Mechanisms of arsenic detoxification by the human microbiome

项目摘要 引言和假设。拟议的项目解决了人类微生物群在 摄取后排毒的砷。砷中毒是对全球公众健康的重大威胁 会导致多种人类疾病，包括癌症。砷相关基因的多态性 新陈代谢和运输在流行病学上与肺、皮肤、膀胱和肝脏风险增加有关。 癌症，但在类似暴露的个人中，癌症存在很大的个体间差异，这表明 其他重要因素也与疾病的外显性有关。我们假设砷的差异 肠道微生物组的代谢，与宿主代谢的变异性相结合，解释了砷中毒 暴露人群的外显性，肠道内受控/工程砷排毒可用于 预防和治疗砷中毒。 与会者。共同派的漫步和麦克德莫特都领导了多学科的研究项目。沃克医生的 背景在临床研究中，无菌小鼠和人类微生物组将补充麦克德莫特博士的 砷生物化学和微生物生物转化背景。CO-I的施密特和博特纳将带来 先进的小鼠模型、代谢组学和硫醇靶向蛋白质组学方面的技术专长。 合作者克里斯·勒博士和塞缪尔·科恩博士将带来多年的人类砷中毒研究经验 以及分析和比较生理学的专业知识。总体而言，集合的团队将确保 圆满完成拟议的研究并对结果进行有见地的解释。 已知的是什么？编码砷活性酶的基因存在于人类肠道微生物组的基因组中 小鼠和人类的成员和肠道内容物在体外可以代谢砷。只有三项研究有 认为微生物组在宿主体内生产有机砷化合物中的作用，但还没有研究 通过实验移除微生物组或建立定义的微生物组(GnotoBiotic)以测试其在 活着。氧化还原和甲基化反应可能是研究最深入的砷解毒作用。 机械装置。然而，与中枢细胞新陈代谢的重叠作用使得对这些 砷代谢中的困难途径及其与微生物组的相互作用尚未得到解决。 建议是什么？--使用无菌小鼠在没有微生物组和无菌环境下建立砷代谢模型。 基因工程菌单基因关联小鼠对特定微生物组的影响 砷的生物转化对宿主健康的影响。--研究微生物群与寄主的协同影响 利用代谢组学和硫醇靶向蛋白质组学揭示一种新的小鼠模型中的氧化还原/甲基化 砷对宿主新陈代谢和蛋白质组的影响。这些共同努力带来了新的实验工具 承担通过人体微生物组最终解决普遍和危险的人类毒素的解毒问题。

Project Summary Introduction & Hypothesis. The proposed project addresses the role of the human microbiome in the detoxifying arsenic following ingestion. Arsenic poisoning is a significant worldwide threat to public health that leads to a variety of human diseases, including cancer. Polymorphisms in genes involved with arsenic metabolism and transport have been epidemiologically linked to increased risk of lung, skin, bladder, and liver cancer, but there is large inter-individual variability in cancers among similarly exposed individuals, indicating other important factors are involved in disease penetrance. We hypothesize that differences in arsenic metabolism by the gut microbiome, in combination with variability in host metabolism, explains arsenicosis penetrance in exposed populations, and that controlled/engineered arsenic detox in the gut can be used for arsenicosis prevention and treatment. Participants. Co-PI's Walk and McDermott have both led multidisciplinary research projects. Dr. Walk's background in clinical research, germ free mice, and the human microbiome will complement Dr. McDermott's background in arsenic biochemistry and microbial biotransformation. Co-I's Schmidt and Bothner will bring technical expertise regarding advanced murine models, metabolomics, and thiol-targeted proteomics. Collaborators, Drs. X. Chris Le and Samuel Cohen, will bring years of human arsenicosis research experience along with analytical and comparative physiology expertise. Collectively, the assembled team will ensure the successful completion of the proposed research and insightful interpretation of results. What is known? Genes encoding arsenic-active enzymes are present in genomes of human gut microbiome members and gut contents from mouse and humans can metabolize arsenic in vitro. Only three studies have considered the microbiome's role in the production of organo-arsenicals in the host, but no study has experimentally removed the microbiome or established a defined microbiome (gnotobiotic) to test its effects in vivo. Redox and methylation reactions are perhaps the most intensively studied arsenic detoxification mechanisms. However overlapping roles with central cellular metabolism have made manipulation of these pathways difficult and their interactions with the microbiome in arsenic metabolism has not been addressed. What is proposed? --Use germ free mice to model arsenic metabolism in the absence of a microbiome and in gnotobiotic mice mono-associated with engineered E. coli to quantify the influence of specific microbiome arsenical biotransformations on host health. --Study cooperative influences of the microbiome and host redox/methylation in a novel mouse model using metabolomics and thiol-targeted proteomics to uncover arsenical impacts on host metabolism and the proteome. These combined efforts bring novel experimental tools to bear to definitively address detoxification of a prevalent and dangerous human toxin by the human microbiome.