Abstract
The Farnesoid-X Receptor, FXR, is a nuclear bile acid receptor. Its originally described function is in bile acid synthesis and regulation within the liver. More recently, however, FXR has been increasingly appreciated for its breadth of function and expression across multiple organ systems, including the intestine. While FXR’s role within the liver continues to be investigated, increasing literature indicates that FXR has important roles in responding to inflammation, maintaining intestinal epithelial barrier function, and regulating immunity within the gastrointestinal (GI) tract. Given the complicated and multi-factorial nature of intestinal barrier dysfunction, it is not surprising that FXR’s role appears equally complicated and not without conflicting data in different model systems. Recent work has suggested translational applications of FXR modulation in GI pathology; however, a better understanding of FXR physiology is necessary for these treatments to gain widespread use in human disease. This review aims to discuss current scientific work on the role of FXR within the GI tract, specifically in its role in intestinal inflammation, barrier function, and immune response, while also exploring areas of controversy.
Highlights
The nuclear Farnesoid-X Receptor (FXR) was discovered in the 1990s and named due to its activation by farnesol metabolites [1]
FXR forms a heterodimer with Retinoid-X receptor (RXR) to target promoters including small heterodimer protein (SHP), fibroblast growth factor 15/19, and intestinal bile acid binding protein (IBABP) [5–7]
Current evidence suggests that FXR modulates the inflammatory response, improves barrier function, limits tumorigenesis, and alters the innate immune response within the GI tract
Summary
The nuclear Farnesoid-X Receptor (FXR) was discovered in the 1990s and named due to its activation by farnesol metabolites [1]. H2S is important for maintenance of gastrointestinal mucosa [45] and has been previously described to be a target of FXR activation [46] These results suggest that FXR activation blunts intestinal inflammation in pathologic states. Inhibition of FXR in Caco cells via Z-guggulsterone blocked CDCA-induced IL8, IL6 and TNFα release and blocked increases in IL8 and IL6 mRNA expression [47] These conflicting results may be attributed to specific animal models or cell lines differences but point to a complex interaction between FXR and the intestine. Acute inflammatory cytokines including TNFα decrease FXR expression by decreasing DNA binding activity at the FXR response element [48], suggesting that does FXR modulate inflammatory signaling, but inflammatory modulators can affect FXR expression This feedback loop is similar to FXRs control over bile acid metabolism [28]. While FXR seems to be protective when activated in the setting of acute inflammation, acute phase responses themselves have a negative feedback effect on FXR expression
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