Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor
- Takeshi Inagaki*,
- Antonio Moschetta†,‡,
- Youn-Kyoung Lee*,
- Li Peng*,
- Guixiang Zhao*,
- Michael Downes§,
- Ruth T. Yu§,
- John M. Shelton¶,
- James A. Richardson¶,
- Joyce J. Repa‖,
- David J. Mangelsdorf†,‡, and
- Steven A. Kliewer*,†,**
- Departments of *Molecular Biology,
- †Pharmacology,
- ¶Pathology, and
- ‖Physiology and
- ‡Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390; and
- §Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037
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Edited by Bert W. O’Malley, Baylor College of Medicine, Houston, TX, and approved December 23, 2005 (received for review November 3, 2005)
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.
Footnotes
- **To whom correspondence should be addressed at: University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Room ND9.502, Dallas, TX 75390-9041. E-mail: steven.kliewer{at}utsouthwestern.edu
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Author contributions: T.I., A.M., J.A.R., J.J.R., D.J.M., and S.A.K. designed research; T.I., A.M., Y.-K.L., L.P., G.Z., M.D., R.T.Y., J.M.S., and J.J.R. performed research; T.I., A.M., Y.-K.L., M.D., R.T.Y., J.A.R., J.J.R., and D.J.M. analyzed data; and D.J.M. and S.A.K. wrote the paper.
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Conflict of interest statement: No conflicts declared.
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This paper was submitted directly (Track II) to the PNAS office.
- Abbreviations:
- FXR,
- farnesoid X receptor;
- RTQ-PCR,
- real-time quantitative PCR;
- CYP27,
- sterol 27-hydroxylase;
- KO,
- knockout;
- BDL,
- bile duct ligation;
- iNOS,
- inducible NO synthase.
- © 2006 by The National Academy of Sciences of the USA
