DescriptionPhysiological adaptations to the intestine-liver axis during pregnancy alter the disposition of xenobiotics and endobiotics. As a result, some pregnant women experience decreased efficacy or adverse reactions to prescription medications (xenobiotic effect), while others may become susceptible to cholestatic liver disease due to enhanced bile acid levels (endobiotic effect). The purpose of this dissertation research was to characterize molecular adaptations in enterohepatic nuclear receptor signaling and downstream bile acid and xenobiotic disposition pathways that can occur during late pregnancy. In ilea collected from mice in late gestation, an overall down-regulation of Farnesoid X Receptor (Fxr/Nr1h4) and Pregnane X Receptor (Pxr/Nr1i2) signaling, including target enzyme and transporter expression, was observed. To explore potential mechanisms, the ability of candidate sex hormones to alter the expression of enzyme and transport genes regulated by FXR and PXR were studied in human intestinal cells. In vitro studies suggest a prominent role for progesterone-mediated interference with PXR signaling in the intestine during pregnancy that could contribute to altered xenobiotic transport. Further assessment of the ability of activated Fxr to modulate hepatic and intestinal regulation of bile acid synthesis and transport pathways during pregnancy was investigated in mice. Treatment of pregnant mice with the specific Fxr agonist GW4064 restored the expression of bile acid synthesis enzymes and transporters towards levels typically observed in virgin mice. This study provides the molecular basis for a novel approach to restore bile acid homeostasis in patients with maternal cholestasis. Finally, loss-of-function studies in pregnant Fxr-null mice revealed that deficiency in the Fxr gene prevents pregnancy-mediated repression of key bile acid regulatory factors and transporters, largely in the intestines. Taken together, these data advance our understanding of alterations in chemical disposition during pregnancy, and the overall “procholestatic†state of pregnancy that sensitizes women to acquiring liver disease.