Project 447542

The etiology of ulcerative colitis (UC) is complex and there is still no cure. Current treatment primarily focuses on controlling the immune response, but this approach remains ineffective for many patients. We identified the Shp-2 protein as a new, critical protective factor for prevention of colon inflammation. Indeed, mice deficient for Shp-2 in their intestinal lining develop severe colitis. Interestingly, an over abundance of "Enterobacteriaceae" bacteria and an under-abundance of "Firmicutes" bacteria in the gut microbiota of these mice, precede the appearance of inflammation. Furthermore, treatment with antibiotics successfully delays the development of colitis and reduces its severity. Changes in the gut microbiota composition (aka "dysbiosis") in Shp-2-deficient mice may therefore play a causative role in inducing colitis. To help identify the mechanisms involved, we will use a powerful model called "colon organoids" to determine if Shp-2 acts by controlling the sensitivity of colonic cells to stimulation by bacterial-derived products. Next, we will examine if early dysbiosis observed in Shp-2-deficient mice is involved in their development of colitis. We will test a probiotic specifically engineered to kill Enterobacteriaceae as a means of preventing and treating dysbiosis in Shp-2 deficient mice. Unlike broad-spectrum antibiotics, this genetically-engineered probiotic is designed to be highly specific. This provides a powerful new tool for fundamental research to achieve clinical applications that can reshape the microbiota. This approach could prove relevant in the clinic since dysbiosis in UC patients features an overabundance of Enterobacteriaceae. Thus, this project focuses on new angles and perspectives to developing useful treatment options for UC.