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Grant Abstract

Grant Number: 1U54DE023798-01
PI Name: Xavier
Project Title: Characterizing the gut microbial ecosystem for diagnosis and therapy in IBD

Abstract: DESCRIPTION (provided by applicant): Inflammatory bow/el diseases (IBD) comprise both Crohn's disease (CD) and-ulcerative colitis (UC) and affect some 1.5 million Americans. -25% of cases occur in children, and overall incidence has increased >400% in the past 50 years. CD and UC are both complex diseases that can manifest and proceed differently among patients, and recent studies have found that their genetic risk is likewise complex. Studies of environmental associations with IBD have not yet resulted in simple diagnostic markers or treatable points of intervention. Instead, IBD has emerged in as one of the most important human conditions linked to the gut microbiota, the complex mixture of bacterial, viral, archaeal, and fungal organisms normally resident in the gut. The association of IBD with gut microbes is again complex, with no single microbe or pathogen appearing to be causal. Instead, IBD has been repeatedly linked to the overall ecology of entire gut microbial ecosystem. This suggests that the disease may be best studied by integrating many different types of measurements of gut microbes as they change within IBD patients and non-IBD controls over time. This project will thus provide such data in an IBD multi'omic database, the IBDMDB, an integrated resource enabling the gut microbial ecosystem as a target for diagnosis, therapy, and mechanistic understanding of IBD. It will leverage existing, well-phenotyped cohorts to provide longitudinal taxonomic, metagenomic, metatranscriptomic, metaproteomic, and metabolomic profiling of the gut microbiome. To further provide data on host interaction mechanisms, we will profile host genetics, epigenetics, and transcriptional activity. These data will be generated from 90 subjects over one year, and they will be made rapidly and accessibly available to the community by building on our current meta'omic computational infrastructure. Both sample collection and bioinformatic protocols will be validated and distributed, and the study will result in fonward-looking platforms for single-cell and host-focused meta'omic assays. Our team includes leaders in the study of the human microbiome, IBD, microbial community ecology and function, and meta'omic data integration. We have organized a diverse group of collaborators, including key players in the Human Microbiome Project. Our organization includes Components for Project Management; Sample Generation and Data Generation; assays including five different multi'omics platforms and Technology Development; and Computational Infrastructure. We are committed to releasing all generated data to the public in a timely manner while maintaining subject privacy using controlled access databases whenever necessary. We have assembled the expertise and resources necessary to construct a definitive multi'omic data resource to understand the gut microbiome's role in IBD. PUBLIC HEALTH RELEVANCE: Studies of the microbes normally associated with the human body have shown that they are linked with many diseases. However, a lack of measurements of multiple aspects of host and microbial biological activity over time has impeded our understanding of how these links occur and how they might be used to promote health. The inflammatory bowel diseases (IBD) in particular, Crohn's disease and ulcerative colitis, together affect millions of individuals worldwide. This project will assess the composition and biomolecular activity of gut microbes in IBD patients over time using many different experimental techniques, which will be combined to provide an extensive data resource aiding our understanding of the disease.

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