Cross-talk between iron metabolism and intestinal inflammation

项目总结 炎症性贫血(AI)是炎症性肠病(IBD)的常见并发症，由 通过肝细胞衍生激素海普西丁的异常高表达， 全身性铁稳态。炎症相关的海普西丁表达增加导致细胞内铁 隔离、低铁血症和红细胞生成受损。AI的有效治疗需要详细的 了解在炎症背景下上调海普西丁的机制。的目标是 建议的研究是使用组织培养方法和小鼠模型来阐明这些机制 IBD的症状。在初步的活体实验中，我们发现肠道微生物区系组成具有显著的 结肠炎对海普西丁表达的影响及其与STAT3活性变化的关系 肝脏中STAT3依赖的基因表达。此外，我们从体外研究中发现， 滞留的肠道细菌能够诱导单核巨噬细胞分泌IL-1β，而这 细胞因子通过一种涉及骨激活的新机制作用于肝细胞上调海普西丁 形态发生蛋白信号通路。根据我们的发现，我们假设 微生物区系对肠道中海普西丁的表达有重要的影响，这是以前未被认识到的。 炎症，澄清这种效应的分子基础可能会导致新的操纵策略 海普西丁水平。我们将在实验中测试这一想法，这些实验将描述两种机制，即 微生物区系影响海普西丁的表达：(1)我们将跟踪我们在体内的初步观察 阐明依赖STAT3的海普西丁上调的哪些方面受到微生物区系的影响。我们会 还可以使用元基因组测序和代谢物图谱来阐明介导 微生物区系对海普西丁表达的影响。(2)跟进我们的初步体外研究结果，我们会 使用体外和体内实验相结合的方法来阐明肠道细菌如何上调海普西丁 通过新的IL-1β介导的骨形态发生蛋白信号依赖机制。我们还将确定其在体内的作用。 这一机制在结肠炎相关的海普西丁中上调。我们的研究成果将会增加 了解AI在IBD中的发病机制，从而促进这一问题的新治疗方法的开发。

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.