Nature：肠道菌胆汁酸代谢研究再获重要进展
- ①对细菌的7α-脱羟基代谢途径中的酶进行纯化和分析，在体外重构了该通路，解析了其中的还原反应部分；
- ②7α-脱羟基作用只需bai操纵子中的6个酶（BaiB/CD/A2/E/F/H）即可完成完整的8步反应，将胆酸转化为DCA；
- ③胆汁酸分子甾体骨架中的A-B环会被短暂转化为一种高度氧化的中间体，作为之后BaiH和BaiCD两种Fe-S黄素酶介导的关键还原反应的底物；
- ④用3个接合质粒将该通路完整转化到生孢梭菌中，获得的工程菌株具有产生DCA和LCA的能力。
主编推荐语
肠道菌群可生成多种次级胆汁酸，其中含量最丰富的包括脱氧胆酸（DCA）和石胆酸（LCA），这些胆汁酸及其衍生物对于宿主生理功能和健康有重要影响。肠道中的特定细菌能通过7α-脱羟基作用将胆酸和鹅去氧胆酸分别转化为DCA和LCA，该代谢过程由编码8个基因的bai操纵子介导。此前研究主要揭示了这一途径中的氧化反应步骤机制，还原反应部分仍有待阐释。《Nature》发表的一项新研究，详细解析了7α-脱羟基途径的完整反应步骤，并通过遗传工程方法将该生物合成通路转入到原本没有7α-脱羟基作用的生孢梭菌中，并在无菌小鼠中证实了这种工程菌能产生DCA。这些工作为解析肠道菌代谢途径提供了一个范例，也为进一步研究靶向肠道细菌调控胆汁酸库的方法提供了新起点。
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A metabolic pathway for bile acid dehydroxylation by the gut microbiome
肠道微生物组对胆汁酸脱羟基化的一种代谢途径
10.1038/s41586-020-2396-4
2020-06-17, Article
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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.
First Authors:
Masanori Funabashi,Tyler L Grove
Correspondence Authors:
Steven C Almo,Michael A Fischbach
All Authors:
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
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