Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine affecting over 1 million Americans. Despite advances in medical therapies, nearly half of the patients requiring biologic medications will develop medically refractory disease. As such, there is an urgent need for new treatment approaches for UC. Emerging data from several randomized controlled trials (RCTs) suggest that fecal microbiota transplantation (FMT) is safe and effective for the treatment of UC. Although extensive pre-clinical research showing a central role for the gut microbiome in regulating animal models of colitis support these encouraging clinical findings, variability in the efficacy of FMT for UC has limited the clinical impact. Research from our own group and others has shown that the composition of the donor microbiome is associated with clinical response. Our preliminary data extend these findings with strain level characterization showing that a core transferable microbiota correlates with clinical response to FMT in UC. A detailed understanding of the mechanisms that promote the transfer and engraftment of these beneficial bacteria is needed to enhance the clinical efficacy of FMT for UC. Diet is a critical regulator of the intestinal microbiome and its subsequent impact on intestinal inflammation, but the effect of diet and/or prebiotic supplementation on microbial engraftment and clinical outcome following FMT has never been tested. It is, therefore, a critical need to assess the role for dietary interventions in shaping the microbiome and clinical outcomes of FMT for UC. This proposal will evaluate the fundamental hypothesis that dietary fiber supplementation can improve the clinical efficacy of FMT by shaping microbial engraftment and function of specific transferable microbes. We propose the following aims to evaluate this hypothesis: (i) to test the potential impact of fiber to improve clinical outcomes of FMT for UC with a randomized, double-blind, placebo-controlled trial of FMT with or without open-label dietary fiber supplementation for the treatment of mild to moderate UC; (ii) to define the impact of fiber supplementation on microbial engraftment and immune cell function after FMT in patients with UC. If successful, our study will offer critical support for the role of dietary fiber in shaping the outcome of FMT. Furthermore, our microbiome, metabolomic, and immunologic characterization will provide key mechanistic analysis to support the design of larger follow-up clinical studies. Given the feasibility and practicality of this intervention, results from this work have the potential to transform FMT for UC as well as other indications.