title: Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease.
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.
authors.affiliation: 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.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Mathewson
authors.affiliation: Adult Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Jenq
authors.affiliation: Internal Medicine, Nephrology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Mathew
authors.affiliation: Internal Medicine, Infectious Disease, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Koenigsknecht
authors.affiliation: Adult Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Hanash
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Toubai
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Oravecz-Wilson
authors.affiliation: 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.
authors.forename: Shin-Rong
authors.initials: SR
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Rossi
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Internal Medicine, Nephrology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Jaeman
authors.initials: J
authors.lastname: Byun
authors.affiliation: Adult Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shono
authors.affiliation: Adult Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lindemans
authors.affiliation: Adult Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Calafiore
authors.affiliation: Internal Medicine, Infectious Disease, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Schmidt
authors.affiliation: RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.affiliation: Internal Medicine, Infectious Disease, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Vincent B
authors.initials: VB
authors.lastname: Young
authors.affiliation: Internal Medicine, Nephrology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.affiliation: Adult Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Marcel
authors.initials: M
authors.lastname: van den Brink
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods; D002087:Butyrates / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D005232:Fatty Acids, Volatile / Q000276:immunology / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D000069196:Gastrointestinal Microbiome / Q000276:immunology* / Q000502:physiology; D015870:Gene Expression / Q000276:immunology; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology* / Q000382:microbiology; D051548:Histone Acetyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006657:Histones / Q000276:immunology / Q000378:metabolism; D015151:Immunoblotting; D007422:Intestines / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D055442:Metabolome / Q000276:immunology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D002087:Butyrates; D005232:Fatty Acids, Volatile; D006657:Histones; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases