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.

Figure 1.. Mammalian glycan classes and monosaccharides.

Cell-surface glycans, including N-glycans, O-glycans, glycosaminoglycans, glycosphingolipids and intracellular O-GlcNAc, are shown. NS, N-sulfated glucosamine (GlcNSO₃); 6S, 6-O-sulfate.

Figure 2.. O-glycan core structures.

Cores 1–9 are shown. Core 1–4-based structures constitute the majority of O-glycans, whereas cores 5–9 are generally absent or a relatively minor component. Cores 1 and 2 are ubiquitous whereas cores 3 and 4 are restricted to the gastrointestinal tract.

Figure 3.. Altered glycan structures and genes in inflammatory bowel disease.

(A) Major O-glycans of the healthy sigmoid colon and alterations in inflammatory bowel disease (IBD) are depicted^,,,,,,,. (B) All candidate genes for Crohn’s disease, ulcerative colitis or both (IBD) are enumerated, with those implicated in glycosylation listed^,–. Genes are divided by function as indicated.

Figure 4.. Immune regulation of epithelial fucosylation.

Cytokines, cytokine receptors and immune cells that reduce (left) or increase (right) epithelial fucosylation are depicted.

Figure 5.. Mucus structure and synthesis.

(A) Topography of the normal colonic mucus layer. Bacteria in the outer mucus layer overlay the inner mucus layer, which is normally impenetrable to bacteria; DAPI (blue), MUC2 (green; sc-15334, H-300), bacteria (16S FISH; red), magnification: 100x¹⁵. (B) The MUC2 glycoprotein has an N-terminal trimerization and a C-terminal dimerization domain with a PTS domain that is rich in proline, threonine, serine in between. The N-terminus contains three von Willebrand D domains and the C-terminus contains one (not shown). The PTS domain is highly O-glycosylated in the Golgi and interspersed by two CysD domains, contributing to intramolecular disulfide bonds and intermolecular non-covalent interactions. (C) MUC2 is synthesized in the endoplasmic reticulum, N-glycosylated and dimerized. It is then transported to the Golgi through an N-glycan-dependent mechanism, where it is O-glycosylated and forms trimers. (D) MUC2 is released and unpacked in the inner mucus layer through alkalinization and chelation of Ca²⁺ ions and then further unpacked in the outer mucus layer through proteolysis; the red line indicates cleavage by host proteases.

Figure 6.. COSMC and O-glycans spatially regulate the gut microbiota.

COSMC regulates extension of O-glycans in intestinal epithelia and formation of the colonic mucus layer, separating the gut microbiota from contact with the intestinal epithelia. In mice, loss of Cosmc leads to loss of extended O-glycans and increased bacterial–epithelial contact in the colon. This loss coincides with a loss of bacterial diversity and the emergence of a pro-inflammatory pathobiont in the colonic mucosa but not in the overlying lumen or ileal mucosa. These changes correspond to the spatial dysbiosis observed in patients with inflammatory bowel disease (IBD).