A role for the stomach in protection from colitis

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Project Summary We have discovered a new function for the stomach in protection from colitis. Specifically, we have found that a protein called gastrokine-1 (Gkn1), made exclusively and abundantly in the stomach, is required for protection against inflammatory bowel disease (IBD). Building on our previous finding that Gkn1 is required for protection from DSS-induced colitis, we have found that Gkn1 is required for protection against T cell mediated colitis. Specifically, Gkn1-/- mice develop more severe colitis in the TNBS (trinitrobenzenesulfonic acid) acute T cell mediated model of IBD. In addition, our preliminary data suggest that Gkn1-/- x RAG1-/- mice develop more severe colitis in the T cell transfer model of model of IBD. Thus Gkn1, a stomach specific protein, protects against colitis. Gkn1 is a small stable protein containing a secretion signal and a BRICHOS (Bri2, chondromodulin, and lung surfactant protein C) domain. The secretion signal results in packaging of Gkn1 into mucus granules of gastric foveolar epithelial cells and release of Gkn1 into the gastric lumen. The BRICHOS domain is found in a limited number of mammalian proteins, all of which studied thus far, including Gkn1, are anti- amyloidogenic. Microbes across all phyla make secreted amyloid containing proteins to facilitate biofilm formation. Given that Gkn1 is a lumenal protein with anti-amyloidogenic activity we tested whether Gkn1 inhibits microbial amyloid formation. Our preliminary data indicates that Gkn1 inhibits microbial amyloid fiber formation and biofilm formation. We hypothesize that the BRICHOS domain of Gkn1 inhibits amyloid based microbial biofilms and protects from colitis. We will test this hypothesis with the following aims: (1) Determine the requirement for Gkn1 in protection from chronic T cell mediated colitis; (2) Characterize the molecular mechanism of action of Gkn1; (3) Determine the functional role of Gkn1 activity in protection from colitis. Together these studies will be significant as they will define a new requirement for Gkn1, a protein made in the stomach, in protection from colitis. Further these studies will characterize the molecular mechanism of action of Gkn1 and implicate control of intestinal amyloids in protection from colitis. Lastly, our work examining preventative and therapeutic feeding of Gkn1 for protection of colitis may open new therapeutic opportunities for treatment of IBD.