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

砷，微生物组

• 批准号: 10582816
• 负责人: George A. O'Toole
• 金额: $ 40.15万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-07 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582816
• 关键词: 12 year old; 3 year old; Address; Affect; Animals; Antibiotics; Arsenic; Back; Bacteroides; Birth; Cell Culture Techniques; Cell model; Child; Clinical; Clinical Research; Cohort Studies; Development; Enrollment; Environmental Epidemiology; Environmental Pollutants; Epidemiology; Exposure to; Feces; Food; Future; Goals; Health; Human; IL8 gene; Immune; Immune system; Immunity; In Vitro; Individual; Infant; Inflammation; Intervention; Intestines; Laboratories; Life; Link; Lung; Mediating; Metal exposure; Metals; Methods; Microbe; Molecular; Mothers; National Institute of Environmental Health Sciences; New Hampshire; Organoids; Outcome; Pattern; Pneumonia; Policies; Prevention; Probiotics; Propionates; Regulation; Resources; Respiratory Disease; Risk; Rural Community; Rural Population; Testing; Time; Toxic Environmental Substances; Training; Upper Respiratory Infections; Volatile Fatty Acids; Water; Wheezing; Work; bioinformatics tool; children with cystic fibrosis; dietary; drinking water; dysbiosis; early childhood; epidemiologic data; epigenome; epigenomics; gut microbiome; gut microbiota; insight; intestinal epithelium; lung health; metabolome; microbiome; microbiome alteration; microbiome composition; microbiome research; mouse model; novel; pulmonary function; respiratory health; risk mitigation; sex; toxic metal; toxicant

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.

抽象的 肠道微生物组直接受到金属暴露和肠道微生物组变化的影响 下游健康。个体的微生物群也会通过改变砷等有毒物质对健康的影响 将它们转化为潜在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，是可实现预防和干预措施以减轻风险的关键 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罕布什尔州出生队列进行的工作 研究正在进行中，预计纳入 3,000 名母婴，确定了有毒物质的影响 在 0-3 岁年龄的关键窗口期（此时需要微生物），金属对发育中的微生物组的影响 用于免疫发育。具体来说，我们的团队表现出性别特异性的生态失调和 暴露于砷的婴儿/儿童中的免疫训练微生物拟杆菌。重要的是，这项工作揭示了 砷暴露、微生物组变化和早期免疫介导的健康之间的关联 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肺之间存在联系 婴儿体内的拟杆菌已耗尽，因此有力地支持了这样的假设：肠道微生物组的组成是 气道健康的关键驱动因素。该项目将检验以下假设：在敏感的早期生命窗口（0-3 年）， 当发育中的免疫系统需要与微生物相互作用时，砷会影响发育中的免疫系统 微生物组，导致拟杆菌及其分泌的代谢物缺乏，并最终与 增加炎症和呼吸系统疾病的风险，如喘息、上呼吸道感染和 晚年罹患肺炎（12 岁以下）。 目标 1. 使用纵向 NHBCS 和新颖的生物信息学工具检验假设，(i) 早期生命 通过食物/水的暴露与肠道微生物组中性别特异性的扰动有关，并且（ii）早期 生活肠道微生物组改变或调节砷暴露对呼吸系统健康结果的影响。 目的 2. 检验 As 由于缺乏关键而增强肠上皮分泌 IL-8 的假设 拟杆菌分泌的短链脂肪酸丙酸，最终是由表观基因组的变化引起的。 目的 3. 测试以下假设：添加拟杆菌可以逆转拟杆菌耗尽粪便的影响 小鼠模型，从而作为益生菌干预的概念验证。