Bacterial adaptions in host-microbe interactions.

宿主-微生物相互作用中的细菌适应。

• 批准号: 10412503
• 负责人: Hiutung Chu
• 金额: $ 58.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-11 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412503
• 关键词: Adopted; Aerobic; Anaerobic Bacteria; Anti-Inflammatory Agents; Bacteroides fragilis; Cells; Chemicals; Chronic; Chronic Phase; Coculture Techniques; Colitis; Collection; Data; Dendritic Cells; Development; Diet; Disease; Environment; Exposure to; Genes; Genetic; Genetic Variation; Genome; Genomics; Gnotobiotic; Goals; Grant; Health; Homeostasis; Human; Human Microbiome; Immune; Immune Tolerance; Immune response; Immunity; Immunologics; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-10; Intestines; Knock-out; Laboratories; Life Style; Link; Metabolic; Metabolic Pathway; Modeling; Mucosal Immune Responses; Mucous Membrane; Mus; Mutation; Output; Oxidative Stress; Oxygen; Oxygen Consumption; Pathogenicity; Phenotype; Property; Reactive Oxygen Species; Research; Research Project Grants; Resistance; Respiration; Sampling; Shapes; T-Lymphocyte; Testing; Time; Tissues; Variant; Work; bacterial metabolism; cohort; commensal bacteria; commensal microbes; field study; fitness; gastrointestinal; genetic variant; genome sequencing; genome-wide; gut bacteria; gut colonization; gut inflammation; gut microbiota; host-microbe interactions; immune function; immunoregulation; insight; intestinal homeostasis; member; metabolomics; microbial; microorganism; murine colitis; novel; prevent; response; transcriptome sequencing; whole genome

PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD) has long been associated with compositional and metabolic changes in the gut microbiota, yet extensive research efforts have failed to identify a single pathogenic microorganism as the causative agent. In this grant, we investigate an alternative hypothesis in which gut inflammation drives adaptations in commensal bacteria that further exacerbates disease in IBD. Though bacterial adaptations are necessary for commensal survival and persistence in the inflamed gut, we currently do not understand how these adaptive strategies alter the function of commensal microbes. These include metabolic and immunomodulatory activities of commensal bacteria that regulate mucosal immune homeostasis in health and disease. Thus, there is a critical need to understand how the inflamed gut environment shapes commensal bacteria metabolism to further exacerbate inflammation in IBD. The long-term goal of this study is to understand how gut bacteria direct immune responses in order to develop rational microbial therapies for inflammatory diseases. Our central hypothesis is that the oxygenated environment of the inflamed gut drives metabolic adaptations in commensal bacteria, resulting in expansion of bacterial strains that exacerbate intestinal inflammation. The central hypothesis will be tested by pursuing three specific aims: 1) define the genetic and functional variation of commensal Bacteroides fragilis in the IBD gut; 2) determine the metabolic adaptations of commensal bacteria during experimental colitis; and 3) identify the impact of oxygen on anaerobic bacterial metabolism and immune modulation. We will examine the genetic variation of B. fragilis strains from healthy and IBD cohorts. This information will enable the construction of strain-specific B. fragilis genome-scale models to elucidate the metabolic output and phenotypic states of IBD-associated strains. Next, we will determine the genetic adaptations of B. fragilis in mouse models of colitis and test the impact of intestinal inflammation on bacterial metabolism and immune modulation. Finally, we will examine how oxygen-adapted strains of B. fragilis may have metabolic and immunological consequences on intestinal homeostasis. The proposed research is significant because defining commensal bacteria adaptations to early stages of gut inflammation will be a powerful strategy for detecting and treating early stages of IBD and preventing progression into the debilitating chronic phase of IBD.

项目概要/摘要 炎症性肠病（IBD）长期以来一直与肠道的成分和代谢变化有关。 肠道微生物群，但广泛的研究工作未能确定单一的病原微生物作为 病原体。在这笔资助中，我们研究了另一种假设，即肠道炎症驱动 共生细菌的适应进一步加剧了 IBD 疾病。尽管细菌的适应是 对于发炎肠道中的共生生存和持续存在所必需的，我们目前不明白这些 适应性策略改变共生微生物的功能。这些包括代谢和免疫调节 调节健康和疾病中粘膜免疫稳态的共生细菌的活性。因此，有 迫切需要了解发炎的肠道环境如何影响共生细菌的代谢 进一步加剧 IBD 的炎症。这项研究的长期目标是了解肠道细菌如何引导 免疫反应，以开发针对炎症性疾病的合理微生物疗法。我们的中央 假设是发炎肠道的含氧环境驱动共生体的代谢适应 细菌，导致细菌菌株扩张，加剧肠道炎症。中央 假设将通过追求三个具体目标来检验：1）定义遗传和功能变异 IBD 肠道中的共生脆弱拟杆菌； 2）确定共生细菌的代谢适应 实验性结肠炎期间； 3）确定氧气对厌氧细菌代谢和免疫的影响 调制。我们将检查健康人群和 IBD 人群中脆弱拟杆菌菌株的遗传变异。这 这些信息将有助于构建菌株特异性脆弱拟杆菌基因组规模模型，以阐明 IBD 相关菌株的代谢输出和表型状态。接下来我们要确定基因 脆弱拟杆菌在结肠炎小鼠模型中的适应性并测试肠道炎症对细菌的影响 新陈代谢和免疫调节。最后，我们将研究脆弱拟杆菌的氧适应菌株如何可能 对肠道稳态具有代谢和免疫学影响。拟议的研究是 意义重大，因为定义共生细菌对肠道炎症早期阶段的适应将是一个 检测和治疗 IBD 早期阶段并防止进展为衰弱的强大策略 IBD 慢性期。