Arsenic, the Microbiome & Health Outcomes: Mechanisms to Methods of Intervention

摘要 肠道微生物群直接受到金属暴露的影响，肠道微生物群的变化也会影响 下游健康。一个人的微生物群也通过改变砷等有毒物质对健康的影响 将它们转化为或多或少有害的物质。因此，了解砷的影响 对微生物组的影响，反之亦然，这是可实现的预防和干预措施的关键，以减轻感染的风险 砷对人类健康的影响--NIEHS的一个关键目标。我们团队之前使用新汉普郡出生队列所做的工作 这项研究正在进行登记，预计有3,000名母婴二胎，确定了有毒物质的影响 在0-3岁的关键时期，需要微生物的时候，发育中的微生物群上的金属 用于免疫发育。具体地说，我们的团队既显示了性别特有的微生物失调，也显示了 接触砷的婴儿/儿童的免疫训练微生物类杆菌。重要的是，这项工作揭示了 砷暴露、微生物组变化与早期免疫介导性健康之间的关系 结果，包括呼吸道疾病。我们团队最近的工作表明砷暴露与肠道和肺之间存在联系 婴儿缺乏类杆菌，因此有力地支持了肠道微生物群组成是一种 呼吸道健康的关键驱动因素。该项目将检验这一假设，即在敏感的早期生命窗口(0-3岁)， 当发育中的免疫系统需要与微生物相互作用时，砷会影响发育 微生物组，导致类杆菌及其分泌代谢物的缺乏，并最终与 增加炎症和呼吸道疾病的风险，如喘息、上呼吸道感染和 晚年肺炎(12岁以下)。 目的1.使用纵向NHBCS和新的生物信息学工具检验假设：(I)早期生命为 通过食物/水暴露与肠道微生物群中特定性别的扰动有关，以及(Ii)早期- 生命肠道微生物群修饰或调节砷暴露对呼吸健康结果的影响。 目的2.验证AS由于缺少一个关键点而促进肠上皮细胞分泌IL-8的假说 类杆菌-分泌的短链脂肪酸，丙酸，最终由表观基因组的变化引起。 目的3.检验添加类杆菌可以逆转排出类杆菌的粪便的作用这一假说 小鼠模型，从而作为益生菌干预的概念验证。

ABSTRACT The gut microbiome is directly impacted by metals exposure and changes in the gut microbiome affect downstream health. An individual’s microbiome also modifies the health effects of toxicants such as arsenic by transforming them into potentially more or less harmful substances. Thus, understanding the impacts of arsenic on the microbiome, and vice versa, is key to achievable prevention and interventions to mitigate the risk of arsenic to human health – a key goal of the NIEHS. Our team’s prior work using the New Hampshire Birth Cohort Study, with ongoing enrollment and a projected size of 3,000 mother-infant dyads, identified an impact of toxic metals on the developing microbiome during the critical window of 0–3 years of age, when microbes are required for immune development. Specifically, our team showed both a sex-specific dysbiosis and a depletion of the immune-training microbe Bacteroides in arsenic-exposed infants/children. Importantly, this work revealed associations between arsenic exposure, changes in the microbiome, and early immune-mediated health outcomes, including respiratory disease. Our team’s recent work indicates a gut-lung link for arsenic-exposed infants depleted for Bacteroides, thus strongly supporting the hypothesis that gut microbiome composition is a key driver of airway health. This project will test the hypothesis that in the sensitive early-life window (0–3 years), when the developing immune system requires interaction with microbes, arsenic affects the developing microbiome, resulting in a paucity of Bacteroides and its secreted metabolites and ultimately associating with increased inflammation and risk of respiratory diseases such as wheeze, upper respiratory tract infection, and pneumonia later in life (out to 12 years of age). AIM 1. Test the hypotheses, using the longitudinal NHBCS and novel bioinformatic tools, that (i) early-life As exposures via food/water are related to sex-specific perturbations in the intestinal microbiome and (ii) the early- life intestinal microbiome modifies or mediates the effects of As exposure on respiratory health outcomes. AIM 2. Test the hypothesis that As enhances secretion of IL-8 from intestinal epithelia due to lack of a key Bacteroides-secreted short chain fatty acid, propionate, ultimately resulting from changes in the epigenome. AIM 3. Test the hypothesis that add-back of Bacteroides can reverse the effect of Bacteroides-depleted stool in a mouse model, thus serving as a proof-of-concept for probiotic interventions.