Commensal bacteria resilience mechanisms in the inflamed intestine

项目总结 人体肠道微生物区系对人类健康具有重要作用。然而，微生物区系是 不断受到挑战，如肠道炎症，这将推动微生物群进入一个不安的 可能导致或加重疾病的状态。因此，微生物的弹性，它保持结构和 肠道微生物群在面对扰动时的功能稳定性，对宿主健康至关重要。尽管中央 关于微生物群在宿主健康中的作用，微生物群复原力的机制仍未得到很好的界定。在肠道中 炎症，被称为营养免疫的宿主过程使肠道微生物从必要的微量营养素中饥饿 例如铁，构成共生菌和病原菌都必须应对的压力才能生存。肠源性 病原体通过一系列精细的机制克服营养免疫，包括编码受体 用于宿主铁结合蛋白，并产生称为铁载体的铁螯合分子。与这些形成对比的是 研究得很好的策略，肠道共生体如何在发炎的肠道中铁饥饿中幸存下来，在很大程度上仍不清楚。 我们认为，维持铁的动态平衡是共生体在 肠道发炎。在初步研究中，我们证明了模型肠道共生类杆菌 Tetaiotaomicron(B.theta)通过盗取肠道病原体的铁载体来获取铁 铁的限制。我们新的初步数据表明，B.theta通过细胞外信号捕获铁载体 脂蛋白。我们进一步表明，沙门氏菌等肠道病原体可以利用这种捕获机制来 从肠道共生体中“重新盗用”铁载体以逃避营养免疫。除了增加铁的摄取， 我们未发表的数据表明B.theta使用小的、非编码的RNA来协调铁 保护细胞内的铁平衡，对抗发炎肠道的营养免疫。 因此，我们的中心假设是B.theta将铁载体的获得与小RNA介导的获得结合在一起 细胞内的铁保存，以维持发炎的肠道的弹性。我们将通过以下方式验证我们的假设： 具体目标如下：1)阐明铁载体的获得如何调节B.theta的弹性和修饰 发炎肠道中的宿主营养免疫；以及2)确定B.theta如何维持细胞内的铁 发炎的肠道内的动态平衡。这项工作的完成将揭示GUT 共生体适应铁的限制，以及这种适应如何塑造结构和功能的稳定性 肠道炎症期间的微生物区系。这项研究具有创新性，因为它增加了共生铁代谢 作为病原体和营养免疫之间错综复杂的相互作用的一个以前未被认识的方面。 这项拟议的工作是有影响的，因为在B.theta建立铁监管模型将提供 洞察炎症者肠道微生物区系的铁代谢如何广泛影响肠道微生物区系的弹性 直觉。

PROJECT SUMMARY The human gut microbiota provides 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 cause or exacerbate diseases. Therefore, microbial resilience, which maintains the structural and functional stability of the gut microbiome in the face of perturbations, is crucial to host health. Despite a central role in host health, the mechanisms underlying microbiota resilience remain poorly defined. During intestinal inflammation, host processes known as nutritional immunity starve gut microbes from essential micronutrients such as iron, constituting stress that both commensal and pathogenic bacteria must cope with to survive. Enteric pathogens overcome nutritional immunity using a series of exquisite mechanisms, including encoding receptors for host iron-binding proteins and producing iron-chelating molecules termed siderophores. In contrast to these well-studied strategies, how gut commensals survive iron starvation in the inflamed gut remains largely unknown. We propose that maintaining iron homeostasis is an essential strategy for commensals to remain resilient during gut inflammation. In preliminary studies, we demonstrated that the model gut commensal Bacteroides thetaiotaomicron (B. theta) acquires iron by pirating siderophores from an enteric pathogen that induces intestinal iron limitation. Our new preliminary data suggest that B. theta captures siderophores using an extracellular lipoprotein. We further show that enteric pathogens such as Salmonella can exploit this capture mechanism to “re-pirate” siderophores from gut commensals to evade nutritional immunity. In addition to increasing iron uptake, our unpublished data demonstrate that B. theta employs small, non-coding RNAs to orchestrate iron conservation to maintain intracellular iron homeostasis and combat nutritional immunity in the inflamed intestine. As such, our central hypothesis is that B. theta couples siderophore acquisition with small RNA-mediated intracellular iron conservation to maintain resilience in the inflamed gut. We will test our hypothesis by pursuing the following specific aims: 1) Elucidate how siderophore acquisition mediates B. theta resilience and modifies host nutritional immunity in the inflamed gut; and 2) Determine how B. theta maintains intracellular iron homeostasis in the inflamed gut. The completion of this work will reveal the mechanisms by which gut commensals adapt to iron limitation and how such adaptation shapes the structural and functional stability of the microbiota during gut inflammation. This research is innovative because it adds commensal iron metabolism as a previously unrecognized dimension to the intricate interactions between pathogen and nutritional immunity. This proposed work is impactful because establishing a model for iron regulation in B. theta will provide insights into how interphylum iron metabolism may broadly contribute to gut microbiota resilience in the inflamed gut.