Host and microbial basis of human ulcerative colitis and pouchitis: Identification, role, mechanisms, and resource development of host susceptibility and pathobiont factors

人类溃疡性结肠炎和储袋炎的宿主和微生物基础：宿主易感性和致病因素的鉴定、作用、机制和资源开发

• 批准号: 10403677
• 负责人: EUGENE B CHANG
• 金额: $ 204.09万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403677
• 关键词: Address; Anabolism; Anastomosis - action; Anus; Bacteroides fragilis; Cells; Clinical; Clinical Management; Colitis; Collaborations; Communities; Cross-Sectional Studies; Data; Data Set; Deposition; Development; Disease; Disease susceptibility; Epigenetic Process; Epithelial; Event; Exhibits; Familial Adenomatous Polyposis Syndrome; Future; Gene Cluster; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Programming; Genetic Transcription; Genome; Genomics; Germ-Free; Heterogeneity; Horizontal Gene Transfer; Human; Ileal Reservoirs; Immune; Immune Complex Diseases; In Vitro; Indigenous; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Interleukin-10; Intervention; Knockout Mice; Knowledge; Lead; Link; Medical; Metadata; Metagenomics; Microbe; Microfluidics; Modeling; Molecular Genetics; Mucositis; Mucous Membrane; Native-Born; Needles; Onset of illness; Organoids; Outcome; Patient-Focused Outcomes; Patients; Persons; Phenotype; Pilot Projects; Polysaccharides; Population; Pouchitis; Predisposition; Prospective Studies; Refractory; Relapse; Research; Research Design; Research Personnel; Resource Development; Resources; Ribosomal RNA; Role; Sampling; Science; Shotguns; Signal Transduction; Stimulus; Study Subject; Target Populations; Time; Tissues; Ulcerative Colitis; Variant; Virulence; Virulence Factors; base; cell type; clinically relevant; cohort; commensal microbes; community based participatory research; differential expression; disorder prevention; functional genomics; genetic element; genetic manipulation; genome sequencing; human subject; improved; in vivo evaluation; insight; lens; metagenome; microbial; microbial host; microbiota; multidisciplinary; novel; pathobiont; patient subsets; rapid detection; response; risk stratification; synergism; transcriptome; transcriptomics; whole genome

PROJECT SUMMARY/ABSTRACT Inflammatory bowel diseases (IBD) result from the convergence of host, environmental, and microbial factors, each necessary, but not sufficient to cause disease. Yet, significant gaps in knowledge remain – among them, what underlies disease susceptibility and precipitates the onset of IBD. The need to better understand the causes that lead to these diseases remains a challenge. Post disease onset, numerous confounders and complications make it problematic to unravel the myriad of contributing factors. Not surprisingly, most human subject studies fail to go beyond description and association. Inability to sort out cause-effect relationship on a temporal basis further hinders efforts to improve clinical management and outcomes and to develop effective strategies for risk stratification and disease prevention. To address this issue, we propose a multi-disciplinary team approach that will use the lens of a unique clinical model to gain transformative insights that will help move the needle in IBD. The model involves a subset of patients with medically-refractory ulcerative colitis (UC) who have undergone total proctocolectomy with ileal pouch anal anastomosis (UC-IPAA) and who can be followed before and after disease development and serve as their own controls. Half of these patients will develop an inflammatory condition of their ileal pouch within two years (pouchitis). In an initial exploratory study of these patients, two discoveries were made which led to the following hypotheses: [1] IBD patients exhibit an anomalous transcriptional response to microbiota-derived signals that renders them susceptible to the development of pouchitis, but is not sufficient to cause disease. [2] Specific mucosal pathobionts that emerge through selection or acquisition of virulence factors trigger pouchitis on the patient's background of genetic susceptibility. With regard to the latter, differences in specific Bacteroides fragilis capsular polysaccharide (CPS) biosynthetic gene clusters among luminal and mucosal strains may transform a commensal microbe to a pathobiont. Three aims are proposed: (1) to investigate the stimuli, role, and functional impact of specific host genes of the anomalous UC pouch transcriptome that may promote disease susceptibility, by employing single-cell approaches to define cell-type and -specific contributions and mechanisms; (2) to identify and isolate microbes involved in promoting pouchitis including CPS variants and determine the their functional impact on host epithelia and immune cells and role and contribution to initiation of disease, (3) to develop a research resource for the broader community to advance discovery-based or hypothesis-generating science. The study will be conducted by a multi-disciplinary team of experts with a proven and successful record of collaboration and synergy. The proposal links basic, translational, and clinical scientific research by focusing on molecular and genetic mechanisms of host and microbial cells with the objective of building a base for future interventions for many types of complex immune diseases; ultimately, we will be able to alter the outcome for these patients.

项目概要/摘要 炎症性肠病（IBD）是宿主、环境和微生物因素共同作用的结果， 每种都是必需的，但不足以引起疾病。然而，知识方面仍然存在巨大差距——其中， 是什么导致了疾病易感性并促使 IBD 发病。需要更好地理解 导致这些疾病的原因仍然是一个挑战。疾病发作后，许多混杂因素和 复杂性使得弄清楚众多影响因素变得困难。毫不奇怪，大多数人类 主题研究未能超越描述和关联。无法理清因果关系 时间基础进一步阻碍了改善临床管理和结果以及开发有效的方法的努力 风险分层和疾病预防策略。为了解决这个问题，我们提出了一个多学科的解决方案 团队方法将使用独特的临床模型的视角来获得变革性的见解，这将有助于 在 IBD 中移动针。该模型涉及医学难治性溃疡性结肠炎患者的子集 (UC) 接受过全直肠结肠切除术联合回肠贮袋肛门吻合术 (UC-IPAA) 的人和可以接受 在疾病发生之前和之后进行跟踪并作为自己的对照。这些患者中有一半会 两年内出现回肠储袋炎症（储袋炎）。在初步探索性研究中 在这些患者中，有两项发现得出以下假设：[1] IBD 患者表现出 对微生物群衍生信号的异常转录反应使它们容易受到 储袋炎的发展，但不足以引起疾病。 [2] 特定粘膜病原体 通过选择或获得毒力因子而出现的病毒会引发患者的储袋炎 遗传易感性背景。对于后者，特定脆弱拟杆菌的差异 管腔和粘膜菌株中的荚膜多糖（CPS）生物合成基因簇可能会改变 致病生物的共生微生物。提出了三个目标：（1）研究刺激、作用和 可能促进疾病的异常 UC 储袋转录组的特定宿主基因的功能影响 敏感性，通过采用单细胞方法来定义细胞类型和特定的贡献和 机制； (2) 识别和分离参与促进储袋炎的微生物，包括 CPS 变体和 确定它们对宿主上皮和免疫细胞的功能影响以及对启动的作用和贡献 (3) 为更广泛的社区开发研究资源，以推进基于发现的或 产生假设的科学。该研究将由多学科专家团队进行 协作和协同作用的可靠且成功的记录。该提案将基础、转化和临床联系起来 专注于宿主和微生物细胞的分子和遗传机制的科学研究 目标是为未来多种复杂免疫疾病的干预奠定基础；最终，我们 将能够改变这些患者的结果。