Novel roles of Fc gamma binding protein in colonic host-microbiota interactions

PROJECT SUMMARY/ABSTRACT The Fc fragment of IgG binding protein (Fc gamma binding protein, FCGBP) is a prominent component of the mucus layer that lines the epithelium of the large intestine. Reduced levels of FCGBP are present in the structurally-weaken colon mucus layer that is characteristic of ulcerative colitis (UC). In addition, either low expression or deficiency due to genetically mutated FCGBP is associated with lower disease-free survival of patients with colorectal cancer (CRC). Normally, the abundance of FCGBP in the colon mucus layer is similar to that of mucin 2 (MUC2), the major secreted mucin in the colon. However, unlike MUC2, the functions of FCGBP are not well understood. In fact, a number of previously described functions of FCGBP, including the IgG interaction from which the name derives, have been subsequently disputed. We posit that the abundance of FCGBP in the barrier-protective colon mucus layer, coupled with the well-established association with diseases of the colon, warrant an improved and definitive understanding of the functions of this protein in health and disease. We have utilized mice with partial or complete loss of Fcgbp to begin to understand the functions of Fcgbp at homeostasis and during inflammation. Our studies suggest previously unknown but essential contributions to the structure of the colon mucus layer and to the composition of the mucus-associated microbiota. Fcgbp deficiency also appears to trigger major compensatory pathways, which potentially underlie the connection between low levels of FCGBP and susceptibility to colon inflammation and cancer. Therefore, in this exploratory proposal, we will determine the contribution of Fcgbp to the overall glycosylation and terminal sialylation of the colon mucus layer and determine how this affects the abundance of specific bacteria in the mucus layer. In addition, we will explore immune pathways that are deployed to limit spontaneous inflammation when expression of Fcgbp is suppressed and determine the possible connections to disease susceptibility. If successful, our studies will define novel functions for Fcgbp in intestinal immune homeostasis and identify key mechanisms whereby reduced Fcgbp impacts disease susceptibility in the large intestine.