MUC17 and the intestinal glycocalyx: structure, regulation, and barrier function in health and disease

Abstract The intestinal epithelial surface is protected by a multilayered barrier system that includes secreted mucus and a membrane-bound glycocalyx. While gel-forming mucins have been extensively studied, the transmembrane mucins that form the enterocyte glycocalyx remain less well understood. MUC17 has emerged as a dominant and functionally important transmembrane mucin of the small intestinal brush border, where its large, extensively O-glycosylated extracellular domain forms a dense, hydrated barrier between luminal microbes and the epithelial membrane. This review summarizes current knowledge of MUC17 biology, from genomic organization and protein architecture to glycosylation, trafficking, developmental regulation, and barrier function. Particular emphasis is placed on how MUC17 contributes to size-selective exclusion, bacterial segregation, and host-microbe homeostasis. This review further discusses the developmental establishment of the MUC17-rich enterocyte glycocalyx during the suckling–weaning transition and covers the mechanisms that regulate MUC17 localization and dynamics in epithelial cells, including apical targeting, membrane retention, recycling, turnover, and responses to inflammatory cues. Finally, the review examines the consequences of altered MUC17 expression or function, with particular emphasis on glycocalyx barrier defects, host-microbe interactions, bacterial access to the epithelium, and the relevance of MUC17 dysfunction to Crohn’s disease and experimental models of intestinal infection. Together, the review positions MUC17 as a central structural and functional component of the intestinal glycocalyx and an underexplored therapeutic axis for restoring epithelial barrier integrity in intestinal disease.