title: Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.
abstract: Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum.
authors: Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, 413 45 Gothenburg, Sweden.
authors: Sama I
authors: SI
authors: Sayin
authors: Annika
authors: A
authors: Wahlström
authors: Jenny
authors: J
authors: Felin
authors: Sirkku
authors: S
authors: Jäntti
authors: Hanns-Ulrich
authors: HU
authors: Marschall
authors: Krister
authors: K
authors: Bamberg
authors: Bo
authors: B
authors: Angelin
authors: Tuulia
authors: T
authors: Hyötyläinen
authors: Matej
authors: M
authors: Orešič
authors: Fredrik
authors: F
authors: Bäckhed
mesh_terms: D000042:Absorption; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000382:microbiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D054892:Metagenome / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013656:Taurocholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D005346:Fibroblast Growth Factors; D018160:Receptors, Cytoplasmic and Nuclear; D013656:Taurocholic Acid; D000099150:Receptor, Farnesoid X-Activated; C108526:fibroblast growth factor 15, mouse; C037351:tauromuricholic acid