How Host-microbiome Interactions Shape Drug Metabolism and Absorption
The unpredictable variation between patients in drug response is a major limitation to modern medicine. Considerable progress has been made in recent years to attribute these differences to environmental factors like dietary intake and mutations in the human genome, but these studies ignore our "second genome", the microbiome — that of the trillions of microbes that thrive in and on the human body. Our lab seeks to understand how the gut microbiome shapes the treatment of human disease. We will identify the microbial genes responsible for the inactivation of essential drugs, and validate their in vivo relevance in germ-free mice and human cohorts. We will also explore if and how gut microbes control host pathways relevant to drug therapy.
Just as the discovery of the cytochrome P450s expressed in the liver and intestine revolutionized drug development, we envision that the identification of the microbial genes that shape drug metabolism and absorption will have profound implications. Synthetic chemists could modify lead compounds to avoid undesirable biotransformations or exploit the gut microbiome to better control the rate and location of drug delivery. There are also clear implications for precision medicine, including microbiome-based diagnostics for predicting drug outcomes and co-therapies that inhibit gut microbial enzymes. Our results will lead to testable hypotheses as to how and why microbial drug metabolism evolved given only transient exposure to foreign compounds, providing new insights into the ill-defined selective factors that control the structure and function of the gut microbiome.