Mapping the Glucuronidome

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Project Summary Mapping the Glucuronidome. One of the most important mammalian detoxification (inactivation) methods is the chemical addition of glucuronic acid to biologically active compounds, glucuronidation. The rate of glucuronidation is altered by dietary compounds and the successful elimination of glucuronidated chemicals is inhibited by microbial removal of the glucuronic acid moiety, regenerating the active, and often toxic, compound. Changes in the pool of glucuronides have important implications for the prevention, diagnosis, and treatment of chronic diseases. Recent research efforts have focused on the role of microbiome manipulation on drug metabolism, specifically the inhibition of microbial β-glucuronidase enzymes for reducing adverse drug reactions to NSAIDs and chemotherapies and improving pharmaceutical treatment efficacy. Comprehensive research of the physiologic implications of host-metabolite-microbe interactions is possible due to recent advances in mass spectrometry methods for identifying and quantifying metabolites in complex mixtures (blood, urine, and feces) and high-throughput -omics techniques for functional analysis of the microbiome. This proposed research aims to develop an integrative multi-omics pipeline incorporating novel metabolomic methods, metagenomic sequencing, and molecular biology techniques to define the physiologic effects of host-glucuronide-microbiome interactions. The training will provide for a collaborative effort between xenobiotic metabolism, mass spectrometry, and microbiome experts to experimentally disrupt glucuronidation, map glucuronide exchange dynamics, and quantify resultant host metabolic signaling. The research will provide for the development of a much needed, first-of-its-kind, comprehensive, and publicly available database of glucuronidation, facilitating the incorporation of powerful metabolomics methods to research advancing the understanding of xenobiotic metabolism. The proposed research will inform the current understanding of host-microbiome interaction effects on xenobiotic metabolism and host health, with important implications for the development of individualized medicine and microbe-targeted therapies.