Novel probiotics to mitigate xenobiotic toxicity through microbial biotransformation

PROJECT SUMMARY / ABSTRACT The human gut microbiome consists of trillions of microorganisms which metabolize a variety of xenobiotic compounds, 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 reactions with microbial enzymes, which is referred to as Microbiome Modulation of Toxicity (MMT). Specific xenobiotic-metabolizing enzymes have been identified, such as azoreductases, nitroreductases, β-glucuronidases, sulfatases, and β-lyases. However, despite many studies that have demonstrated the significance of the gut microbiome in xenobiotic toxicity, the role of microbial biotransformation in toxicity response is largely ignored. Specifically, there is a significant lack of predictive methods to identify potential microbial strains that could mitigate xenobiotic toxicity, as probiotics, by transforming those compounds into metabolites with a reduced toxicity profile. This Phase I proposal seeks to address this critical need by developing a predictive computational-experimental platform to characterize the microbial biotransformation of xenobiotics and identify naturally occurring gut microbial strains that offer protection to the host from xenobiotic toxicity. We will employ advanced computational techniques and in vitro assays to test thousands of microbial enzymes and their associated microorganisms to identify species that could detoxify a set of targeted xenobiotics. Our hybrid platform combines the high-throughput capabilities of in silico methods with the accuracy of experimental techniques to provide cost-effective yet accurate and actionable predictions. The primary outcome of this project will be the identification, characterization, and validation of novel probiotics to protect humans from the toxicity of a range of xenobiotics, including environmental exposure, food contamination, and water pollution, by detoxifying them into metabolites with a reduced toxicity profile. For the proof-of-concept in Phase I, we will focus on the microbial metabolism of arsenicals, which have been the highest-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 project will provide a novel set of probiotics to mitigate the risks associated with a range of xenobiotics, including arsenicals, affecting millions of lives around the world. 1