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The Influence Of Gut Microbiota Stability In Inflammatory Bowel Disease

肠道菌群稳定性对炎症性肠病的影响

基本信息

批准号：
10587382
负责人：
Jeremiah James Faith
金额：
$ 60.49万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-04 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587382
关键词：
Acute Affect Animal Model Award Bacteria Characteristics Chronic Clinical Research Clostridium difficile Colitis Collection Communities Crohn&apos s disease Disease Disease remission Donor person Engraftment Environmental Risk Factor Escherichia coli Future Gastrointestinal tract structure Genetic Germ-Free Gnotobiotic Goals Human IL2RA gene Immune Immune response Individual Inflammation Inflammatory Inflammatory Bowel Diseases Intervention Intestines Metagenomics Methods Microbe Minor Mucosal Immune System Mucous Membrane Mus Nature Organism Pathogenicity Patients Penetrance Persons Pharmaceutical Preparations Phenotype Placebos Predisposition Prevention Randomized, Controlled Trials Recurrence Relapse Role Sampling Severities Severity of illness Structure System T-Lymphocyte Testing Therapeutic Time Translations Transplant Recipients Ulcerative Colitis clinical remission fecal microbiota fecal transplantation genome sequencing gut microbes gut microbiome gut microbiota human disease improved member metagenomic sequencing microbial microbiome microbiota murine colitis novel novel therapeutic intervention novel therapeutics pathogen post-transplant prevent relapse patients relapse prediction transplantation therapy virtual

项目摘要

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.

项目总结