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.

Interaction of gut microbiota with bile acid metabolism and its influence on disease states

“…The mechanisms of inhibition vary depending on whether FXRα in the liver or intestine is activated (Kim et al 2007; Chiang 2009), with FXRα working through a small heterodimer partner (SHP) in the liver or fibroblast growth factor 19 (FGF-19; FGF-15 is an ortholog in mice) (Holt et al 2003; Inagaki et al 2005; Kim et al 2007; Chiang 2009). Recently bile acids have been postulated to regulate proliferation of intestinal cells via FXRα and epidermal growth factor receptor signaling pathways (Dossa et al 2016). Repression of bile acid synthesis has also been suggested to be coordinately regulated by both hepatic and intestinal FXRα, where intestinal FXRα has a strong effect on CYP7A1, but not CYP8B1.…”

Motion Sensing Superpixels (MOSES): A systematic framework to quantify and discover cellular motion phenotypes

“…The main cause of BE is bile acid reflux (39, 40). Bile acid activates epidermal growth factor receptor (EGFR) (41, 42), a receptor tyrosine kinase that is frequently mutated in EAC (43) and sometimes overexpressed in BE (44, 45). We therefore used EGF, the ligand of EGFR, as a stimulus to activate the EGFR signalling pathway.…”

Correlated high expression of FXR and Sp1 in cancer cells confers a poor prognosis for pancreatic cancer: A study based on TCGA and tissue microarray

“…However, there were various reports that FXR was elevated in multiple human cancers responsible for their initiation and progression [28, 29]. For instance, it is stated that FXR could suppress the proliferation of liver cancer via the inhibition of mTOR/S6K signaling [8].…”