Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor.
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.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Takeshi
T
Inagaki
Antonio
A
Moschetta
Youn-Kyoung
YK
Lee
Li
L
Peng
Guixiang
G
Zhao
Michael
M
Downes
Ruth T
RT
Yu
John M
JM
Shelton
James A
JA
Richardson
Joyce J
JJ
Repa
David J
DJ
Mangelsdorf
Steven A
SA
Kliewer
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D053493:Cholestanetriol 26-Monooxygenase; D004268:DNA-Binding Proteins / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000172:deficiency / Q000235:genetics; D014157:Transcription Factors / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D053493:Cholestanetriol 26-Monooxygenase; D004268:DNA-Binding Proteins; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D013250:Steroid Hydroxylases; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C506831:CYP27A1 protein, human; C506832:Cyp27a1 protein, mouse; C412815:GW 4064