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 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 six months for four years, the fecal microbiota of individuals with Inflammatory Bowel Disease (UC or CD) whose gut microbiota induces disease when colonized in the gnotobiotic T-cell transfer mouse model of colitis. 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.
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. Finally in Aim 3, we will determine if colitogenic and colitoprotective strains drive unique baseline immune tones when colonized in unchallenged gnotobiotic mice. 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.
The nature of Inflammatory Bowel Disease (IBD) suggests genetically susceptible individuals are persistently colonized with mildly pathogenic microbial strains or communities that drive the chronic progressive intestinal disease. The majority of human gut microbiota strains remain stably colonized in our gastrointestinal tract from years to decades. Using microbial strain tracking methods, gnotobiotic mouse models of colitis, and human fecal and serum samples, we will test the hypothesis that proinflammatory microbes in the gastrointestinal tract of individuals with IBD will be preferentially found amongst the stable members of their gut microbiota.