The human gut microbiome consists of trillions of microorganisms which metabolize a variety of xenobioticcompounds, including environmental chemicals, thereby affecting their overall toxicity to the host organism.Gut microorganisms can either increase or decrease the toxicity of xenobiotic compounds based on reactionswith microbial enzymes, which is referred to as Microbiome Modulation of Toxicity (MMT). Specificxenobiotic-metabolizing enzymes have been identified, such as azoreductases, nitroreductases,β-glucuronidases, sulfatases, and β-lyases. However, despite many studies that have demonstrated thesignificance of the gut microbiome in xenobiotic toxicity, the role of microbial biotransformation in toxicityresponse is largely ignored. Specifically, there is a significant lack of predictive methods to identify potentialmicrobial strains that could mitigate xenobiotic toxicity, as probiotics, by transforming those compounds intometabolites with a reduced toxicity profile.This Phase I proposal seeks to address this critical need by developing a predictivecomputational-experimental platform to characterize the microbial biotransformation of xenobiotics and identifynaturally occurring gut microbial strains that offer protection to the host from xenobiotic toxicity. We will employadvanced computational techniques and in vitro assays to test thousands of microbial enzymes and theirassociated microorganisms to identify species that could detoxify a set of targeted xenobiotics. Our hybridplatform combines the high-throughput capabilities of in silico methods with the accuracy of experimentaltechniques to provide cost-effective yet accurate and actionable predictions.The primary outcome of this project will be the identification, characterization, and validation of novel probioticsto protect humans from the toxicity of a range of xenobiotics, including environmental exposure, foodcontamination, and water pollution, by detoxifying them into metabolites with a reduced toxicity profile. For theproof-of-concept in Phase I, we will focus on the microbial metabolism of arsenicals, which have been thehighest-ranked substances of concern on the US Agency for Toxic Substances and Disease Registry (ATSDR)and the US EPA's Priority List of Hazardous Substances since 1977. The successful outcome of this projectwill provide a novel set of probiotics to mitigate the risks associated with a range of xenobiotics, includingarsenicals, affecting millions of lives around the world.1
Public Health Relevance Statement: PROJECT NARRATIVE
While gut microbiome-mediated metabolism has been suggested to detoxify different environmental chemicals,
its potential xenobiotic detoxifying capacity has remained a largely untapped field with great potential.
Accordingly, this project seeks to identify and characterize specific gut microbiome species for the
detoxification of hazardous compounds using an integrated computational-experimental platform.
Project Terms: <β-D-Glucuronoside glucuronosohydrolase><β-glucuronidase><3-Dimensional><3-D><3D>
