Gut Microbiota Regulates Bile Acid Metabolism by Reducing the Levels of Tauro-Beta-Muricholic Acid, a Naturally Occurring FXR Antagonist

Cell Metab. 2013 Feb 5;17(2):225-35. doi: 10.1016/j.cmet.2013.01.003.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorption
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Bile Acids and Salts / metabolism*
  • Cholesterol 7-alpha-Hydroxylase / genetics
  • Cholesterol 7-alpha-Hydroxylase / metabolism
  • Feedback, Physiological / drug effects
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Gastrointestinal Tract / drug effects
  • Gastrointestinal Tract / microbiology*
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Ileum / drug effects
  • Ileum / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Metagenome* / drug effects
  • Metagenome* / genetics
  • Mice
  • Models, Biological
  • Organ Specificity / drug effects
  • Organ Specificity / genetics
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Taurocholic Acid / analogs & derivatives*
  • Taurocholic Acid / metabolism
  • Taurocholic Acid / pharmacology

Substances

  • Anti-Bacterial Agents
  • Bile Acids and Salts
  • Receptors, Cytoplasmic and Nuclear
  • fibroblast growth factor 15, mouse
  • farnesoid X-activated receptor
  • tauromuricholic acid
  • Taurocholic Acid
  • Fibroblast Growth Factors
  • Cholesterol 7-alpha-Hydroxylase