Commensal bacteria resilience mechanisms in the inflamed intestine

发炎肠道中的共生细菌恢复机制

• 批准号: 10568188
• 负责人: Wenhan Zhu
• 金额: $ 37.04万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-07 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568188
• 关键词: Affinity; Animal Disease Models; Animal Model; Bacteria; Bacterial Model; Bacteroides thetaiotaomicron; Bacteroidetes; Binding; Binding Proteins; Biological Availability; Colitis; Couples; Coupling; Data; Dimensions; Disease; Equilibrium; Expenditure; Goals; Health; Homeostasis; Human; In Vitro; Inflammation; Intestines; Iron; Iron Chelating Agents; Iron Chelation; Iron-Binding Proteins; Knowledge; LCN2 gene; Lipoproteins; Mediating; Membrane; Microbe; Micronutrients; Modeling; Molecular; Nutritional; Nutritional Immunity; Organism; Play; Predisposition; Process; Regulation; Reporting; Research; Research Project Grants; Role; Salmonella; Salmonella typhimurium; Series; Shapes; Siderophores; Small RNA; Starvation; Stress; Structure; Surface; Testing; Untranslated RNA; Vesicle; Work; beneficial microorganism; combat; commensal bacteria; coping; dysbiosis; enteric pathogen; experimental study; extracellular; fitness; gut inflammation; gut microbes; gut microbiome; gut microbiota; in vivo; innovation; insight; iron metabolism; member; microbial; microbiome; microbiota; pathogen; pathogenic bacteria; prevent; receptor; resilience; response; uptake

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.

项目摘要 人类肠道微生物群在人类健康中提供了重要功能。但是，微生物群是 不断受到诸如肠道炎症之类的挑战 可能引起或加剧疾病的状态。因此，保持结构和 面对扰动，肠道微生物组的功能稳定性对于宿主健康至关重要。尽管有一个中心 在宿主健康中的作用，微生物菌弹性的基础机制的定义仍然很差。在肠道期间 炎症，宿主过程称为营养免疫，来自必需微量营养素 例如铁，构成共生和致病细菌必须应付才能生存的压力。肠 病原体使用一系列独家机制克服营养免疫，包括编码接收器 用于宿主铁结合蛋白，并产生称为铁载体的铁螯合分子。与这些相反 经过充分研究的策略，肠道的肠道如何在发炎的肠道中幸存下来，这在很大程度上是未知的。 我们建议保持铁稳态是在 肠道注射。在初步研究中，我们证明了模型肠道共生细菌 Thetaiotaomicron（B。theta）通过从诱导肠道的肠道病原体中盗版铁载体来获取铁 铁的限制。我们的新初步数据表明，B。theta使用细胞外捕获了铁载体 脂蛋白。我们进一步表明，诸如沙门氏菌之类的肠道病原体可以将这种捕获机制利用为 从肠道共性避免营养免疫的“重新海盗”铁载体。除了增加铁的吸收外 我们未发表的数据表明，B。Theta员工小型，非编码的RNA可以协调铁 保护肠内的细胞内铁稳态和作战营养免疫。 因此，我们的中心假设是theta夫妇用小的RNA介导 细胞内铁的保存以保持发炎的肠道中的弹性。我们将通过追求来检验我们的假设 以下特定目的：1）阐明铁载体采集如何介导B. theta的弹性和修饰符 发炎的肠道中宿主营养免疫； 2）确定B. theta如何维持细胞内铁 在发炎的肠道中体内平衡。这项工作的完成将揭示肠道的机制 统一适应铁的限制以及这种适应如何塑造结构和功能稳定性 肠道注射过程中的微生物群。这项研究具有创新性，因为它增加了共生铁代谢 作为先前无法识别的维度，与病原体和营养免疫之间的复杂相互作用。 这项提出的工作具有影响力，因为在B. theta中建立铁制模型 洞察力中铁代谢如何在发炎中有助于肠道菌群的弹性广泛贡献 肠。