Understanding the Contributions of Commensal Bacteria to Human Fe Metabolism

了解共生细菌对人类铁代谢的贡献

• 批准号: 9376511
• 负责人: Jennifer L DuBois
• 金额: $ 21.28万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9376511
• 关键词: Address; Affect; Anaerobic Bacteria; Anemia; Animals; Bacteria; Biochemistry; Biological; Biological Availability; Blood Circulation; Chemicals; Chemistry; Colon; Colon Carcinoma; Complex; Consult; Dependence; Developed Countries; Developing Countries; Development; Diet; Dietary Iron; Disease; Engineering; Environment; Epithelial; Excretory function; Future; Gastrointestinal tract structure; Generations; Germ-Free; Gnotobiotic; Goals; Health; Heme; Heme Iron; Human; Human Microbiome; In Vitro; Intestines; Investigation; Iron; Knowledge; Label; Link; Magnetism; Malignant Neoplasms; Malnutrition; Meat; Metabolic; Metabolism; Methodology; Methods; Microbe; Microbial Biofilms; Mission; Modeling; Monitor; Montana; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nuclear; Nutrition Disorders; Nutritional; Pathway interactions; Play; Population; Probiotics; Process; Research Personnel; Rest; Role; Source; Stable Isotope Labeling; Surface; System; Testing; Time; Universities; Work; absorption; base; commensal microbes; dietary heme; dietary supplements; experimental study; gut microbiome; human disease; improved; in vitro Model; in vivo; iron deficiency; iron metabolism; metabolic abnormality assessment; microbial; microbial community; microbiome; microbiota; microorganism; planetary Atmosphere; preference; probiotic therapy; residence; uptake

PROJECT SUMMARY Iron-deficiency and associated anemia are the most prevalent nutritional disorders worldwide, shared by nearly a third of the human population. These disorders persist even though the diet often contains sufficient iron. Extensive effort focused on discovering how to improve the bioavailability of dietary iron and supplements. However, little is known about how the complex microbiota within the digestive tract, which take up and process host dietary iron for their own needs, influence the efficiency with which iron is absorbed by the host. At the same time, unmetabolized heme iron from red meat diets that remains in the colon has been associated with the development of colon cancer, with microbial activity postulated to play a key role. Understanding how microbial iron metabolism promotes or ameliorates human disease represents a critical knowledge gap. The long-term goal of this work is to treat iron deficiency and associated iron-related disorders by probiotic therapies and/or engineered manipulation of the gut microbiome, supporting the mission of the NIDDK. In this proposal, we hypothesize that, because bacteria absorb iron for their own needs, the microbiome acts as a sink for dietary iron, increasing its residence time in the gut, altering its chemical speciation, and minimizing fecal excretion. Specifically, we hypothesize that the limited O2 environment of the digestive tract and the varying ability of the resident microbiota to use it are key variables controlling the rate of uptake and ultimate fate of iron. These hypotheses will be tested via two aims. In Aim 1, we will examine the uptake, heme/non-heme source dependence, and fate of iron supplied to representative gut bacteria and consortia under controlled O2 atmospheres. These ex situ experiments will allow us to predict how bacteria might interact with dietary iron inside the digestive tract of an animal host. In Aim 2, we will determine how the presence of specific microbes and microbial communities influence the bioavailability and metabolic fate of iron in germ free mice compared to mice with defined microbiomes, including the monocultures and consortia from Aim 1 and complex murine and human microbiomes. Successful completion of this work will provide a first-ever assessment of the bacterial contribution to iron metabolism in an animal host. It will establish working experimental systems and collaborative relationships that will allow for increasingly sophisticated future investigations.

项目摘要 铁缺乏症和相关性贫血是全球最普遍的营养疾病，几乎由 人口的三分之一。即使饮食经常含有足够的铁，这些疾病仍然存在。 广泛的努力集中在发现如何改善饮食铁和补品的生物利用度。 但是，关于消化道中的复杂微生物群如何占用并进行处理，知之甚少 寄主饮食铁的需求，会影响宿主吸收铁的效率。同样 时间，仍然存在于结肠中的红肉饮食中的无代谢血红素铁与 结肠癌的发展，假定具有关键作用的微生物活性。了解微生物 铁代谢促进或改善人类疾病代表着一个关键的知识差距。长期 这项工作的目标是通过益生菌疗法和/或治疗铁缺乏症和相关的与铁相关疾病 对肠道微生物组的工程操纵，支持NIDDK的任务。在这个建议中，我们 假设这一点，因为细菌满足铁的需求，微生物组充当饮食的水槽 铁，增加了其在肠道中的停留时间，改变了其化学物种形成，并最大程度地减少了粪便排泄。 具体而言，我们假设消化道的有限的O2环境和能力的不同能力 使用它的居民微生物群是控制铁的摄取速度和最终命运的关键变量。这些 假设将通过两个目标进行检验。在AIM 1中，我们将检查摄取，血红素/非血红素来源 依赖性，以及在受控的O2下提供给代表性肠道细菌和财团的铁的命运 气氛。这些现场实验将使我们能够预测细菌如何与饮食铁相互作用 在动物宿主的消化道内。在AIM 2中，我们将确定特定微生物的存在如何 相比 具有定义微生物组的小鼠，包括AIM 1和复杂鼠的单一培养和财团， 人类微生物组。成功完成这项工作将提供对细菌的首次评估 在动物宿主中对铁代谢的贡献。它将建立工作实验系统和协作 将允许越来越复杂的未来调查的关系。