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：
10207533
负责人：
Timothy McDermott
金额：
$ 33.06万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207533
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 genetic manipulation 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.

项目摘要简介和假设。拟议的项目解决了人类微生物组在摄入后砷排毒。砷中毒是全球对公共卫生的重大威胁导致各种人类疾病，包括癌症。与砷有关的基因中的多态性代谢和运输在流行病学上与肺，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，表明其他重要因素涉及疾病的渗透率。我们假设砷的差异肠道微生物组的代谢，结合宿主代谢的变异性，解释了砷症裸露的人群中的渗透性以及肠道中的受控/工程砷排毒可用于预防和治疗砷。参与者。 Co-Pi的Walk和McDermott都领导了多学科研究项目。 Walk博士临床研究的背景，无细菌小鼠和人类微生物组将补充麦克德莫特博士砷生物化学和微生物生物转化的背景。 Co-I的Schmidt和Bothner会带来有关高级鼠模型，代谢组学和硫醇靶向蛋白质组学的技术专长。合作者，博士。 X. Chris Le和Samuel Cohen，将带来多年的人类砷研究经验以及分析和比较生理学专业知识。集体团队将确保成功完成了拟议的研究和对结果的有见地的解释。知道什么？编码砷活性酶的基因存在于人肠道微生物组的基因组中小鼠和人类的成员和肠道含量可以在体外代谢砷。只有三个研究有被认为是微生物组在宿主中有机歧义物产生中的作用，但没有研究通过实验去除微生物组或建立了定义的微生物组（Gnotobiotic），以测试其在体内。氧化还原和甲基化反应可能是最深入研究的砷排毒机制。但是，与中央细胞代谢的重叠作用使这些作用使这些操纵尚未解决途径困难及其与砷代谢中的微生物组的相互作用。提出了什么建议？ - 在没有微生物组和在 gnotobiotic小鼠与工程大肠杆菌单一相关，以量化特定微生物组的影响关于宿主健康的砷生物转化。 - 微生物组和宿主的研究合作影响新型小鼠模型中的氧化还原/甲基化，使用代谢组学和含硫靶向蛋白质组学揭示砷对宿主代谢和蛋白质组的影响。这些综合努力带来了新颖的实验工具以人类微生物组对普遍存在和危险的人类毒素的排毒作用。