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肠道微生物组脱胆汁酸羟基代谢途径
2020-06-18 22:11

美国斯坦福大学Michael A. Fischbach研究组取得最新进展。他们揭示了肠道微生物组对胆汁酸脱羟基的代谢途径。2020年6月17日出版的《自然》杂志发表了这一成果。

他们通过为其还原臂中的每个步骤分配和表征酶来完成通往脱氧胆酸(DCA)和石胆酸(LCA)的途径,揭示了一种策略,其中类固醇核心的A–B环在进行的两个还原步骤中被瞬时转化为电子受体,由Fe-S黄素酶去除。使用厌氧体外重构,他们确定一组六种酶对于胆酸到DCA的八步转化是必要和充分的。然后,他们将途径改造为产孢梭状芽胞杆菌,赋予在非生产性定植中生产DCA和LCA的能力,并证明微生物组来源的途径可以被异源表达和控制。这些数据建立了通往胆汁酸池中两个主要成分的完整途径。

研究人员表示,肠道菌群合成了数百个分子,其中许多会影响宿主生理。在最丰富的代谢产物中,有次级胆汁酸DCA和LCA,它们以约500μM的浓度积累,并已知能阻断艰难梭菌的生长,促进肝细胞癌并通过G蛋白偶联受体TGR5。更广泛地说,DCA、LCA及其衍生物是胆汁酸循环池的主要组成部分。该池的大小和组成是原发性胆源性胆管炎和非酒精性脂肪性肝炎的治疗目标。然而,尽管DCA和LCA对宿主生理有明显影响,但是对其生物合成基因的不完全了解以及缺乏能够对其天然微生物生产者进行修饰的遗传工具,仍然限制了人们调节宿主中次级胆汁酸水平的能力。

附:英文原文

Title: A metabolic pathway for bile acid dehydroxylation by the gut microbiome

Author: Masanori Funabashi, Tyler L. Grove, Min Wang, Yug Varma, Molly E. McFadden, Laura C. Brown, Chunjun Guo, Steven Higginbottom, Steven C. Almo, Michael A. Fischbach

Issue&Volume: 2020-06-17

Abstract: The gut microbiota synthesize hundreds of molecules, many of which influence host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at concentrations of around 500 μM and are known to block the growth of Clostridium difficile1, promote hepatocellular carcinoma2 and modulate host metabolism via the G-protein-coupled receptor TGR5 (ref. 3). More broadly, DCA, LCA and their derivatives are major components of the recirculating pool of bile acids4; the size and composition of this pool are a target of therapies for primary biliary cholangitis and nonalcoholic steatohepatitis. Nonetheless, despite the clear impact of DCA and LCA on host physiology, an incomplete knowledge of their biosynthetic genes and a lack of genetic tools to enable modification of their native microbial producers limit our ability to modulate secondary bile acid levels in the host. Here we complete the pathway to DCA and LCA by assigning and characterizing enzymes for each of the steps in its reductive arm, revealing a strategy in which the A–B rings of the steroid core are transiently converted into an electron acceptor for two reductive steps carried out by Fe–S flavoenzymes. Using anaerobic in vitro reconstitution, we establish that a set of six enzymes is necessary and sufficient for the eight-step conversion of cholic acid to DCA. We then engineer the pathway into Clostridium sporogenes, conferring production of DCA and LCA on a nonproducing commensal and demonstrating that a microbiome-derived pathway can be expressed and controlled heterologously. These data establish a complete pathway to two central components of the bile acid pool.

DOI: 10.1038/s41586-020-2396-4

Source: https://www.nature.com/articles/s41586-020-2396-4

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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