Novel probiotics to mitigate xenobiotic toxicity through microbial biotransformation

项目总结/摘要 人类肠道微生物组由数万亿微生物组成，它们代谢各种异生物质。 这些化合物，包括环境化学品，从而影响它们对宿主生物体的总体毒性。 肠道微生物可以根据反应增加或减少异生物质化合物的毒性 这被称为微生物组毒性调节（MMT）。具体 已经鉴定了异生物质代谢酶如偶氮还原酶，硝基还原酶， β-葡萄糖醛酸酶、硫酸酯酶和β-裂解酶。然而，尽管许多研究表明， 肠道微生物组在异生物质毒性中的意义，微生物生物转化在毒性中的作用 答案在很大程度上被忽略了。具体而言，显著缺乏预测方法来识别潜在的 微生物菌株，可以减轻外源性毒性，作为益生菌，通过将这些化合物转化为 代谢产物的毒性降低。 本第一阶段提案旨在通过开发预测性的 计算实验平台，以表征异生物质的微生物生物转化并识别 天然存在的肠道微生物菌株，为宿主提供保护，使其免受异生物质毒性的影响。我们会委聘 先进的计算技术和体外测定，以测试数千种微生物酶及其 相关的微生物，以确定物种，可以解毒一套目标异生物质。我们的混合 该平台结合了计算机模拟方法的高通量能力和实验方法的准确性， 技术，以提供具有成本效益，但准确和可操作的预测。 这个项目的主要成果将是新益生菌的鉴定、表征和验证 保护人类免受一系列外源性物质的毒性，包括环境暴露，食物 通过将其解毒为毒性降低的代谢物，可以减少污染和水污染。为 在第一阶段的概念验证中，我们将重点关注砷的微生物代谢，这一直是 美国有毒物质和疾病登记署（ATSDR）最高关注物质 和美国环保署自1977年以来的有害物质优先清单。这个项目的成功 将提供一套新的益生菌，以减轻与一系列外源性物质相关的风险，包括 砷，影响世界各地数百万人的生活。 1

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