Precise GI Drug Delivery and Modeling with Pharmacomicrobiomics

Precise GI Drug Delivery and Modeling with Pharmacomicrobiomics Project Summary/Abstract The gut microbiome plays a critical role in modulating drug metabolism, efficacy, and safety, influencing how therapeutic compounds are absorbed, distributed, and processed in the body. This is particularly important in prodrug design, which seeks to achieve specific gastrointestinal (GI) targeting, sustained release, and reduced side effects, for GI-related disease and chronic treatments. Variations in microbiome composition can lead to significant differences in drug responses among individuals. Conversely, many oral drugs can also alter the microbiome, inducing imbalances (or dysbiosis) that negatively affect gut health and immune function. Understanding the bidirectional interactions between drugs and the microbiome is essential for advancing precision medicine, particularly in gut-targeted therapies. However, there remains a significant gap and a lack of tools to understand how the microbiome affects drug pharmacokinetics (PK) and efficacy, as well as how therapeutics impact microbiome composition and the production of metabolites that maintain host immune homeostasis. This research program focuses on developing a novel nano-prodrug delivery platform that targets microbiome-modulating molecules to the distal GI tract, where most of commensal bateria resides, and integrates physiologically-based pharmacokinetic (PBPK) modeling with pharmacomicrobiomics. The project aims to reveal the bidirectional interactions between microbiome composition and prodrug metabolism, exploring how variations in the gut microbiome influence drug release and response, and conversely, how drugs alter microbiome composition and function. We will use short-chain fatty acids (SCFAs) and tryptophan metabolites— key microbial metabolites known to regulate immune, metabolic, and microbiome health—as model drugs to achieve two primary goals: 1) designing a nano-prodrug platform capable of delivering therapeutics and modulating microbiome functions in the distal gut, coupled with a PBPK model for precise GI drug delivery; and 2) coupling PBPK modeling with pharmacomicrobiomics to study the interactions between microbial metabolites and the microbiome using nano-prodrugs. By integrating drug delivery systems with PBPK models and pharmacomicrobiomics, this research will advance our understanding of the temporal and spatial release kinetics from various oral drug formulations and their downstream effects on both the host and the microbiome. These insights will contribute to a broader understanding of clinical pharmacology and drug metabolism across multiple systems, paving the way for future therapeutic strategies that target both microbiome health and disease intervention.