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

Mon, 2016-08-22 14:29 -- voskuhlt
TitleGut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease.
Publication TypeJournal Article
Year of Publication2016
AuthorsMathewson ND, Jenq R, Mathew AV, Koenigsknecht M, Hanash A, Toubai T, Oravecz-Wilson K, Wu S-R, Sun Y, Rossi C, Fujiwara H, Byun J, Shono Y, Lindemans C, Calafiore M, Schmidt TC, Honda K, Young VB, Pennathur S, van den Brink M, Reddy P
JournalNat Immunol
Volume17
Issue5
Pagination505-13
Date Published2016 May
ISSN1529-2916
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.

DOI10.1038/ni.3400
Alternate JournalNat. Immunol.
PubMed ID26998764
PubMed Central IDPMC4836986
Grant ListR01 CA173878 / CA / NCI NIH HHS / United States
R01 HL090775 / HL / NHLBI NIH HHS / United States
R01 HL124112 / HL / NHLBI NIH HHS / United States
R01 HL128046 / HL / NHLBI NIH HHS / United States
U24 DK097153 / DK / NIDDK NIH HHS / United States