Modulation of gut dysbiosis with Enterobacteriaceae-targeted antiproliferative agents to treat inflammatory bowel disease

The goal of this project is to develop a small molecule drug that modulates the proliferation of proinflammatory bacteria in the gut as a novel therapeutic for the treatment of inflammatory bowel diseaseIBDOvermillion Americans suffer from IBDan umbrella term to describe chronic inflammation of all or part of the digestive tractincluding Crohn s disease and ulcerative colitisIBD is a complex immune disorder that can be caused by geneticsenvironmentaberrant immune response and disruption of the digestive tract microbiotaIBD ranks as one of the five most expensive GI disorderswith an annual direct medical cost burden between $billionapproximately half of which are for prescription drugsMost current strategies to manage or treat IBD involve suppressing the immune systemhowever many of these drugs are not intended for long term useand others have no effect in up to half of patients treatedThuscurrently available therapies do not meet the needs of all patientsand new treatment approaches are neededWe are developing novelsymbiotic drugsthat target one of the known causes of digestive tract inflammationthe microbiomeOur pilot studies demonstrate the feasibility of our microbiome targeting approach in slowing the growth and proliferation of proinflammatory Enterobacteriaceae bacteria without compromising the growth of protective bacteriaIn this proposal we will confirm and extend our pilot studies with the development of cell based assays to screen our library of microbiome targeting small molecule drugsAimsandWe will select the most potent inhibitors of Enterobacteriaceae proliferation and evaluate their in vivo effects including the modulation ofclinical andmolecular markers of IBDas well as theirantiproliferative efficacy in a rat experimental m odel of intestinal colitisAimBecause Enterobacteriaceae expansion is a conserved feature of IBDindependent of genetic variants or environmental triggersour therapeutic approach is expected to have broad utility in IBD treatmentOur approach uniquely recognizes the multifactorial nature of IBD pathogenesis with the development of microbiota specificrather than host specifictherapeutics This project aims to discover and develop microbiome targeting therapeutics that selectively target the proinflammatory bacteria associated with chronic inflammatory bowel diseaseMicrobial based therapies represent a new treatment paradigm for IBD managementwhen used alone or in combination with existing therapeutics that target the host response pathwayOur approach uniquely recognizes the multifactorial nature of IBD pathogenesis with the development of microbiota specificrather than host specifictherapeutics