PROJECT SUMMARY/ABSTRACT: Despite an incidence of 1:8,000-1:18,000, biliary atresia (BA) is the leading indication for pediatric liver transplantation. BA is a progressive fibrostenotic disease of the extrahepatic biliary tree of unknown etiology. The Kasai portoenterostomy (KP), a surgical procedure to allow bile flow, is currently the only treatment for BA besides liver transplant. Successful bile flow after KP improves morbidity and predicts early liver-transplant free outcomes.2,3 However 50% of infants who receive a timely KP require liver transplant or die in the first two years of life.7,8 Thus, there is desperate need to understand the pathophysiological factors responsible for the absence or presence of bile flow after KP. Recent investigations suggest that there is bidirectional interplay between the intestinal microbiome and bile acid homeostasis. While bile can change the microbiome, due to our exciting preliminary data, we believe that microbial factors may be key to BA outcomes. Thus, the grant’s hypothesis is that the microbiome influences BA outcomes by affecting bile flow. A prospective study of microbiome in infants with cholestasis and BA will allow testing of this hypothesis in 3 aims. In aim 1, a multi- center prospective stool biobank from cholestatic infants will be developed. In aim 2, the effects of bile flow on early microbial signatures will be compared using whole genome sequencing in infants with cholestasis. In aim 3 microbial signatures associated with positive outcomes in BA will be identified. The expected outcome is that we will elucidate the complex relationship of the microbiome and bile flow in infants with cholestasis, specifically BA. Dr. Tessier is a board-certified pediatric gastroenterologist and tenure-track Assistant Professor at Baylor College of Medicine. Her long-term goal is to become an independent NIH-funded physician-scientist investigating the interactions of the microbiome in pediatric cholestasis. The research aims support the PI’s career development by building on her background in pediatric gastroenterology to provide master’s level training in clinical trial design and implementation, microbiome and whole genome sequencing analysis and biostatical interpretation. This will be fulfilled via 1) A mentorship and advisory team which includes internationally-recognized, independently funded investigators with an expertise in pediatric cholestasis, particularly BA, the infant microbiome, and clinical trial design; 2) advanced course work in bioinformatics, advanced sequencing technologies and biostatistics; and 3) scholarly activities to lead to independence. Finally, the candidate’s research environment is a preeminent academic research institution in the world’s largest medical center allied with the nation’s largest children’s hospital. This environment will provide a productive and collaborative atmosphere to accomplish her research and training goals in a timely manner. In summary, this tr...