Intestinal epithelial glycosylation in homeostasis and gut microbiota interactions in IBD

Abstract

Inflammatory bowel disease (IBD) affects 6.8 million people globally. A variety of factors have been implicated in IBD pathogenesis, including host genetics, immune dysregulation and gut microbiota alterations. Emerging evidence implicates intestinal epithelial glycosylation as an underappreciated process that interfaces with these three factors. IBD is associated with increased expression of truncated O-glycans as well as altered expression of terminal glycan structures. IBD genes, glycosyltransferase mislocalization, altered glycosyltransferase and glycosidase expression and dysbiosis drive changes in the glycome. These glycan changes disrupt the mucus layer, glycan–lectin interactions, host–microorganism interactions and mucosal immunity, and ultimately contribute to IBD pathogenesis. Epithelial glycans are especially critical in regulating the gut microbiota through providing bacterial ligands and nutrients and ultimately determining the spatial organization of the gut microbiota. In this Review, we discuss the regulation of intestinal epithelial glycosylation, altered epithelial glycosylation in IBD and mechanisms for how these alterations contribute to disease pathobiology. We hope that this Review provides a foundation for future studies on IBD glycosylation and the emergence of glycan-inspired therapies for IBD. Intestinal epithelial glycosylation is influenced by host genetics, the environment and the gut microbiota. In this Review, Kudelka et al. describe the functions of epithelial glycans and discuss the role of epithelial glycosylation in Crohn’s disease and ulcerative colitis. A large set of transcriptional and enzymatic pathways spatially and developmentally regulate glycosylation in the gut. Host genetics, environment and the gut microbiota influence intestinal epithelial glycosylation. Epithelial glycans have many functions; they act as ligands and nutrient sources and establish immunological tone, for the gut microbiota. Genome-wide association studies and biochemical studies implicate altered intestinal epithelial glycosylation in Crohn’s disease and ulcerative colitis. Disrupted glycosylation contributes to inflammation by perturbing intestinal barrier function, glycan–lectin interactions, the gut microbiota and mucosal immunity. Targeting epithelial glycans in the intestine provides an opportunity to combat inflammatory bowel disease. A large set of transcriptional and enzymatic pathways spatially and developmentally regulate glycosylation in the gut. Host genetics, environment and the gut microbiota influence intestinal epithelial glycosylation. Epithelial glycans have many functions; they act as ligands and nutrient sources and establish immunological tone, for the gut microbiota. Genome-wide association studies and biochemical studies implicate altered intestinal epithelial glycosylation in Crohn’s disease and ulcerative colitis. Disrupted glycosylation contributes to inflammation by perturbing intestinal barrier function, glycan–lectin interactions, the gut microbiota and mucosal immunity. Targeting epithelial glycans in the intestine provides an opportunity to combat inflammatory bowel disease.