco Calafiore, Thomas C. Schmidt, Kenya Honda, Vincent B. Young, Subramaniam Pennathur, Marcel Van Den BrinkPavan Reddy

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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.

Original languageEnglish
Pages (from-to)505-513
Number of pages9
JournalNature Immunology
Volume17
Issue number5
DOIs
Publication statusPublished - 2016 May 1

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mathewson, N. D., Jenq, R., Mathew, A. V., Koenigsknecht, M., Hanash, A., Toubai, T., Oravecz-Wilson, K., Wu, S. R., Sun, Y., Rossi, C., Fujiwara, H., Byun, J., Shono, Y., Lindemans, C., Calafiore, M., Schmidt, T. C., Honda, K., Young, V. B., Pennathur, S., ... Reddy, P. (2016). Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nature Immunology, 17(5), 505-513. https://doi.org/10.1038/ni.3400