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  • Review Article
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Intestinal epithelial glycosylation in homeostasis and gut microbiota interactions in IBD

Nature Reviews Gastroenterology & Hepatology volume 17, pages 597–617 (2020)Cite this article

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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.

Key points

  • 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.

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Fig. 1: Mammalian glycan classes and monosaccharides.
Fig. 2: O-glycan core structures.
Fig. 3: Altered glycan structures and genes in IBD.
Fig. 4: Immune regulation of epithelial fucosylation.
Fig. 5: Mucus structure and synthesis.
Fig. 6: COSMC and O-glycans spatially regulate the gut microbiota.

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Acknowledgements

The authors were supported by NIH grants U01CA168930 and P41GM103694 (R.D.C.), the Burroughs Wellcome Trust Career Award for Medical Scientists and the NIH Early Independence Grants DP5OD019892 (S.R.S.) and DK89763 and AI64462 (A.S.N.).

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  1. Matthew R. Kudelka

    Present address: Department of Internal Medicine, Weill Cornell Medicine, New York, NY, USA

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  1. Medical Scientist Training Program, Emory University School of Medicine, Atlanta, GA, USA

    Matthew R. Kudelka

  2. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Sean R. Stowell & Andrew S. Neish

  3. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Richard D. Cummings

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A.S.N. and M.R.K. researched data for the article, made a substantial contribution to discussion of content, wrote the manuscript, and reviewed/edited the manuscript before submission. S.R.S. and R.D.C. made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission.

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Supplementary information

Glossary

Glycans

Carbohydrates consisting of at least two monosaccharides linked together.

Lectin

A non-antibody glycan-binding protein isolated from animals or plants.

Sequon

A defined series of amino acids that serve as an attachment site for a glycan.

Lewis antigens

Lewis (Le) antigens are fucosylated non-ABO blood group antigens. The basic Le structure consists of a terminal galactose attached via β-linkage to a subterminal N-acetylglucosamine (GlcNAc), which is modified by attachment of a fucose in α-linkage. The galactose can be attached to the 3 or 4 position of the GlcNAc and the fucose can be attached to the open 4 or 3 position, depending on which position is available. This basic Le structure (Lea or Lex, depending on the exact linkages) can be further modified by additionally adding a fucose to the galactose to form Ley or Leb depending on the exact linkages and/or by addition of sulfate or sialic acid to either galactose or GlcNAc. FUT3 attaches fucose to the GlcNAc, whereas FUT2 attaches fucose to the galactose.

Cad antigen

A non-ABO blood group antigen present on red blood cells and secretions. Structurally, a Cad antigen consists of a galactose modified by addition of sialic acid and N-acetylgalactosamine (GalNAc) at two different positions on the galactose ring: GalNAcβ1,4(Neu5Acα2,3)Galβ-R.

Molecular mimicry

In glycobiology, this term refers to the process of foreign microorganisms, typically bacteria, expressing glycan structures that resemble host glycan structures. This prevents immune recognition of the bacteria as a foreign invader and is used by pathogens and commensals alike.

O-GlcNAcylation

This is a class of nucleocytoplasmic glycosylation defined by β-linkage of unmodified N-acetylglucosamine on serine or threonine on glycoproteins. Unlike the majority of cell surface glycans, which last for the lifespan of the protein, O-GlcNAc is added and removed rapidly throughout the lifespan of a protein. O-GlcNAcylation often occurs at the same site as phosphorylation and similarly regulates cell signalling.

Glycosite

The amino acid position within a protein where a specific glycan is attached.

Polysaccharide utilization loci

Bacterial gene clusters that encode proteins that bind, degrade and transport extracellular polysaccharides across the bacterial cell membrane and into the bacterial cell.

Peyer’s patches

An organized collection of immune cells with a specific microarchitecture that is found in the gut, most commonly in the mucosal and submucosal layers of the ileum.

Diapedesis

The process of blood cells travelling between endothelial cells as the blood cells exit the blood vessel and enter the tissue.

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Kudelka, M.R., Stowell, S.R., Cummings, R.D. et al. Intestinal epithelial glycosylation in homeostasis and gut microbiota interactions in IBD. Nat Rev Gastroenterol Hepatol 17, 597–617 (2020). https://doi.org/10.1038/s41575-020-0331-7

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