Mechanisms of arsenic detoxification by the human microbiome

人体微生物组的砷解毒机制

基本信息

批准号：
9750648
负责人：
Timothy McDermott
金额：
$ 32.07万
依托单位：
MONTANA STATE UNIVERSITY - BOZEMAN
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750648
关键词：
Acute Address Arsenic Arsenic Poisoning Arsenicals Bacteria Biochemistry Blood Vessels Cells Chronic Clinical Research Code Comparative Physiology Complement Dangerousness Development Diabetes Mellitus Disease Disulfides Drug Metabolic Detoxication Effectiveness Engineering Ensure Enzymes Epidemiology Escherichia coli Excretory function Exposure to Feces Foundations Frequencies Genes Genetic Engineering Genetic Polymorphism Genome Genotype Germ-Free Glutathione Glutathione S-Transferase Gnotobiotic Goals Haplotypes Health Hepatic Heterogeneity High Pressure Liquid Chromatography Homeostasis Human Human Microbiome In Vitro Incidence Individual Inductively Coupled Plasma Mass Spectrometry Ingestion Interdisciplinary Study Knowledge Lead Link Liver Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of urinary bladder Mass Spectrum Analysis Measures Metabolic Biotransformation Metabolism Methionine Methylation Methyltransferase Modeling Molecular Mus Outcome Output Oxidation-Reduction Oxidoreductase Participant Pathology Pathway interactions Penetrance Phenotype Play Population Prevention Preventive Probiotics Production Proteome Proteomics Public Health Reaction Research Research Project Grants Risk Role S-Adenosylmethionine Series Skin Cancer Sulfhydryl Compounds System TXN gene Technical Expertise Testing Therapeutic Tissues Toxic effect Toxin Uniport Ursidae Family Walking base cell type cooperative study experience experimental study gut microbiome host microbiome human disease in vivo in vivo evaluation insight inter-individual variation liver metabolism metabolomics microbial microbiome microbiome components mortality mouse model mutant novel prevent therapeutic effectiveness tool

项目摘要

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.

项目概要介绍与假设。拟议的项目探讨了人类微生物组在摄入砷后解毒。砷中毒是全球范围内对公众健康的重大威胁导致多种人类疾病，包括癌症。与砷相关的基因多态性流行病学表明，代谢和运输与肺、皮肤、膀胱和肝脏风险增加有关癌症，但在类似暴露的个体中，癌症的个体间差异很大，这表明其他重要因素也与疾病外显率有关。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率，并且肠道中的受控/工程砷排毒可用于砷中毒的预防和治疗。参与者。联合首席研究员沃克和麦克德莫特都领导了多学科研究项目。沃克博士的临床研究、无菌小鼠和人类微生物组的背景将补充麦克德莫特博士的研究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有关先进小鼠模型、代谢组学和硫醇靶向蛋白质组学的技术专业知识。合作者，博士。 X. Chris Le和Samuel Cohen，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专业知识。集合起来的团队将共同确保成功完成拟议的研究并对结果进行富有洞察力的解释。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类的成员和肠道内容物可以在体外代谢砷。只有三项研究考虑了微生物组在宿主体内产生有机砷的过程中的作用，但没有研究表明通过实验去除微生物组或建立确定的微生物组（gnotobiotic）以测试其在体内。氧化还原和甲基化反应可能是砷解毒研究最深入的反应机制。然而，与中央细胞代谢的重叠作用已经使得这些砷代谢途径的困难及其与微生物组的相互作用尚未得到解决。有什么建议？ --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大肠杆菌单一关联的无菌小鼠，以量化特定微生物组的影响砷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硫醇靶向蛋白质组学来揭示新型小鼠模型中的氧化还原/甲基化砷对宿主代谢和蛋白质组的影响。这些共同努力带来了新颖的实验工具致力于明确解决人类微生物组对普遍且危险的人类毒素的解毒问题。