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|Title:||Drug Metabolism by the Human Gut Microbiome: An Investigation of Metabolic Capacity, Interpersonal Variability, and Genetic Mechanisms|
|Contributors:||Molecular Biology Department|
|Publisher:||Princeton, NJ : Princeton University|
|Abstract:||The human gut microbiome harbors hundreds of bacterial species with diverse biochemical capabilities. Personalized factors affecting drug metabolism have generally been attributed to differences in the human genome, but the human microbiome’s contribution to this process has also been recognized: i.e., how bacterial species and enzymes transform drugs and modulate drug response. In the first chapter, I focus on the downstream effects of a subset of these transformations – ones that cause adverse drug reactions (ADR). I highlight cases where the microbiome plays a role in mediating various ADR through both microbiome-derived metabolism of drugs (MDM) as well as the reverse dynamic, the effect of drugs on microbiome composition and metabolic pathways (DEM). In the second chapter I explain my contribution toward the development of a quantitative experimental framework for mapping the ability of the human gut microbiome to metabolize small molecule drugs: Microbiome-Derived Metabolism (MDM)-Screen. Included are a batch culturing system for sustained growth of subject-specific gut microbial communities, an ex vivo drug metabolism screen, and targeted and untargeted functional metagenomic screens to identify microbiome-encoded genes responsible for specific metabolic events. Our framework identifies novel drug-microbiome interactions that vary between individuals and demonstrates how the gut microbiome might be used in drug development and personalized medicine. In the third chapter, I focus on a specific case study of MDM. Since the human gut microbiome acetylation of drugs has not been well-characterized, I laid the groundwork for the first microbiome-based genetic characterization for two structurally similar anti-Parkinson’s drugs, tolcapone and entacapone. I show that these drugs’ N-acetylated metabolites can be produced by homologous genes among different members of the gut microbial community and demonstrate interpersonal variability in vitro. Despite their structurally similarity, these two drugs are not transformed by the same bacterial species and genes, highlighting the dynamic nature and complexity of microbiome-derived metabolism of drugs studied in a community. Lastly, I propose a methodology for integrating the microbiome into the drug development pipeline in an effort to identify and ameliorate potential microbiome-mediated causes of drug trial failures.|
|Alternate format:||The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog: catalog.princeton.edu|
|Type of Material:||Academic dissertations (Ph.D.)|
|Appears in Collections:||Molecular Biology|
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