Mechanisms of arsenic detoxification by the human microbiome

项目摘要 介绍与假设。拟议的项目解决了人类微生物组在 在摄入砷后解毒。砷中毒是全球范围内对公共健康的重大威胁， 导致多种人类疾病，包括癌症。砷相关基因的多态性 在流行病学上，代谢和转运与肺、皮肤、膀胱和肝脏的风险增加有关。 癌症，但在类似暴露的个体中，癌症的个体间差异很大，表明 其他重要因素也与疾病的发病率有关。我们假设砷含量的差异 肠道微生物组的代谢，结合宿主代谢的变化，解释了砷中毒 暴露人群中的砷中毒，以及肠道中的受控/工程砷排毒可用于 砷中毒防治 参与者共同PI的步行和麦克德莫特都领导了多学科的研究项目。Walk医生 临床研究背景，无菌小鼠和人类微生物组将补充McDermott博士的 具有砷生物化学和微生物生物转化的背景。我的施密特和博特纳会带 在先进的小鼠模型、代谢组学和巯基靶向蛋白质组学方面的技术专长。 合作者，X博士。Chris Le和Samuel Cohen将带来多年的人类砷中毒研究经验 沿着分析和比较生理学专业知识。总的来说，集合的团队将确保 成功完成拟议的研究和对结果的深刻解释。 什么是已知的？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 小鼠和人的肠组织和肠内容物可以在体外代谢砷。只有三项研究 考虑到微生物组在宿主中产生有机砷的作用，但没有研究 实验性地去除微生物组或建立一个确定的微生物组（gnotobiotic），以测试其对 vivo.氧化还原和甲基化反应可能是研究最深入的砷解毒反应 机制等然而，与中央细胞代谢的重叠作用使得操纵这些 砷代谢途径的复杂性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的情况下模拟砷代谢， 与工程E.以量化特定微生物组的影响 砷的生物转化对宿主健康的影响。- 研究微生物组和宿主的合作影响 使用代谢组学和巯基靶向蛋白质组学在新型小鼠模型中进行氧化还原/甲基化， 砷对宿主代谢和蛋白质组的影响。这些共同的努力带来了新颖的实验工具 承担明确解决人类微生物组对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.