Bacterial adaptions in host-microbe interactions.

宿主-微生物相互作用中的细菌适应。

• 批准号: 10590688
• 负责人: Hiutung Chu
• 金额: $ 55.72万
• 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/10590688
• 关键词: Adopted; Aerobic; Anaerobic Bacteria; Anti-Inflammatory Agents; Bacteroides fragilis; Cells; Chemicals; Chronic; Chronic Phase; Coculture Techniques; Colitis; Collection; Colon; 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; 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; lonely individuals; 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.

项目摘要/摘要 炎症性肠病（IBD）长期以来一直与组成和代谢变化有关 肠道菌群，但广泛的研究工作未能识别出单一的致病微生物作为 因果剂。在这笔赠款中，我们研究了肠道炎症驱动的替代假设 共生细菌的适应，进一步加剧了IBD的疾病。虽然细菌适应是 对于发炎的肠道中的共生生存和持久性所必需的，我们目前不了解这些 自适应策略改变了共生微生物的功能。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，那里 了解发炎的肠道环境如何形成共生细菌的代谢是至关重要的 进一步加剧了IBD的炎症。这项研究的长期目标是了解肠道细菌如何直接 免疫反应以开发炎症性疾病的理性微生物疗法。我们的中心 假设是发炎肠道的氧化环境驱动了共生的代谢适应 细菌，导致细菌菌株的扩大，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）定义的遗传和功能变化 IBD肠道中的共生细菌fragilis； 2）确定共生细菌的代谢适应 在实验性结肠炎期间； 3）确定氧对厌氧细菌代谢和免疫的影响 调制。我们将检查健康和IBD队列中脆弱链球菌菌株的遗传变异。这 信息将使菌株特异性B.脆弱的基因组规模模型构建以阐明 IBD相关菌株的代谢输出和表型态。接下来，我们将确定遗传 在结肠炎小鼠模型中的脆弱芽孢杆菌的适应并测试肠炎对细菌的影响 代谢和免疫调节。最后，我们将研究Fragilis的氧气适应菌株如何 对肠内稳态产生代谢和免疫学后果。拟议的研究是 意义重大，因为定义共生细菌适应肠道炎症的早期阶段将是一个 检测和治疗IBD的早期阶段并防止衰弱的强大策略 IBD的慢性阶段。