Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells
Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells
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DOI：
10.1038/nature12721
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发表时间：
2013-12-19
期刊：
影响因子：
64.8
通讯作者：
Ohno, Hiroshi
中科院分区：
文献类型：
--
作者：
Furusawa, Yukihiro;Obata, Yuuki;Ohno, Hiroshi
肠道共生微生物通过调节多种类型 T 细胞的分化和扩增来塑造粘膜免疫系统(1-5)。梭状芽胞杆菌是一类占主导地位的共生微生物，可以诱导结肠调节性 T (T-reg) 细胞，该细胞在抑制炎症和过敏反应中发挥核心作用(3)。然而，共生微生物诱导结肠 T-reg 细胞的分子机制尚不清楚。在这里，我们展示了大肠微生物发酵产物丁酸盐可诱导小鼠结肠 T-reg 细胞的分化。基于 NMR 的比较代谢组分析表明，短链脂肪酸的管腔浓度与结肠中 T-reg 细胞的数量呈正相关。在短链脂肪酸中，丁酸在体外和体内诱导T-reg细胞的分化，并改善Rag1(-/-)小鼠中CD4(+) CD45RB(hi) T细胞过继转移诱导的结肠炎的发展。在 T-reg 细胞极化条件下用丁酸盐处理幼稚 T 细胞，增强了 Foxp3 基因座启动子和保守非编码序列区域的组蛋白 H3 乙酰化，这表明微生物来源的丁酸盐调节 T-reg 细胞分化的可能机制。我们的研究结果为宿主-微生物相互作用在肠道中建立免疫稳态的机制提供了新的见解。
Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell(1-5). Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (T-reg) cells, which have a central role in the suppression of inflammatory and allergic responses(3). However, the molecular mechanisms by which commensal microbes induce colonic T-reg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic T-reg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of T-reg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of T-reg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the T-reg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of T-reg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.