Microbial mechanisms of methylmercury metabolism in humans

摘要 汞(Hg)继续对人类健康构成重大风险，这从它在美国机构中的排名第三可见一斑。 有毒物质和疾病登记处的危险物质优先清单，仅次于砷和铅。 最令人担忧的是接触到食用鱼类时产生的毒性更大的甲基汞(MeHg)。40亿 世界各地的人们都依赖鱼类作为食物蛋白质和必需营养素的重要来源。因此， “汞问题”不是简单地避免接触的主要来源就能解决的。另一方面，什么 构成有害水平的甲基汞暴露仍有相当大的不确定性。例如，联邦(美国环保局) 鱼类消费指南基于甲基汞摄入量的参考剂量(RfD)值，该值 加入了10倍的“不确定因素”。众所周知，这种不确定性很大程度上源于这样一个事实： 代谢甲基汞的速度差异很大，结果是两个大小相似的人消耗了相同的 大量的鱼积累的甲基汞可能会有四倍的差异。对此的解决方案 问题在于开发知识和工具来确定个人积累的倾向 甲基汞。然而，关于人体如何代谢和消除代谢的知识存在着几个根本的空白 甲基汞仍然存在。之前的研究，主要是在实验室动物身上，支持肠道中的微生物是 有效的生物转化(去甲基化)和排泄有毒的甲基汞所必需的。我们最近做了 获得了确凿的证据，证明人体内甲基汞的消除速度依赖于肠道微生物。 重要的是，我们发现，特定个体的甲基汞排除率会随着时间的推移而变化很大， 此外，接触抗生素会显著减慢速度。有了这些证据，我们将检验这一假设 一个人在体内达到有害水平的甲基汞的易感性是由选定的数字控制的 人类肠道中常见的微生物。我们预测这些微生物将以不同的数量存在于不同的 因此可作为甲基汞代谢倾向的生物标志物。我们还预测， 这些微生物的丰富可以通过益生菌饮食补充剂来实现。我们将在下面测试我们的假设 由甲基汞暴露和新陈代谢、肠道微生物生态方面的专家参与的协调小组工作 在小鼠模型中，以及微生物汞的生物转化和基因组学。我们将在三个具体目标中确立： 在人体内表现出快和慢甲基汞动力学的肠道微生物组样本(Aim1)，验证微生物组的 无菌小鼠模型(AIM2)在甲基汞动力学中的作用及微生物种类的鉴定和分离 负责人体肠道中的甲基汞去甲基化(Aim3)。凭借这项研究的知识，我们打算 通过以下方式改进人类健康做法：1)开发非侵入性工具，以识别易患艾滋病的人 积累甲基汞和2)确定膳食补充剂方法，以增强个人的能力 代谢和排泄有毒的甲基汞。

Abstract Mercury (Hg) continues to pose a significant risk to human health reflected by its #3 ranking on the U.S. Agency of Toxic Substances and Disease Registry priority list of hazardous substances, behind only arsenic and lead. Of greatest concern is exposure to the more toxic methylmercury (MeHg) that comes with eating fish. Four billion people world-wide rely on fish as a significant source of dietary protein and essential nutrients. Thus, the “mercury problem” cannot be solved by simply avoiding the major source of exposure. On the other hand, what constitutes a harmful level of MeHg exposure remains considerably uncertain. For example, federal (US EPA) guidelines for fish consumption are based on a Reference Dose (RfD) value for intake of MeHg, which incorporates 10-fold “uncertainty factor”. It is known that much of this uncertainty stems from the fact that people metabolize MeHg at widely variable rates and as a result two similarly sized individuals consuming equal amounts of fish could experience as much as a four-fold difference in accumulated MeHg. A solution to this problem lies in developing the knowledge and tools to determine an individual’s predisposition to accumulate MeHg. Yet, several fundamental gaps in the knowledge of how the human body metabolizes and eliminates MeHg remain. Prior research, largely in laboratory animals, supports the notion that microbes in the gut are required for the efficient biotransformation (demethylation) and excretion of toxic MeHg. We have recently obtained substantiating evidence that the rate of MeHg elimination in the human body is reliant on gut microbes. Importantly, we discovered that MeHg elimination rate in a given individual can vary significantly over time and, furthermore, is significantly slowed with exposure to antibiotics. With this evidence, we will test the hypothesis that an individual’s susceptibility for reaching harmful levels of MeHg in the body is regulated by a select number of microbes common to the human gut. We predict these microbes will be present in variable amounts in different individuals, and thus could serve as a biomarker for MeHg metabolism disposition. We also predict a change in abundance of these microbes can be achieved with a probiotic diet supplement. We will test our hypothesis in a coordinated team effort involving experts in MeHg exposure and metabolism in humans, gut microbial ecology in mouse models, and microbial Hg biotransformation and genomics. In three Specific Aims we will: establish gut microbiome samples that exhibit “fast” and “slow” MeHg kinetics in humans (Aim1), validate the microbiome’s role in MeHg kinetics using germ free mouse modeling (Aim2) and identify and isolate microbial species responsible for MeHg demethylation in the human gut (Aim3). With knowledge from this study we intend to improve human health practices by: 1) deriving non-invasive tools to identify individuals susceptible to accumulating MeHg and 2) identifying dietary supplement approaches to enhance an individual’s capacity to metabolize and excrete toxic MeHg.