The Interplay of Host Genetic Variation and the Gut Microbiome in Crohn's Disease

摘要 克罗恩病(CD)是一种自身免疫性疾病，导致慢性炎症和瘢痕形成。 消化道。可用的治疗方法包括免疫抑制剂和手术，这些都是昂贵的，有许多 仍在经历生活质量下降的个人。CD的原因尚不清楚，但相信会发生 由于遗传和环境因素，包括饮食。患有肠易激综合征的人肠道微生物群会发生改变 CD，导致宿主和微生物转录和代谢格局的失调。此外， 许多与CD相关的遗传风险变异位于宿主基因中，这些基因在宿主对CD的反应中发挥作用 微生物组。因此，表征CD中宿主-微生物组的相互作用对于理解CD CD的发病机制和寻找新的治疗途径。在这项拟议的研究中，我的目标是 描述宿主遗传变异与调节宿主基因的肠道微生物群之间的相互作用 以CD表示。我将使用两种互补的方法。我将使用微生物组/肠道有机化合物 共培养方法，以确定宿主基因表达的变化，以响应CD衍生的微生物群，以及 利用等位基因特异性表达分析调节这些变化的宿主遗传变异。我也会利用 可通过人类微生物组计划炎症性肠病多组学数据库获得的数据 进行eQTL定位，并将我的所有发现与GWAS和Twas整合，以验证 用于CD风险的GxM。这些研究将提供对改变遗传风险的宿主-微生物组相互作用的洞察力 治疗克罗恩氏病。此外，我将确定可能成为潜在治疗药物的特定微生物 CD的目标。

ABSTRACT Crohn’s Disease (CD) is an autoimmune disease which leads to chronic inflammation and scarring of the digestive tract. The available treatments involve immunosuppressants and surgery which are costly, with many individuals still experiencing a decreased quality of life. The cause of CD is unknown, but is believed to occur due to both genetic and environmental factors, including diet. The gut microbiome is altered in individuals with CD, leading to dysregulation of the host and microbial transcriptional and metabolic landscape. Furthermore, many genetic risk variants associated with CD are in host genes known to function in host response to the microbiome. Thus, characterizing host-microbiome interactions in CD is imperative for understanding the pathogenesis of CD and identifying potential new therapeutic routes. In this proposed research, I aim to characterize the interactions between host genetic variation and the gut microbiome that regulate host gene expression in CD. I will use two complementary approaches. I will use a microbiome/intestinal organoids co-culturing approach to identify host gene expression changes in response to CD-derived microbiomes, and host genetic variants that modulate these changes using allele-specific expression analysis. I will also utilize data available through the Human Microbiome Project Inflammatory Bowel Disease Multi’omics Database to perform eQTL mapping, and integrate all of my findings with GWAS and TWAS to validate the significance of GxM for CD risk. These studies will provide insight into host-microbiome interactions that modify genetic risk for Crohn’s Disease. Furthermore, I will identify specific microbes that could become potential therapeutic targets for CD.