Project Summary The goal of this project is to develop a small molecule drug as a novel therapeutic for the modulation of gut dysbiosis in patients with inflammatory bowel disease (IBD). Over 1.6 million Americans suffer from IBD, an umbrella term used to describe chronic inflammation of all or part of the digestive tract, including Crohn’s disease and ulcerative colitis. IBD is a complex immune disorder that can be caused by genetics, environment, aberrant immune response and disruption of the digestive tract microbiota. IBD ranks as one of the five most expensive GI disorders, with an annual direct medical cost burden between 11 and 28 billion dollars, approximately half of which are for prescription drugs. Current strategies to manage or treat IBD involve suppressing the immune system, however many of these drugs are not intended for long term use, and others have no effect in up to half of patients treated. Therefore, currently available therapies do not meet the needs of all patients and new treatment approaches are needed. Symberix, Inc. is developing a novel class of small molecule drugs that specifically target and inhibit one of the known causes of digestive tract inflammation: the microbiome. Pilot studies demonstrate the preliminary feasibility of blocking the activity of bacterial beta glucuronidases (GUS enzymes) and slowing the growth of harmful bacteria without compromising the growth of protective bacteria. Small molecule GUS inhibitors also show potent activity in ex vivo assays using biological samples derived from patients with IBD. This Phase I proposal will focus on confirming and extending pilot studies by rigorously evaluating the biological activity of two candidate small molecule drugs in an in vivo mouse model of ulcerative colitis and an ex vivo inhibition assay using IBD patient-derived stool samples.