Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease.
Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease.
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DOI：
10.1038/ni.3400
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发表时间：
2016-05
影响因子：
30.5
通讯作者：
Reddy P
中科院分区：
文献类型：
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作者：
Mathewson ND;Jenq R;Mathew AV;Koenigsknecht M;Hanash A;Toubai T;Oravecz-Wilson K;Wu SR;Sun Y;Rossi C;Fujiwara H;Byun J;Shono Y;Lindemans C;Calafiore M;Schmidt TM;Honda K;Young VB;Pennathur S;van den Brink M;Reddy P
肠道微生物区系的变化对微生物代谢产物和移植物抗宿主病(GVHD)等疾病过程的影响尚不清楚。在这里，我们进行了无偏倚的分析，以确定异基因骨髓移植(allo-BMT)后胃肠道微生物区系衍生的短链脂肪酸(SCFA)的新变化。只有一种单链脂肪酸丁酸盐的含量发生变化，仅在肠道组织中观察到。异体骨髓移植后CD326+肠上皮细胞(IECs)内丁酸减少导致组蛋白乙酰化减少，外源性丁酸局部应用可恢复组蛋白乙酰化。丁酸盐修复改善了IEC连接的完整性，减少了细胞凋亡，减轻了移植物抗宿主病。此外，对17株合理选择的高产丁酸梭菌的本土微生物区系进行了改变，也降低了GVHD。这些数据显示了微生物代谢产物迄今未被认识到的作用，并提示微生物代谢产物的局部和特异性改变对GVHD靶组织具有直接有益的影响，并可以减轻其严重性。
The impact of alterations in intestinal microbiota on microbial metabolites and on disease processes, such as graft-versus-host disease (GVHD), is not known. Here we performed unbiased analysis to identify novel alterations in gastrointestinal microbiota-derived short chain fatty acids (SCFA) after allogeneic bone marrow transplant (allo-BMT). Alterations in the amounts of only one SCFA, butyrate, were observed only within the intestinal tissue. The reduced butyrate in CD326+ intestinal epithelial cells (IECs) after allo-BMT resulted in decreased histone acetylation, which was restored upon 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 its severity.