Asset Details
Do you wish to reserve the book?
A metabolic pathway for bile acid dehydroxylation by the gut microbiome
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
A metabolic pathway for bile acid dehydroxylation by the gut microbiome
Do you wish to request the book?
A metabolic pathway for bile acid dehydroxylation by the gut microbiome
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
A metabolic pathway for bile acid dehydroxylation by the gut microbiome
2020
Overview
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 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 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.
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 631/45
/ 82
/ 82/16
/ 82/83
/ Analysis
/ Animals
/ Bile
/ Bile Acids and Salts - chemistry
/ Bile Acids and Salts - metabolism
/ Deoxycholic Acid - chemistry
/ Deoxycholic Acid - metabolism
/ Enzymes
/ Gastrointestinal Microbiome - genetics
/ Gastrointestinal Microbiome - physiology
/ Genes
/ Humanities and Social Sciences
/ Identification and classification
/ Lithocholic Acid - chemistry
/ Lithocholic Acid - metabolism
/ Male
/ Metabolic Networks and Pathways - genetics
/ Mice
/ Microbiota (Symbiotic organisms)
/ Science
/ Steroids
