The functional role of the MUC17-based glycocalyx

Abstract: Our gastrointestinal tract harbors trillions of bacteria that are chemically and spatially separated from the intestinal epithelium. Maintaining an intact mucosal barrier is essential as increased bacterial contact is associated with inflammatory bowel diseases such as Crohn´s disease. The secreted mucus layer constitutes the outermost barrier whereas membrane mucins positioned at the microvillar tips of enterocytes form a second defense line. Yet, exactly how membrane mucins protect the intestinal epithelium remains undefined. Therefore, we have investigated the functional role of the MUC17-based glycocalyx in intestinal enterocytes in three independent studies. First, we assessed the formation of the glycocalyx during the postnatal period in mice. We discovered that IL-22 specifically upregulates a MUC17-based glycocalyx during the weaning-suckling transition that creates a physical barrier against bacteria in the small intestine. To further characterize how the MUC17-based glycocalyx is regulated in adulthood, we deployed an inductive approach to identify proteins involved in MUC17 trafficking and targeting to the brush border membrane. We detected the motor proteins MYO1B, MYO5B and sorting nexin SNX27 that regulate MUC17 apical targeting. Since our first study showed that glycocalyx forming MUC17 keep bacteria away from the intestinal epithelial, we asked whether the glycocalyx can prevent binding of secreted bacterial enterotoxins. We used cholera toxin (Ctx) from pathogenic Vibrio cholerae that colonize and infect the small intestine where the majority of MUC17 is expressed. We found that MUC17 prevents GM1 dependent and independent Ctx binding to intestinal epithelial cells. Moreover, we demonstrated that the MUC17 mucin domain was responsible for blocking Ctx surface binding and subsequent Ctx-induced intoxication. Together, our results highlight the importance of a tightly regulated MUC17-based glycocalyx throughout life. Brush border components including MUC17 are downregulated in Crohn´s disease patients, suggesting that these proteins play a key role in regulating mucosal barrier functions. Future studies will aim to improve our understanding of the MUC17-based glycocalyx in microbial interactions, intestinal inflammation, and infection.