Commensal resilience mechanisms in the inflamed intestine

项目总结 人们越来越认识到人体肠道微生物区系在人类健康中具有重要作用。然而， 微生物区系不断受到挑战，如肠道炎症，这推动了微生物区系 进入一种可能会加剧疾病的不安状态。因此，微生物的弹性，维持了 肠道微生物群在面对扰动时的结构和功能稳定性，对宿主的健康至关重要。 我们研究计划的首要目标是阐明支配共生的分子机制。 在发炎的肠子里有弹性。在肠道炎症期间，宿主的过程被称为营养免疫 让肠道微生物从铁等必需的微量营养素中饥饿。与经过充分研究的策略形成对比的是 病原体用来克服宿主的营养免疫，对肠道共生菌如何存活铁知之甚少 发炎的肠子里的饥饿。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共生铁平衡的弹性机制。肠源性 病原体通过产生被称为铁载体的铁螯合分子来克服营养免疫。在这里，我们 显示模型肠道共生类杆菌thetaiotaomicron(B.theta)通过以下方式在发炎的肠道中获得铁 从一种引起肠道铁限制的肠道病原体盗用铁载体。值得注意的是，B.theta捕捉到 铁载体使用一种独特的系统，在其他革兰氏阴性菌中没有。然而，这样的捕获 肠道病原体可以利用这种机制从肠道共生体中重新盗用铁载体，从而逃避 营养免疫力。除了增加铁的摄取，我们还表明B.theta使用了小的非编码RNA 在发炎的肠道中协调铁保护和维持细胞内铁的动态平衡。有了这个 Mira奖，我们将通过处理两个相关但独立的 基础细菌生理学中的问题：1)外源含铁载体的获得如何调节B.theta 肠道炎症中的弹性？2)B.theta是如何在炎症患者中管理细胞内铁稳态的 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。这个 这些研究项目的完成将揭示肠道共生体适应铁的机制。 肠道发炎的局限性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。这项拟议的工作具有创新性，因为它增加了共生铁新陈代谢 病原体和营养免疫之间错综复杂的相互作用的一个未被认识的方面。这项工作是 有影响力，因为它将提供急需的洞察力，了解门间铁代谢如何对肠道做出贡献 发炎的肠道中的微生物群的弹性。

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.