Autophagy genes and the microbiome in Crohn's Disease

描述（由申请人提供）：宿主的遗传、免疫系统和肠道微生物群落之间的相互作用是一种影响健康和疾病状态的动态力量。该提案将评估与IBD相关的遗传变异如何塑造微生物群以及改变宿主反应和最终病理性炎症的功能后果。我们专注于自噬相关的遗传变异，以确定克罗恩病（CD）的遗传亚群是否与腔内微生物组的特定变化相关。我们将探索CD中微生物群落结构、功能和代谢，以及微生物组与宿主的相互作用。我们将利用IBDGC以及其他几个IBD登记处（马萨诸塞州总医院、波士顿儿童医院和海洋州克罗恩病和结肠炎地区登记处，罗德岛的一个初始队列）的广泛资源和详细表型信息，招募具有ATG16L1、IRGM和NOD2疾病相关变异的受试者。以及有或没有这些风险等位基因的健康人。利用16S核糖体测序的luminal样品，我们将应用新的生物统计学技术将微生物组中的生物体或进化支与CD状态和宿主遗传学联系起来。随后的全基因组测序和转录组学将使我们能够超越疾病相关细菌的分类，了解与CD相关的生态失调的功能含义。利用自噬等位基因变异的小鼠模型，我们将通过将非生物小鼠与人类研究样本进行关联来确认微生物组的遗传影响，并研究宿主对这些微生物变化的反应。乳糜泻基本上是由肠道微生物因素形成的，这些因素可能在具有确定遗传风险的个体中引发疾病。在乳糜泻期间，微生物或肠道微生物组代谢的具体作用仍然不明确，并且是破译该疾病病理生理学的新兴领域。这些研究的预期结果将通过确定宿主遗传学、微生物组和免疫反应如何相互作用和影响导致克罗恩病，从而促进我们对乳糜泻的理解。

DESCRIPTION (provided by applicant): The interplay between a host's genetics, immune system, and intestinal microbial communities is a dynamic force influencing health and disease status. This proposal will assess how genetic variants associated with IBD shape the microbiota and the functional consequences that alter host responses and culminate pathologic inflammation. We focus on autophagy-linked genetic variants to determine whether genetic subsets of Crohn's disease (CD) are associated with specific changes in the luminal microbiome. We will explore microbial community structure, function and metabolism, and the microbiome's interaction with its host in CD. We will leverage the extensive resources and detailed phenotypic information of the IBDGC as well as several other IBD registries (Massachusetts General Hospital, Boston Children's Hospital, and the Ocean State Crohn's and Colitis Area Registry, an inception cohort in Rhode Island) to enroll subjects with ATG16L1, IRGM, and NOD2 disease-associated variants, as well as healthy individuals with and without these risk alleles. Using 16S ribosomal sequencing of luminal samples, we will apply novel biostatistical techniques to associate organisms or clades within the microbiome with CD status and host genetics. Subsequent whole genome sequencing and transcriptomics will allow us to advance beyond categorization of disease-associated bacteria to understand the functional implications of the dysbiosis associated with CD. Utilizing mouse models of the autophagy allele variants, we will confirm the genetic impact of the microbiome by performing association in gnotobiotic mice with the human study samples and investigate the host response to these microbial changes. CD is fundamentally shaped by intestinal microbial factors, which may provoke the disease in individuals with defined genetic risks. The specific roles of organisms or metabolism in the intestinal microbiome during CD remain poorly defined and are emerging frontiers in deciphering the pathophysiology of the disease. The results anticipated from these studies will advance our understanding of CD by determining how the interactions and influences of host genetics, the microbiome and the immune response contribute to Crohn's disease.