Commensal resilience mechanisms in the inflamed intestine

项目摘要 人类肠道微生物群越来越被认为对人类健康具有重要作用。然而，在这方面， 微生物群不断受到诸如肠道炎症的挑战，肠道炎症驱动微生物群， 进入一种会加剧疾病的不安状态。因此，微生物的恢复力， 肠道微生物组在面对扰动时的结构和功能稳定性对宿主健康至关重要。 我们研究计划的首要目标是阐明控制肿瘤的分子机制。 在发炎的肠道恢复能力。在肠道炎症过程中，宿主的营养免疫过程 使肠道微生物缺乏铁等必需微量营养素。与那些经过充分研究的策略相反， 病原体用来克服宿主的营养免疫力，很少有人知道肠道菌如何生存铁 饥饿在发炎的肠道。我们未来五年研究计划的主要目标是确定 在肠道炎症期间维持体内铁稳态的弹性机制。肠溶 病原体通过产生称为铁载体的铁螯合分子来克服营养免疫。这里我们 结果表明，该模型肠道多形拟杆菌（B. theta）通过以下方式在发炎的肠道中获得铁： 从导致肠道铁限制的肠道病原体中掠夺铁载体。值得注意的是，B。θ捕捉 铁载体使用在其他革兰氏阴性细菌中不存在的独特系统。然而，这样的捕获 肠道病原体可以利用这一机制从肠道黏膜“重新掠夺”铁载体， 营养免疫除了增加铁的吸收，我们表明，B。theta使用小的非编码RNA 以协调铁的保存并维持发炎肠中的细胞内铁稳态。与此 MIRA奖，我们将通过解决两个相关但独立的问题来定义企业弹性机制 基础细菌生理学中的问题：1）异铁载体的获得如何介导B。Theta 肠道炎症时的恢复力2)B. Theta调节炎症细胞内铁稳态 肠子？我们将使用由尖端组学组成的跨学科管道来解决这些问题 实验，细菌和宿主遗传学，以及对体内细菌生理学的机械理解。的 这些研究项目的完成将揭示肠道神经适应铁的机制 炎症肠道的限制以及这种适应如何塑造肠道的结构和功能稳定性 微生物组这项工作是创新的，因为它增加了体内铁代谢， 病原体和营养免疫之间错综复杂的相互作用的未被重视的方面。这项工作是 具有影响力，因为它将为了解门际铁代谢如何对肠道做出贡献提供急需的见解 微生物群在发炎的肠道中的恢复力。

PROJECT SUMMARY The human gut microbiota is increasingly recognized as having essential functions in human health. However, the microbiota is constantly subjected to challenges such as intestinal inflammation, which drives the microbiota into a perturbed state that can exacerbate diseases. Therefore, microbial resilience, which maintains the structural and functional stabilities of the gut microbiome in the face of perturbations, is critical to host health. The overarching goal of our research program is to elucidate the molecular mechanisms that govern commensal resilience in the inflamed intestine. During intestinal inflammation, host processes known as nutritional immunity starve gut microbes from essential micronutrients such as iron. In contrast to the well-studied strategies that pathogens employ to overcome host nutritional immunity, little is known about how gut commensals survive iron starvation in the inflamed gut. The primary goal of our research program for the next five years is to define the resilience mechanisms that maintain commensal iron homeostasis during gut inflammation. Enteric pathogens overcome nutritional immunity by producing iron-chelating molecules termed siderophores. Here, we show that the model gut commensal Bacteroides thetaiotaomicron (B. theta) acquires iron in the inflamed gut by pirating siderophores from an enteric pathogen that causes intestinal iron limitation. Notably, B. theta captures siderophores using a unique system absent in other Gram-negative bacteria. However, such a capture mechanism can be exploited by enteric pathogens to “re-pirate” siderophores from gut commensals to evade nutritional immunity. In addition to increasing iron uptake, we show that B. theta employs small, non-coding RNAs to orchestrate iron conservation and maintain intracellular iron homeostasis in the inflamed intestine. With this MIRA award, we will define commensal resilience mechanisms by addressing two related but independent questions in fundamental bacterial physiology: 1) How does xenosiderophore acquisition mediate B. theta resilience during gut inflammation? 2) How does B. theta manage intracellular iron homeostasis in the inflamed intestine? We will approach these questions using an interdisciplinary pipeline consisting of cutting-edge omics experiments, bacterial & host genetics, and a mechanistic understanding of bacterial physiology in vivo. The completion of these research projects will reveal the mechanisms by which gut commensals adapt to iron limitation in the inflamed gut and how such adaptation shapes the structural and functional stability of the gut microbiome. The proposed work is innovative because it adds commensal iron metabolism as a previously unappreciated dimension to the intricate interactions between pathogen and nutritional immunity. This work is impactful because it will provide much-needed insights into how interphylum iron metabolism contributes to gut microbiota resilience in the inflamed gut.