Oral medicinal drugs can exhibit incomplete absorption in the upper gastrointestinal tract or reach the gut after enterohepatic circulation. In these circumstances, drugs encounter enormous densities of commensal microbes. These microbes collectively encode 150-fold more genes than the human genome, including a rich repository of enzymes with the potential to metabolize drugs. However, the contribution of the microbiome to drug and drug metabolite exposure in the GI tract and in circulation is largely unexplored. I will describe examples that suggest that gut microbial activity can be responsible for a significant portion of systemic exposure to a toxic drug metabolite, even if the drug exhibits high bioavailability, if the same metabolite is readily produced by hepatic extracts in vitro, and if drug metabolite levels are low in feces. I will also introduce our efforts to explore the spectrum of microbiome-encoded drug metabolizing activities and to identify microbial genes that predict the capacity of an individual’s gut microbiome to metabolize a drug.

Previously, the Turnbaugh group identified the enzyme responsible for the gut bacterial inactivation of the cardiac drug digoxin; however, the broader relevance of this enzyme in digoxin naive patients remained unclear. Dr Turnbaugh will discuss unpublished studies where we show that this diet-dependent digoxin metabolizing enzyme triggers autoimmune disease in mouse models and is associated with disease in patients.

Within the human body, there are trillions of microbes that contribute to normal physiology, and disruption of these microbes is associated with various disease states. This is true in cancer, where microbes within tumors themselves may contribute to cancer development and therapy response. In addition, microbes in the gut can shape immunity and cancer immunotherapy response, and therapeutic strategies targeting these microbes are currently being developed

Despite knowledge for over 10 years that P-gp plays a central role in GI homeostasis, the precise molecular mechanism that controls its regulation and function remains unclear. Since the resident microbiota contribute to tolerance and homeostasis, studies in the McCormick lab address how the functional core microbiome governs intestinal homeostasis via maintenance of the P-gp axis by uniting with a key pathway in xenobiotic metabolism.