Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.
Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.
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作者：
肠道微生物为多细胞宿主提供营养并赋予其抵抗感染的能力。促炎和抗炎机制之间的微妙平衡对于肠道免疫稳态至关重要，受到共生微生物群落组成的影响。表达转录因子 Foxp3 的调节性 T (Treg) 细胞在限制肠道炎症反应中发挥着关键作用。尽管已发现共生微生物群落的特定成员能够增强抗炎性 Treg 或促炎性 Th17 细胞的生成，但驱动这一过程的分子线索仍然难以捉摸。考虑到共生微生物提供的重要代谢功能，我们假设它们的代谢副产物被免疫系统细胞感知并影响促炎细胞和抗炎细胞之间的平衡。我们发现共生微生物在淀粉发酵过程中产生的短链脂肪酸（SCFA）丁酸可以促进 Treg 细胞的胸腺外生成。提供丁酸盐后 Treg 细胞数量的增加是由于 Treg 细胞胸腺外分化的增强，因为观察到的现象依赖于内含子增强子 CNS1，其对于胸腺外 Treg 细胞分化是必需的，但对于胸腺 Treg 细胞分化是可有可无的。除了丁酸之外，丙酸（另一种能够抑制 HDAC 的微生物来源的 SCFA）也增强了外周 Treg 细胞的从头生成，但醋酸酯则没有这种活性，因此不能。我们的结果表明，细菌代谢物介导共生微生物群和免疫系统之间的通讯，影响促炎和抗炎机制之间的平衡。
Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T (Treg) cells expressing transcription factor Foxp3 play a key role in limiting inflammatory responses in the intestine. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory Th17 cells, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we hypothesized that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We found that a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg cell numbers upon provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells as the observed phenomenon was dependent upon intronic enhancer CNS1, essential for extrathymic, but dispensable for thymic Treg cell differentiation. In addition to butyrate, de novo Treg cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of HDAC inhibition, but not acetate, lacking this activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.
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影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
影响因子：
8.8
作者：
Song X;Li B;Xiao Y;Chen C;Wang Q;Liu Y;Berezov A;Xu C;Gao Y;Li Z;Wu SL;Cai Z;Zhang H;Karger BL;Hancock WW;Wells AD;Zhou Z;Greene MI
通讯作者：
Greene MI
DOI：
10.1016/s0006-291x(03)00488-1
发表时间：
2003-04-18
影响因子：
3.1
作者：
Nilsson, NE;Kotarsky, K;Olde, B
通讯作者：
Olde, B
DOI：
10.1126/science.1198469
发表时间：
2011-01-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Atarashi K;Tanoue T;Shima T;Imaoka A;Kuwahara T;Momose Y;Cheng G;Yamasaki S;Saito T;Ohba Y;Taniguchi T;Takeda K;Hori S;Ivanov II;Umesaki Y;Itoh K;Honda K
通讯作者：
Honda K
影响因子：
20.3
作者：
MacDonald, Kelli P. A.;Kuns, Rachel D.;Hill, Geoffrey R.
通讯作者：
Hill, Geoffrey R.