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

克罗恩病（CD）的回肠纤维化是超过30%的CD患者的并发症，并导致手术 在近75%的人口中虽然存在治疗CD相关炎症的疗法，但尚未批准 存在预防或管理纤维化的药物，手术是唯一的选择。尽管手术切除了 纤维化狭窄，他们经常复发，需要反复手术。预测谁更有可能 发展这些并发症，并确定治疗干预的目标是必要的。我们的长期 我们的目标是为CD患者开发一种筛查方法，该方法将患者的多基因风险评分、肠道 微生物群谱和代谢组，以识别患有纤维化疾病的高风险个体（对于新的 诊断的患者）和疾病复发倾向（在已经接受手术的个体中， 去除狭窄）。同时，我们希望确定与纤维化密切相关的关键微生物群，并定义 它们的作用机制，因此微生物导向疗法可能成为这些疾病的可行治疗选择。 患者我们在这项提案中的目标是确定多基因风险、微生物组和 肠和肠周环境导致回肠CD中的纤维化亚表型。中央 这一建议的假设是，发生纤维化疾病和复发性狭窄的CD患者代表了一种 亚表型特征为回肠免疫细胞和周围成纤维细胞的高反应性 肠系膜脂肪和某些微生物群。我们假设回肠和回肠中对这些微生物群的免疫反应性 和肠系膜脂肪可以通过个体的多基因风险评分来确定。我们的理由是， 鉴定预测纤维化发展的机制将提供新的治疗机会。我们 具体的目的将测试以下假设：（目的1）回肠纤维化的遗传易感性是由 对爬行脂肪（CrF）微生物的过度免疫反应;（目的2）回肠成纤维细胞表达胶原蛋白 基质基因在炎症的背景下，是微生物驱动的，并与复发的倾向， 狭窄;和（目的3）与CrF相关的微生物将增加狭窄率，严重程度和/或缩短 自发性纤维化模型中的发病时间。这一贡献意义重大，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， 来定义这个复杂的表型这些见解有可能提供新的目标和点， 在并发症发生之前进行干预。此选项当前不存在。此外，这项研究将提供 最全面的表征爬行脂肪的日期，并帮助回答为什么这个谜， 现象发生。这一贡献是创新的，因为迄今为止还没有研究调查回肠CD 考虑到蠕动脂肪对纤维化环境的贡献，纤维化。了解肠道周围 环境，结合微生物目标，和一个人的基因型代表了组合， 分析，这是新的，临床相关的，并最终转化为未来的病人护理。

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.