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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acetylation / drug effects
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Animals
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Bone Marrow Transplantation / adverse effects
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Bone Marrow Transplantation / methods
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Butyrates / immunology
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Butyrates / metabolism
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Butyrates / pharmacology
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Cells, Cultured
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Epithelial Cells / immunology*
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Epithelial Cells / metabolism
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Epithelial Cells / microbiology
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Fatty Acids, Volatile / immunology
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Fatty Acids, Volatile / metabolism
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Female
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Gas Chromatography-Mass Spectrometry
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Gastrointestinal Microbiome / immunology*
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Gastrointestinal Microbiome / physiology
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Gene Expression / immunology
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Graft vs Host Disease / etiology
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Graft vs Host Disease / immunology*
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Graft vs Host Disease / microbiology
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Histone Acetyltransferases / genetics
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Histone Acetyltransferases / immunology
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Histone Acetyltransferases / metabolism
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Histone Deacetylases / genetics
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Histone Deacetylases / immunology
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Histone Deacetylases / metabolism
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Histones / immunology
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Histones / metabolism
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Immunoblotting
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Intestines / cytology
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Intestines / immunology*
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Intestines / microbiology
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Metabolome / immunology*
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Transplantation, Homologous
Substances
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Butyrates
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Fatty Acids, Volatile
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Histones
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Histone Acetyltransferases
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Histone Deacetylases