A metabolic pathway for bile acid dehydroxylation by the gut microbiome

doi:10.1038/s41586-020-2396-4

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2396-4
	A metabolic pathway for bile acid dehydroxylation by the gut microbiome
	Zhong, Miao 1,2; Tran, Kevin 3; Min, Yimeng 1; Wang, Chuanhao 1; Wang, Ziyun 1; Dinh, Cao-Thang 1; De Luna, Phil 4,8; Yu, Zongqian 3; Rasouli, Armin Sedighian 1; Brodersen, Peter 5; Sun, Song 6; Voznyy, Oleksandr 1; Tan, Chih-Shan 1; Askerka, Mikhail 1; Che, Fanglin 1; Liu, Min 1; Seifitokaldani, Ali 1; Pang, Yuanjie 1; Lo, Shen-Chuan 7; Ip, Alexander 1; Ulissi, Zachary 3; Sargent, Edward H.1
	2020-05-01
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
文章类型	Article;Early Access
语种	英语
国家	USA; Japan
英文关键词	The biosynthetic pathway that produces the secondary bile acids DCA and LCA in human gut microbes has been fully characterized, engineered into another bacterial host, and used to confer DCA production in germ-free mice-an important proof-of-principle for the engineering of gut microbial pathways. 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 mu M and are known to block the growth ofClostridium difficile(1), promote hepatocellular carcinoma(2)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 acids(4) 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 intoClostridium 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.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000541024900004
WOS关键词	STRAIN VPI 12708 ; SALT BIOTRANSFORMATIONS ; GENE ; EXPRESSION ; BACTERIA ; COENZYME ; RECEPTOR ; ENCODES
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281006
专题	地球科学资源环境科学气候变化
作者单位	1.Univ Toronto, Dept Elect & Comp Engn, Toronto, ON, Canada; 2.Nanjing Univ, Collaborat Innovat Ctr Adv Microstruct, Natl Lab Solid State Microstruct, Coll Engn & Appl Sci, Nanjing, Peoples R China; 3.Carnegie Mellon Univ, Chem Engn, Pittsburgh, PA 15213 USA; 4.Univ Toronto, Mat Sci Engn, Toronto, ON, Canada; 5.Univ Toronto, Ontario Ctr Characterizat Adv Mat OCCAM, Toronto, ON, Canada; 6.Univ Sci & Technol China, Natl Synchrotron Radiat Lab, Hefei, Peoples R China; 7.Ind Technol Res Inst, Mat & Chem Res Labs, Hsinchu, Taiwan; 8.Natl Res Council Canada, Ottawa, ON, Canada
推荐引用方式 GB/T 7714	Zhong, Miao,Tran, Kevin,Min, Yimeng,et al. A metabolic pathway for bile acid dehydroxylation by the gut microbiome[J]. NATURE,2020.
APA	Zhong, Miao.,Tran, Kevin.,Min, Yimeng.,Wang, Chuanhao.,Wang, Ziyun.,...&Sargent, Edward H..(2020).A metabolic pathway for bile acid dehydroxylation by the gut microbiome.NATURE.
MLA	Zhong, Miao,et al."A metabolic pathway for bile acid dehydroxylation by the gut microbiome".NATURE (2020).