Counter-Regulatory Role of Bile Acid Activated Receptors in Immunity and Inflammation

In addition to their role in dietary lipid absorption bile acids are signaling modules activating nuclear receptors and at least one G-protein coupled receptor named the TGR5. With a different rank of potency primary and secondary bile acids activate a subset of nuclear receptors including the farnesoid-X-receptor (FXR, NR1H4); the constitutive androstane receptor (CAR, NR1H3), the pregnane-x- receptor (PXR, NR1H2), and the vitamin D receptor (VDR, NR1H1). Originally, these receptors were characterized for their role as bile acid and xenobiotic sensors, emerging evidence, however, indicates that FXR, PXR and VDR and their ligands are important for the modulation of immune and inflammatory reactions in entero-hepatic tissues. The immune phenotype FXR deficient mice indicates that these receptors are essential for the maintenance of immune homeostasis. A common theme of all bile acid-activated receptor is their ability to counter-regulate effector activities of cells of innate immunity establishing that signals generated by these receptors and their ligands function as braking signals for inflammation in entero-hepatic tissues. In this review, we will spotlight the molecular mechanisms of receptor/ligand function and how bile acid-activated receptors regulate the innate immunity in the gastrointestinal tract and liver. The ability of these receptors to integrate metabolic and inflammatory signaling makes them particularly attractive targets for intervention in immune-mediated diseases.