Bile acid transport and arachidonic acid influence hepatic CYP2D6 activity: implications for drug metabolism in a gut-liver microphysiological system

The liver plays a central role in xenobiotic metabolism, and its activity is strongly influenced by physiological interactions with the gut. However, the molecular signals mediating this gut-liver crosstalk and their impact on drug-metabolizing enzymes remain poorly understood. Here, we used a human-derived gut-liver microphysiological system (MPS) to investigate how bile acid transport and arachidonic acid (ARA) metabolism regulate hepatic cytochrome P450 (CYP) activity under normal physiological conditions. Intestinal expression of the bile acid transporter ASBT was elevated in coculture, suggesting active bile acid uptake and signaling. Inhibition of ASBT significantly reduced ARA levels in the circulating medium and selectively decreased hepatic CYP activity, particularly CYP2D6. These findings indicate that bile acid transport can influence lipid mediator balance, which in turn modulates CYP activity. Our results highlight a potential mechanism by which gut-liver communication contributes to drug metabolism and may inform the development of improved models for toxicological evaluation.