Journal Article

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

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

2016

Overview

Irradiation to condition hosts for bone marrow transplantation leads to alterations in intestinal microbiota. Reddy and colleagues demonstrate that these changes result in reduced butyrate production and breakdown of intestinal barrier function. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 14 / 14/28 / 631/250 / 631/250/1904 / 631/326/41 / 631/80/458/1275 / 692/699/249/1529 / 82 / 82/58 / Acetylation - drug effects / Animals / Biomedicine / Bone marrow / Bone Marrow Transplantation - adverse effects / Bone Marrow Transplantation - methods / Butyrates - immunology / Butyrates - metabolism / Butyrates - pharmacology / Cells, Cultured / Development and progression / Epithelial Cells - immunology / Epithelial Cells - metabolism / Epithelial Cells - microbiology / Fatty acids / Fatty Acids, Volatile - immunology / Fatty Acids, Volatile - metabolism / Female / Gas Chromatography-Mass Spectrometry / Gastrointestinal Microbiome - immunology / Gastrointestinal Microbiome - physiology / Gene Expression - immunology / Genetic aspects / Graft versus host reaction / Graft vs Host Disease - etiology / Graft vs Host Disease - immunology / Graft vs Host Disease - microbiology / Health aspects / Histone Acetyltransferases - genetics / Histone Acetyltransferases - immunology / Histone Acetyltransferases - metabolism / Histone Deacetylases - genetics / Histone Deacetylases - immunology / Histone Deacetylases - metabolism / Histones - immunology / Histones - metabolism / Immunoblotting / Immunology / Infectious Diseases / Intestines - cytology / Intestines - immunology / Intestines - microbiology / Metabolites / Metabolome - immunology / Mice, Inbred BALB C / Mice, Inbred C57BL / Microbiota (Symbiotic organisms) / Properties / Reverse Transcriptase Polymerase Chain Reaction / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Transplantation, Homologous