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

被引：512

作者：

Mathewson, Nathan D. ^{[1
,2
]}

Jenq, Robert ^{[3
]}

Mathew, Anna V. ^{[4
]}

Koenigsknecht, Mark ^{[5
]}

Hanash, Alan ^{[3
]}

Toubai, Tomomi ^{[1
]}

Oravecz-Wilson, Katherine ^{[1
]}

Wu, Shin-Rong ^{[1
,2
]}

Sun, Yaping ^{[1
]}

Rossi, Corinne ^{[1
]}

Fujiwara, Hideaki ^{[1
]}

Byun, Jaeman ^{[4
]}

Shono, Yusuke ^{[3
]}

Lindemans, Caroline ^{[3
]}

Calafiore, Marco ^{[3
]}

Schmidt, Thomas C. ^{[5
]}

Honda, Kenya ^{[6
]}

Young, Vincent B. ^{[5
]}

Pennathur, Subramaniam ^{[4
]}

van den Brink, Marcel ^{[3
]}

Reddy, Pavan ^{[1
]}

机构：

[1] Univ Michigan, Dept Internal Med, Ctr Comprehens Canc, Div Hematol Oncol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Sch Med, Grad Program Immunol, Ann Arbor, MI USA

[3] Mem Sloan Kettering Canc Ctr, Adult Bone Marrow Transplantat Serv, 1275 York Ave, New York, NY 10021 USA

[4] Univ Michigan Hlth Syst, Div Nephrol, Dept Internal Med, Ann Arbor, MI USA

[5] Univ Michigan Hlth Syst, Div Infect Dis, Dept Internal Med, Ann Arbor, MI USA

[6] RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan

来源：

NATURE IMMUNOLOGY | 2016年 / 17卷 / 05期

基金：

美国国家卫生研究院;

关键词：

CHAIN FATTY-ACIDS; HISTONE DEACETYLASE INHIBITION; BONE-MARROW-TRANSPLANTATION; REGULATORY T-CELLS; STEM-CELL; GASTROINTESTINAL-TRACT; SODIUM-BUTYRATE; PERMEABILITY; COLON; HYPERTENSION;

D O I：

10.1038/ni.3400

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：505 / +

页数：11

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