The intestine is the main site that orally administered drugs are primarily metabolized, absorbed, and distributed. The trillions of bacteria... Show moreThe intestine is the main site that orally administered drugs are primarily metabolized, absorbed, and distributed. The trillions of bacteria that inhabit the intestine influence health and regulate important biochemical factors, such as the activity of enzymes pertinent to drug metabolism. However, this has not been systematically studied partly due to the challenges of recapitulating the unique and complex intestinal microenvironment that includes (1) the presence of mammalian and microbial cells and (2) a unique partitioned oxygenation proļ¬le across the lumen to the subepithelial mucosa from anaerobic to the richly vascularized oxygenated. This thesis reports the development of a microfluidic device in which is integrated a membrane synthesized from a key element of mucosal basal lamina, collagen, and precisely controlled partitioned oxygen environment. The device enabled excellent cell viability and long-term function. More importantly, it enabled the coculture of intestinal epithelial cells and aerobic and anaerobic bacteria in the partitioned oxygen environment. These experiments on one hand allowed the measurement of cellular oxygen consumption rate under perfusion, which could be used to study microbial regulation of oxidative metabolism in epithelial cells. On the other hand, the device allowed a systematic examination of the role of different gut bacteria strains on the regulation of factors that are important in drug metabolism, namely, transporters and phase I enzymes. Our studies highlighted the importance of direct communication between the intestinal cells and the gut bacteria with major findings being that species-specific differences exist in the regulation of drug metabolism. This work will be useful for (1) the discovery of novel regulators of drug metabolizing enzymes, (2) developing new pharmacokinetic models, and (3) advancing precision medicine models for patients. Show less
