Bacterial, Viral, and Host Interactions in the Pathogenesis of Inflammatory Bowel Disease

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PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD) affects an estimated 1.3% of adults in the United States and is increasing in prevalence globally. Host-microbiome interactions are an important contributor to IBD pathogenesis and disease flares, but the role of non-bacterial components of the microbiome, such as eukaryotic viruses and viruses that infect bacteria (bacteriophages), are less understood. Therefore, we propose a study of the effect of the viral component of the microbiome (i.e. virome) on IBD pathogenesis. Preliminary studies suggest that stool from humans with IBD is pro-inflammatory, even when combined with stool from healthy individuals. However the factors driving this effect are not fully known. We hypothesize that the virome in IBD exerts a pro- inflammatory effect through modulation of the bacterial microbiota. Improved understanding of the role of viruses in IBD will inform the development of microbial therapeutics and prediction of clinical outcomes. This study’s goal is to characterize the effects of fecal virome transfer on colitis using a humanized mouse model. To address this goal, we propose: 1. To quantify the changes in host pathology, molecular pathways, and bacterial communities following fecal viral transfer and 2. To evaluate whether changes in IBD disease activity in patients is accompanied by changes in fecal viruses and their inflammatory effects. The fellowship applicant aspires to become an independent investigator and academic gastroenterologist, with most of her time spent conducting translational and basic science research. Her long-term goal is to understand the role of viruses in the maintenance of microbiome stability and response to stress in IBD to develop novel targets for treatment and prevention. Under this fellowship, she will acquire a rigorous methodological foundation in immunology and microbial ‘omics through coursework and interdisciplinary mentorship. This training will be essential to address the proposed research question, develop the skills necessary as an independent investigator, and achieve her long-term career goals. Specific goals for this fellowship include: 1. Developing expertise in the analysis of viral metagenomic data, 2. Fostering high proficiency in mechanistic microbiota-based experimental design, 3. Building excellence in the use of animal models for IBD, 4. Maintaining an active understanding of trends and developments in human immunology, microbial ‘omics, and translational research in inflammatory bowel disease, 5. Continued communication of findings through scientific writing and oral presentations, and 6. Actively pursuing career development opportunities to support transitioning to independence. At the start of the funding period, the applicant will have already completed one year of clinical gastroenterology training and one year of basic science training on a T32 at the University of Michigan.