Role of microbiota, host genetics and mesenteric adipose in Crohn's disease fibrosis and post-op recurrence.

微生物群、宿主遗传学和肠系膜脂肪在克罗恩病纤维化和术后复发中的作用。

• 批准号: 10549289
• 负责人: Suzanne Devkota
• 金额: $ 38.25万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-20 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10549289
• 关键词: Adipose tissue; Attenuated; Automobile Driving; Bacteria; Bacterial Translocation; Biological; Biology; Biopsy; Blood; Cells; Chronic; Classification; Collagen; Collection; Complex; Complication; Crohn' s disease; Data; Deposition; Development; Disease; Environment; Excision; Face; Famines; Fatty acid glycerol esters; Feces; Fibroblasts; Fibrosis; Fingers; Future; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Germ-Free; Goals; Hyperplasia; Immune; Immune response; Immunologics; Individual; Inflammation; Intervention; Intestinal Fibrosis; Intestines; Left; Macrophage; Mediating; Mesentery; Metagenomics; Modeling; Mucous Membrane; Mus; Myelogenous; Newly Diagnosed; Operative Surgical Procedures; Organism; Patient Care; Patients; Pattern; Penetrance; Pharmaceutical Preparations; Phenotype; Physiological Processes; Play; Pliability; Population; Postoperative Period; Predisposition; Prevalence; Process; Public Health; Recurrence; Recurrent disease; Repeat Surgery; Research; Risk; Role; Severities; Site; Small Intestines; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transgenic Mice; Visual; cell type; clinically relevant; fungus; grasp; gut inflammation; gut microbiota; high risk; ileum; immune activation; innovation; insight; metabolome; metabolomics; microbial; microbiome; microbiome research; microbiota; microbiota profiles; microorganism; novel therapeutics; overexpression; patient subsets; polygenic risk score; prevent; programs; response; screening; single-cell RNA sequencing; targeted treatment

Ileal fibrosis in Crohn’s Disease (CD) represents a complication in over 30% of CD patients, and leads to surgery in nearly 75% of this population. While therapies exist to manage CD-related inflammation, no approved medication exists to prevent or manage fibrosis, with surgery left as the only option. Despite surgical removal of fibrotic strictures, they often recur, requiring repeated surgeries. Strategies to predict who is more likely to develop these complications, and identification of targets for therapeutic intervention is needed. Our long-term goal is to develop a screening process for CD patients that incorporates a patient’s polygenic risk score, gut microbiota profile, and metabolome to identify individuals at high risk for developing fibrotic disease (for newly diagnosed patients) and propensity for disease recurrence (in individuals who have undergone surgery for removal of strictures). In parallel, we hope to identify key microbiota strongly associated with fibrosis and define their mechanism of action, so that microbially-directed therapy may become a viable therapeutic option for these patients. Our objective in this proposal is to define the relationship between polygenic risk, the microbiome, and the intestinal and peri-intestinal environment contributing to the fibrotic sub-phenotype in ileal CD. The central hypothesis of this proposal is that CD patients who develop fibrotic disease and recurrent strictures represent a sub-phenotype characterized by a hyper-reactivity of ileal immune cells, and fibroblasts in surrounding mesenteric fat, to certain microbiota. We hypothesize that immune reactivity to these microbiota in both the ileum and mesenteric fat may be determined by an individual’s polygenic risk score. Our rationale is that the identification of mechanisms to predict development of fibrosis will offer new therapeutic opportunities. Our specific aims will test the following hypotheses: (Aim 1) genetic susceptibility to ileal fibrosis is mediated by an excessive immune response to creeping fat (CrF) microorganisms; (Aim 2) ileal fibroblasts express collagen matrix genes in the context of inflammation, is microbially-driven, and is related to propensity for recurrent strictures; and (Aim 3) microorganisms associated with CrF will increase penetrance, severity, and/or shorten time to disease in a model of spontaneous fibrosis. This contribution is significant because it will add new aspects to our understanding of CD fibrosis by studying the microbiome, mesenteric fat, and polygenic risk scores to help define this complicated phenotype. These insights have the potential to offer new targets and points of intervention before complications occur. This option currently does not exist. Furthermore, this study will provide the most comprehensive characterization to-date of creeping fat and help answer the mystery of why this phenomenon occurs. This contribution is innovative because no studies to-date have investigated ileal CD fibrosis taking into account the contribution of creeping fat to the fibrotic milieu. Insight into the peri-intestinal environment, combined with microbial targets, and an individual’s genotype represents a combination of analyses that is both new, clinically relevant, and ultimately, translatable into future patient care.

克罗恩病 (CD) 中的回肠纤维化是超过 30% 的克罗恩病患者的并发症，需要进行手术 虽然存在治疗 CD 相关炎症的疗法，但尚未获得批准。 存在预防或控制纤维化的药物，尽管手术切除了纤维化，但手术是唯一的选择。 纤维化狭窄，它们经常复发，需要重复手术来预测谁更有可能发生。 出现这些并发症，需要确定我们的长期治疗干预目标。 目标是为 CD 患者开发一种筛查流程，其中包含患者的多基因风险评分、肠道 微生物群概况和代谢组学，以识别患有纤维化疾病高风险的个体（对于新近 确诊患者）和疾病复发倾向（接受过手术的个体） 与此同时，我们希望确定与纤维化密切相关的关键微生物群并对其进行定义。 它们的作用机制，因此微生物定向疗法可能成为这些疾病的可行治疗选择 我们本提案的目标是定义多基因风险、微生物组和疾病之间的关系。 肠道和肠周环境导致回肠 CD 纤维化亚表型。 该提议的假设是，出现纤维化疾病和复发性狭窄的 CD 患者代表了 亚表型的特征是回肠免疫细胞和周围成纤维细胞的高反应性 肠系膜脂肪，对某些微生物群，我们对抗回肠中这些微生物群的免疫反应。 肠系膜脂肪可能由个体的多基因风险评分决定。 确定预测纤维化发展的机制将为我们提供新的治疗机会。 具体目标将检验以下假设：（目标 1）回肠纤维化的遗传易感性是由 对蠕动脂肪 (CrF) 微生物的过度免疫反应；（目标 2）回肠成纤维细胞表达胶原蛋白 炎症背景下的基质基因是微生物驱动的，并且与复发倾向有关 狭窄；和（目标 3）与 CrF 相关的微生物会增加外显率、严重程度和/或缩短 这一贡献非常重要，因为它将增加新的方面。 通过研究微生物组、肠系膜脂肪和多基因风险评分来帮助我们了解 CD 纤维化 这些见解有可能提供新的目标和观点。 此外，本研究将提供在并发症发生之前进行干预的选择。 迄今为止对蠕动脂肪最全面的表征，并帮助解答其原因之谜 这一贡献具有创新性，因为迄今为止还没有研究调查回肠 CD。 纤维化考虑到蠕动脂肪对纤维化环境的影响。 环境、微生物目标以及个体的基因型代表了以下因素的组合 这些分析都是新颖的、与临床相关的，并且最终可以转化为未来的患者护理。