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细菌胆汁酸代谢促进pTreg生成
2020-04-17 13:26

美国斯隆凯特林研究所Alexander Y. RudenskyClarissa Campbell研究组合作取得进展。他们的最新研究发现细菌胆汁酸代谢促进外周调节性T细胞(pTreg)的生成。相关论文于2020415日发表在《自然》杂志上。

他们筛选了解偶联胆汁酸的主要种类以增强pTreg细胞的分化能力。他们发现,次级胆汁酸3β-羟基脱氧胆酸(isoDCA)通过作用于树突状细胞(DC)来减弱其免疫刺激特性,从而增加Foxp3诱导作用。

敲除DC中的一种受体,即法呢素X受体,可增强Treg细胞的生成,并产生类似于isoDCA诱导的转录谱,表明该胆汁酸与核受体之间存在相互作用。为了研究体内的isoDCA,他们那采用了合成生物学方法,并设计了包含工程化拟杆菌菌株的最小微生物菌群。产生IsoDCA群体以保守非编码序列1CNS1)依赖性方式增加了表达结肠RORγtTreg细胞的数量,表明胸腺外分化增强。

研究人员表示,肠道健康取决于CD4 + Treg细胞的免疫抑制活性。转录因子Foxp3的表达定义了这个谱系,可以由饮食或共生抗原在胸腺外诱导,该过程由Foxp3增强子协助进行,该过程称为CNS1。包括丁酸盐在内的微生物发酵产物促进了外周诱导的Treg细胞的生成,表明代谢产物决定了结肠免疫细胞群的组成。除饮食成分外,细菌还修饰宿主来源的分子,从而产生许多生物活性物质。胆汁酸的细菌转化体现了这一点,胆汁酸产生了一系列具有多种生理功能的类固醇。

附:英文原文

Title: Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells

Author: Clarissa Campbell, Peter T. McKenney, Daniel Konstantinovsky, Olga I. Isaeva, Michail Schizas, Jacob Verter, Cheryl Mai, Wen-Bing Jin, Chun-Jun Guo, Sara Violante, Ruben J. Ramos, Justin R. Cross, Krishna Kadaveru, John Hambor, Alexander Y. Rudensky

Issue&Volume: 2020-04-15

Abstract: Intestinal health relies on the immunosuppressive activity of CD4+ regulatory T (Treg) cells1. Expression of the transcription factor Foxp3 defines this lineage, and can be induced extrathymically by dietary or commensal-derived antigens in a process assisted by a Foxp3 enhancer known as conserved non-coding sequence 1 (CNS1)2,3,4. Products of microbial fermentation including butyrate facilitate the generation of peripherally induced Treg (pTreg) cells5,6,7, indicating that metabolites shape the composition of the colonic immune cell population. In addition to dietary components, bacteria modify host-derived molecules, generating a number of biologically active substances. This is epitomized by the bacterial transformation of bile acids, which creates a complex pool of steroids8 with a range of physiological functions9. Here we screened the major species of deconjugated bile acids for their ability to potentiate the differentiation of pTreg cells. We found that the secondary bile acid 3β-hydroxydeoxycholic acid (isoDCA) increased Foxp3 induction by acting on dendritic cells (DCs) to diminish their immunostimulatory properties. Ablating one receptor, the farnesoid X receptor, in DCs enhanced the generation of Treg cells and imposed a transcriptional profile similar to that induced by isoDCA, suggesting an interaction between this bile acid and nuclear receptor. To investigate isoDCA in vivo, we took a synthetic biology approach and designed minimal microbial consortia containing engineered Bacteroides strains. IsoDCA-producing consortia increased the number of colonic RORγt-expressing Treg cells in a CNS1-dependent manner, suggesting enhanced extrathymic differentiation.

DOI: 10.1038/s41586-020-2193-0

Source: https://www.nature.com/articles/s41586-020-2193-0

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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