Cross-talk between iron metabolism and intestinal inflammation

项目摘要 炎症性贫血（AI）是炎症性肠病（IBD）的常见并发症， 肝细胞源性激素hepcidin的表达异常升高， 全身铁稳态。炎症相关的铁调素表达增加导致细胞内铁 隔离、低铁血症和红细胞生成受损。有效治疗AI需要详细的 了解在炎症背景下上调铁调素的机制。的目标 建议的研究是使用组织培养方法以及小鼠模型来阐明这些机制 IBD。在初步的体内实验中，我们已经发现肠道微生物群组成具有显著的 结肠炎期间对铁调素表达的影响，这种影响与STAT 3活性改变有关 和肝脏中STAT 3依赖性基因表达。此外，我们从体外研究中发现， 常驻肠道细菌能够诱导单核细胞-巨噬细胞分泌IL-1β， 细胞因子作用于肝细胞，通过一种涉及骨活化的新机制上调铁调素 形态发生蛋白（BMP）信号通路。基于我们的发现，我们假设 微生物群在肠内感染期间对铁调素表达具有重要的、以前未被认识到的作用。 阐明这种效应的分子基础可能会导致新的策略， 铁调素水平。我们将在实验中测试这一想法，这些实验将描述两种机制， 微生物群影响铁调素表达：（1）我们将继续我们的初步体内观察， 阐明STAT 3依赖性铁调素上调的哪些方面受到微生物群的影响。我们将 还使用宏基因组测序和代谢物分析来阐明介导 微生物群对铁调素表达的影响。(2)根据我们的初步体外研究结果，我们将 使用体外和体内实验的组合来阐明肠道细菌如何上调铁调素 通过新的IL-1β介导的BMP信号依赖性机制。我们还将确定在体内的作用， 结肠炎相关hepcidin上调的机制。我们的研究成果会越来越多 因此，本发明的目的在于了解IBD中的AI发病机制，从而促进针对该问题的新治疗的开发。

PROJECT SUMMARY The anemia of inflammation (AI) is a frequent complication of inflammatory bowel disease (IBD) and is caused by abnormally elevated expression of the hepatocyte-derived hormone hepcidin, the central regulator of systemic iron homeostasis. Inflammation-associated increases in hepcidin expression lead to intracellular iron sequestration, hypoferremia and compromised erythropoiesis. Effective treatment of AI requires detailed knowledge of the mechanisms that up-regulate hepcidin in the context of inflammation. The goal of the proposed studies is to elucidate these mechanisms using tissue culture approaches as well as mouse models of IBD. In preliminary in vivo experiments, we have found that gut microbiota composition has a significant influence on hepcidin expression during colitis and that this influence is associated with altered STAT3 activity and STAT3-dependent gene expression in the liver. In addition, we have found from in vitro studies that resident gut bacteria are able to induce the secretion of IL-1β by monocyte-macrophages, and that this cytokine acts on hepatocytes to up-regulate hepcidin by a novel mechanism involving activation of the bone morphogenetic protein (BMP) signaling pathway. Based on our findings, we hypothesize that the gut microbiota has an important, previously unappreciated, effect on hepcidin expression during intestinal inflammation, and that clarifying the molecular basis of this effect may lead to new strategies for manipulating hepcidin levels. We will test this idea in experiments that will characterize 2 mechanisms by which the microbiota influences hepcidin expression: (1) We will follow up on our preliminary in vivo observations to clarify which aspects of STAT3-dependent hepcidin up-regulation are influenced by the microbiota. We will also use metagenomic sequencing and metabolite profiling to shed light on the mechanisms that mediate the effects of the microbiota on hepcidin expression. (2) Following up on our preliminary in vitro findings, we will use a combination of in vitro and in vivo experiments to clarify how resident gut bacteria up-regulate hepcidin via the novel IL-1β-mediated, BMP signaling-dependent mechanism. We will also determine the in vivo role of this mechanism in colitis-associated hepcidin up-regulation. The results of our studies will increase understanding of AI pathogenesis in IBD, and thus facilitate development of new treatments for this problem.