Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota
Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota
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DOI：
10.1038/nature12331
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发表时间：
2013-08-08
期刊：
影响因子：
64.8
通讯作者：
Honda, Kenya
中科院分区：
文献类型：
--
作者：
Atarashi, Koji;Tanoue, Takeshi;Honda, Kenya
肠道微生物群的操纵为炎症和过敏性疾病的治疗带来了巨大的希望（1，2）。尽管已经鉴定了许多益生菌微生物（3），但仍然迫切需要发现引起更强的治疗反应、与宿主相容并且可以以良好控制的生理方式影响宿主免疫系统的特定臂的生物体。在这里，我们使用合理的方法从人类固有的微生物群中分离出CD 4（+）FOXP 3（+）调节性T（T-reg）细胞诱导细菌菌株。从健康的人粪便样品开始，应用一系列选择步骤以获得用富含T-reg细胞诱导物质的人微生物群定殖的小鼠。从这些小鼠中，我们分离并选择了17株细菌，其基础是它们在接种到无菌小鼠后在T-reg细胞中增强T-reg细胞丰度和诱导重要抗炎分子-包括白细胞介素-10（IL-10）和诱导型T细胞共刺激分子（ICOS）-的高效力。基因组测序显示，这17个菌株属于梭菌属的簇IV、XIVa和XVIII，它们缺乏突出的毒素和毒力因子。这17种菌株作为一个社区提供细菌抗原和富含TGF-β的环境，以帮助T-reg细胞的扩增和分化。在结肠炎和过敏性腹泻模型中，向成年小鼠口服17种菌株的组合减轻了疾病。使用分离的菌株可以允许对人免疫病症进行定制的治疗操作。
Manipulation of the gut microbiota holds great promise for the treatment of inflammatory and allergic diseases(1,2). Although numerous probiotic microorganisms have been identified(3), there remains a compelling need to discover organisms that elicit more robust therapeutic responses, are compatible with the host, and can affect a specific arm of the host immune system in a well-controlled, physiological manner. Here we use a rational approach to isolate CD4(+)FOXP3(+) regulatory T (T-reg)-cell-inducing bacterial strains from the human indigenous microbiota. Starting with a healthy human faecal sample, a sequence of selection steps was applied to obtain mice colonized with human microbiota enriched in T-reg-cell-inducing species. From these mice, we isolated and selected 17 strains of bacteria on the basis of their high potency in enhancing T-reg cell abundance and inducing important anti-inflammatory molecules-including interleukin-10 (IL-10) and inducible T-cell co-stimulator (ICOS)-in T-reg cells upon inoculation into germ-free mice. Genome sequencing revealed that the 17 strains fall within clusters IV, XIVa and XVIII of Clostridia, which lack prominent toxins and virulence factors. The 17 strains act as a community to provide bacterial antigens and a TGF-beta-rich environment to help expansion and differentiation of T-reg cells. Oral administration of the combination of 17 strains to adult mice attenuated disease in models of colitis and allergic diarrhoea. Use of the isolated strains may allow for tailored therapeutic manipulation of human immune disorders.