TY - JOUR
T1 - Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease
AU - Mathewson, Nathan D.
AU - Jenq, Robert
AU - Mathew, Anna V.
AU - Koenigsknecht, Mark
AU - Hanash, Alan
AU - Toubai, Tomomi
AU - Oravecz-Wilson, Katherine
AU - Wu, Shin Rong
AU - Sun, Yaping
AU - Rossi, Corinne
AU - Fujiwara, Hideaki
AU - Byun, Jaeman
AU - Shono, Yusuke
AU - Lindemans, Caroline
AU - Calafiore, Marco
AU - Schmidt, Thomas C.
AU - Honda, Kenya
AU - Young, Vincent B.
AU - Pennathur, Subramaniam
AU - Van Den Brink, Marcel
AU - Reddy, Pavan
N1 - Funding Information:
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.)).
Publisher Copyright:
© 2016 Nature America, Inc. All rights reserved.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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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U2 - 10.1038/ni.3400
DO - 10.1038/ni.3400
M3 - Article
C2 - 26998764
AN - SCOPUS:84961392222
SN - 1529-2908
VL - 17
SP - 505
EP - 513
JO - Nature Immunology
JF - Nature Immunology
IS - 5
ER -