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; 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.

克罗恩氏病（CD）中的回肠纤维化代表了30％以上的CD患者的并发症，并导致手术 在几乎75％的人群中。虽然存在管理与CD相关的炎症的疗法，但尚无批准 存在药物以预防或管理纤维化，而手术是唯一的选择。尽管外科手术 纤维化狭窄，经常复发，需要重复手术。预测谁更有可能 需要开发这些并发症，并确定治疗干预靶标。我们的长期 目标是为CD患者开发筛查过程，该CD患者结合了患者的多基因风险评分，肠道 微生物群和代谢组，以识别患有纤维化疾病的高风险的个体（新的 诊断患者）和疾病复发的承诺（在接受手术的个体中 清除狭窄）。同时，我们希望识别与纤维化密切相关的关键菌群并定义 它们的作用机制，以便以微生物为导向的治疗可能成为这些可行的治疗选择 患者。我们在此提案中的目标是定义多基因风险，微生物组和 肠内和肠周周围环境有助于回肠CD中的纤维化亚表型。中央 该提议的假设是患有纤维化疾病和经常性狭窄的CD患者代表 亚型以回肠免疫球的过度反应性和周围的成纤维细胞为特征 肠系膜脂肪，到某些微生物群。我们假设在两个回肠中对这些微生物群的免疫反应性 肠系膜脂肪可以由个人的多基因风险评分决定。我们的理由是 识别预测纤维化发展的机制将为新的治疗机会提供。我们的 具体目的将检验以下假设：（目标1）遗传对回肠纤维化的敏感性是由 对蠕虫脂肪（CRF）微生物的过度免疫反应； （AIM 2）ILEAL成纤维细胞表达胶原蛋白 在炎症的背景下基因基因是微生物驱动的，并且与反复发作有关 狭窄； （AIM 3）与CRF相关的微生物将增加外渗，严重性和/或缩短 在赞助纤维化模型中疾病的时间。这项贡献很重要，因为它将增加新方面 通过研究微生物组，肠系膜脂肪和多基因风险评分来理解CD纤维化 定义这种复杂的表型。这些见解有可能提供新的目标和点 并发症发生前干预。此选项当前不存在。此外，这项研究将提供 最全面的表征蠕动脂肪的日期，并帮助回答了为什么这一谜团的谜团 现象发生。这种贡献具有创新性 纤维化考虑了蠕动脂肪对纤维化环境的贡献。深入了解肠内 环境，结合微生物靶标，一个人的基因型代表 分析既是新的，临床上相关的，也可以最终转化为未来的患者护理。