The Influence Of Gut Microbiota Stability In Inflammatory Bowel Disease

项目摘要 炎症性肠病（IBD），包括溃疡性结肠炎（UC）和克罗恩病（CD）， 是肠道的慢性进行性炎症。大量证据表明 它们的起源在于宿主免疫系统对肠道微生物群的过度攻击性反应 在一个基因易感的宿主中我们假设IBD的一个关键特征是持续的定植 在缺乏足够的大肠杆菌保护菌株的情况下， 几十年的时间可以驱动与IBD相关的进行性炎症和损伤。为了验证这一 假设我们提出三个目标。在目标1中，我们将在五年内每年对粪便进行采样， 图2显示了患有炎性肠病（UC或CD）的个体和健康对照的微生物群的图。到 了解肠道微生物群稳定性在肠道微生物群操纵背景下的意义 为了进行干预，我们还将对粪便微生物群移植（FMT）的接受者进行纵向采样， 溃疡性结肠炎，FMT治疗结束后，长达5年。我们将使用宏基因组学 结合高通量微生物分离和基因组测序，以鉴定稳定的 每个人的微生物群中的瞬时微生物，并确定IBD患者是否有 显著改变了肠道微生物群的稳定性。我们还将跟踪移植FMT供体菌株的丢失情况 在FMT后缓解的受试者中，将应变损失与长期复发相关联。在目标2中， 我们将使用每种微生物群的亚群定植的非菌性T细胞转移结肠炎小鼠， 大肠杆菌和大肠杆菌保护性微生物菌株，并确定是否是大肠杆菌或大肠杆菌保护性微生物菌株 生物体优先在稳定定殖的群落成员中发现。我们还将 确定大肠杆菌和大肠杆菌保护菌株是否驱动独特的基线免疫色调， 在未受攻击的知菌小鼠中定殖。为了实现未来的人工翻译，我们将 从先前鉴定的大肠杆菌保护性群落中寻找最小的大肠杆菌保护性子集， 我们将确定FMT后丢失的菌株是否具有结肠保护作用， 缓解但随后复发。这些目标将帮助我们确定， 炎症性肠病富含稳定定殖的大肠杆菌生物体， 消除可能会形成一种新的治疗干预，用于治疗或预防炎症 肠道疾病，如果健康个体富含稳定定植的大肠杆菌保护性微生物 这可能会成为一种新型IBD治疗方法的基础。

PROJECT SUMMARY Inflammatory Bowel Diseases (IBD), consisting of Ulcerative colitis (UC) and Crohn's disease (CD), are chronic progressive inflammatory conditions of the intestine. Numerous lines of evidence suggest their origins lie in an overaggressive response of the host immune system towards the gut microbiota in a genetically susceptible host. We hypothesize a key feature of IBD is the persistent colonization by colitogenic microbial strains in the absence of sufficient colitoprotective strains that over years to decades can drive the progressive inflammation and damage associated with IBD. To test this hypothesis we propose three Aims. In Aim 1, we will sample, every year for five years, the fecal microbiota of individuals with Inflammatory Bowel Disease (UC or CD) and healthy controls. To understand the implications of gut microbiota stability in the context of a gut microbiota manipulation intervention, we will also longitudinally sample recipients of fecal microbiota transplantation (FMT) for ulcerative colitis, after FMT therapy has ended, for up to 5 years. We will use metagenomics combined with high throughput microbial isolation and genome sequencing to identify the stable and transient microbes in each individual's microbiota and determine if individuals with IBD have significantly altered gut microbiota stability. We will also track the loss of engrafted FMT donor strains in subjects in remission post-FMT overtime to associate strain loss with long-term-relapse. In Aim 2, we will use gnotobiotic T-cell transfer colitis mice colonized with subsets of each microbiota to identify colitogenic and colitoprotective microbial strains and to determine if colitogenic or colitoprotective organisms are preferentially found in the stably colonized community members. We will also determine if colitogenic and colitoprotective strains drive unique baseline immune tones when colonized in unchallenged gnotobiotic mice. With an aim towards future human translation, we will search for minimal colitoprotective subsets from previously identified colitoprotective communities, and we will determine if strains lost post-FMT are colitoprotective, in UC subjects that achieve remission but subsequently relapse. Together these aims will help us determine if individuals with Inflammatory Bowel Disease are enriched in stably colonized colitogenic organisms whose elimination might form a novel therapeutic intervention for the treatment or prevention of Inflammatory Bowel Disease and if healthy individuals are enriched in stably colonized colitoprotective organisms that might form the basis of a novel IBD therapeutic.