Understanding the Contributions of Commensal Bacteria to Human Fe Metabolism

项目摘要 缺铁和相关贫血是世界范围内最普遍的营养失调， 三分之一的人口。即使饮食中通常含有足够的铁，这些疾病仍然存在。 广泛的努力集中在发现如何提高膳食铁和补充剂的生物利用度。 然而，人们对消化道内复杂的微生物群是如何吸收和加工的知之甚少。 宿主饮食中的铁对自身的需要，影响宿主吸收铁的效率。在同一 同时，来自红肉饮食的未代谢的血红素铁留在结肠中， 结肠癌的发展，与微生物活性假定发挥关键作用。了解微生物如何 铁代谢促进或改善人类疾病代表了关键的知识空白。长期 这项工作的目标是通过益生菌疗法治疗铁缺乏症和相关的铁相关疾病，和/或 对肠道微生物组的工程操纵，支持NIDDK的使命。在本提案中，我们 我假设，因为细菌吸收铁为自己的需要，微生物组作为一个水槽的饮食 铁，增加其在肠道中的停留时间，改变其化学形态，并最大限度地减少粪便排泄。 具体而言，我们假设消化道有限的O2环境和消化道的变化能力， 居民微生物群使用它是控制铁的吸收率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。在目标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O2下供应给代表性肠道细菌和聚生体的铁的命运 空气.这些非原位实验将使我们能够预测细菌如何与膳食铁相互作用 在动物宿主的消化道内在目标2中，我们将确定特定微生物的存在如何 和微生物群落影响无菌小鼠铁的生物利用度和代谢命运， 具有确定的微生物组的小鼠，包括来自Aim 1的单一培养物和聚生体以及复杂的鼠和 人体微生物组这项工作的成功完成将提供有史以来第一次评估的细菌 在动物宿主中的铁代谢的贡献。它将建立工作实验系统和协作 这些关系将使未来的调查更加复杂。

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.