Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor

Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3920-5. doi: 10.1073/pnas.0509592103. Epub 2006 Feb 10.

Abstract

Obstruction of bile flow results in bacterial proliferation and mucosal injury in the small intestine that can lead to the translocation of bacteria across the epithelial barrier and systemic infection. These adverse effects of biliary obstruction can be inhibited by administration of bile acids. Here we show that the farnesoid X receptor (FXR), a nuclear receptor for bile acids, induces genes involved in enteroprotection and inhibits bacterial overgrowth and mucosal injury in ileum caused by bile duct ligation. Mice lacking FXR have increased ileal levels of bacteria and a compromised epithelial barrier. These findings reveal a central role for FXR in protecting the distal small intestine from bacterial invasion and suggest that FXR agonists may prevent epithelial deterioration and bacterial translocation in patients with impaired bile flow.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism*
  • Cholestanetriol 26-Monooxygenase
  • DNA-Binding Proteins / agonists
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation / drug effects
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Intestinal Mucosa / pathology
  • Intestine, Small / metabolism*
  • Intestine, Small / microbiology*
  • Intestine, Small / pathology
  • Isoxazoles / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / deficiency
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Steroid Hydroxylases / deficiency
  • Steroid Hydroxylases / genetics
  • Transcription Factors / agonists
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Bile Acids and Salts
  • DNA-Binding Proteins
  • Isoxazoles
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • farnesoid X-activated receptor
  • Steroid Hydroxylases
  • CYP27A1 protein, human
  • Cholestanetriol 26-Monooxygenase
  • Cyp27a1 protein, mouse
  • GW 4064