title: Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling.
abstract: Bile acids (BAs) are synthesized in the liver and secreted into the intestine. In the lumen, enteric bacteria metabolize BAs from conjugated, primary forms into more toxic unconjugated, secondary metabolites. Secondary BAs can be injurious to the intestine and may contribute to disease. The epidermal growth factor receptor (EGFR) and the nuclear farnesoid X receptor (FXR) are known to interact with BAs. In this study we examined the effects of BAs on intestinal epithelial cell proliferation and investigated the possible roles for EGFR and FXR in these effects. We report that taurine-conjugated cholic acid (TCA) induced proliferation, while its unconjugated secondary counterpart deoxycholic acid (DCA) inhibited proliferation. TCA stimulated phosphorylation of Src, EGFR, and ERK 1/2. Pharmacological blockade of any of these pathways or genetic ablation of EGFR abrogated TCA-stimulated proliferation. Interestingly, Src or EGFR inhibitors eliminated TCA-induced phosphorylation of both molecules, suggesting that their activation is interdependent. In contrast to TCA, DCA exposure diminished EGFR phosphorylation, and pharmacological or siRNA blockade of FXR abolished DCA-induced inhibition of proliferation. Taken together, these results suggest that TCA induces intestinal cell proliferation via Src, EGFR, and ERK activation. In contrast, DCA inhibits proliferation via an FXR-dependent mechanism that may include downstream inactivation of the EGFR/Src/ERK pathway. Since elevated secondary BA levels are the result of specific bacterial modification, this may provide a mechanism through which an altered microbiota contributes to normal or abnormal intestinal epithelial cell proliferation.
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Avafia Y
authors.initials: AY
authors.lastname: Dossa
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Escobar
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Jamie
authors.initials: J
authors.lastname: Golden
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California; and Pediatrics, Biochemistry, and Molecular Biology, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Frey
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California; Keck School of Medicine, University of Southern California, Los Angeles, California; and.
authors.forename: Henri R
authors.initials: HR
authors.lastname: Ford
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California; Keck School of Medicine, University of Southern California, Los Angeles, California; and cgayer@chla.usc.edu.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Gayer
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D019826:Cholic Acid / Q000494:pharmacology; D003840:Deoxycholic Acid / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D019826:Cholic Acid; D003840:Deoxycholic Acid; D066246:ErbB Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C483803:Egfr protein, rat
keywords: bile acid; intestine; necrotizing enterocolitis; proliferation