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Nat Immunol. 2016 May;17(5):505-513. doi: 10.1038/ni.3400. Epub 2016 Mar 21.

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

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Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.
Adult Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Internal Medicine, Nephrology, University of Michigan Health System, Ann Arbor, MI, USA.
Internal Medicine, Infectious Disease, University of Michigan Health System, Ann Arbor, MI, USA.
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Contributed equally


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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