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.
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