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.

项目摘要/摘要 炎症性肠道疾病（IBD）是由宿主，环境和微生物因子的收敛引起的， 每一种必要的，但不足以引起疾病。然而，知识的显着差距仍然存在 - 其中， 是什么是疾病敏感性的基础，并引起了IBD的发作。需要更好地了解 导致这些疾病的原因仍然是一个挑战。疾病发作，许多混杂因素和 并发症使得揭开无数促成因素的问题是有问题的。毫不奇怪，大多数人 学科研究无法超越描述和关联。无法整理出在 临时基础进一步阻碍了改善临床管理和成果并发展有效的努力 风险分层和预防疾病的策略。为了解决这个问题，我们提出了一个多学科 团队方法将使用独特的临床模型的镜头来获得变革性的见解，这将有助于 在IBD中移动针头。该模型涉及一部分患有医疗溃疡性溃疡性结肠炎的患者 （UC）患有肠ical肛门吻合（UC-IPAA）的总前闭塞切除术（UC），可以是 紧随疾病发展前后，并作为自己的控制。这些患者中有一半会 在两年内发展出回肠袋的炎症状况（袋）。在最初的探索性研究中 在这些患者中，有两个发现导致以下假设：[1] IBD患者表现出来 对微生物群衍生信号的异常转录响应，使它们容易受到影响 小袋炎的发展，但不足以引起疾病。 [2]特定的粘膜病原体 通过选择或获取病毒因子触发囊炎的出现 遗传敏感性的背景。关于后者，特异性杀菌剂脆弱的差异 囊囊多糖（CPS）生物合成基因簇之间的腔内和粘膜菌株可能会改变A 与病原体的共生微生物。提出了三个目标：（1）研究刺激，角色和 异常的UC袋转录组的特定宿主基因的功能影响，该基因可能促进疾病 通过采用单细胞方法来定义细胞类型和特异性贡献，并且 机制； （2）识别和分离参与促进囊炎的微生物，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开始的作用和贡献 疾病，（3）为更广泛的社区开发一种研究资源，以推动基于发现的或 假设生成科学。该研究将由一个多学科专家团队进行 合作和协同作用的经过验证和成功的记录。该提案链接基本，翻译和临床 科学研究是通过关注宿主和微生物细胞的分子和遗传机制 为许多类型的复杂免疫疾病建立未来干预措施的基础的目的；最终，我们 将能够改变这些患者的结果。