Immune, Microbial, and Metabolic Factors that Impact Clostridioides difficile and Inflammatory Bowel Disease in Children

项目总结

PROJECT SUMMARY Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea in the United States, causing 12,900 deaths in 2017. CDI has demonstrated a rapid increase in incidence in the last two decades, with rate increases most pronounced in pediatric patients with inflammatory bowel disease (IBD). IBD, a chronic disease characterized by inflammation of the gastrointestinal tract, has also demonstrated increasing incidence in children worldwide and is considered a globally important pediatric disease. The co- occurrence of IBD and CDI is associated with worse outcomes including longer hospital stays, higher charges, and greater need for blood transfusions. Conversely, children with IBD also have high rates of C. difficile colonization, defined as the presence of C. difficile in the absence of symptoms attributable to C. difficile. Symptoms of CDI in IBD patients are indistinguishable from symptoms of an IBD flare in patients with C. difficile colonization. Microbial perturbations, biomolecules associated with germination and metabolism, and antitoxin antibodies have been studied individually for their influence on colonization and CDI but primarily in cross-sectional approaches and not applied to children with IBD. The research detailed in this proposal responds directly to the need to better understand the determinants and sequalae of CDI and C. difficile colonization in pediatric patients with IBD and includes the following specific aims: 1) To investigate the role of germination and metabolic mediators as they relate to the development of, and recovery from, C. difficile colonization, symptomatic CDI, and IBD flares. 2) To examine differences in the intestinal microbiome that are predictive of C. difficile colonization, disease, and recovery in children with IBD. 3) To determine the prevalence and impact of C. difficile antitoxin antibodies in children with IBD. For the past 8 years the candidate has worked closely with her mentor, Dr. Kathryn Edwards on a variety of CDI-related projects which have included the prospective enrollment of over 360 pediatric patients. Through this project, the candidate plans to longitudinally follow children with IBD with serial sampling of stool and serum to better understand the interaction of CDI and IBD. The overarching objective of this mentored career development experience is for the candidate to emerge as an independent clinical investigator of C. difficile and IBD, become established in metabolite determination and microbiome analysis, and serve as an interface between clinical research and laboratory sciences through carefully planned translational approaches. To accomplish this goal, the candidate will augment her prior training with advanced coursework in microbiome analysis, clinical research, and leadership training. Throughout the award period, the candidate will work closely with a multidisciplinary team of mentors including experts in infectious diseases, IBD, biostatistics, microbiome analysis, and molecular techniques to carry out her stated aims and career goals.