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Mucosal glycans: key drivers of the development of inflammatory bowel disease and a potential new therapeutic target

Nature Reviews Gastroenterology & Hepatology (2026)Cite this article

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Abstract

Glycans are essential components of homeostatic networks, acting as fine tuners of immunological responses, and are therefore promising targets for manipulating immune tolerance. Glycans shield the entire gut mucosa surface, contributing to epithelial barrier integrity. Moreover, most microorganisms expose glycoconjugates on their surfaces, making glycans essential molecules in the crosstalk between host immune response and the gut microbiota. The vast amount of biological information encoded by mucosal glycans is deciphered by a variety of glycan-binding proteins that translate glycan recognition into either pro-inflammatory or anti-inflammatory responses. Current evidence from inflammatory bowel disease (IBD) has highlighted the prominent role of glycans in establishing and regulating key cellular and molecular pathways underlying the transition from health to intestinal inflammation, with implications for understanding IBD immunopathogenesis and for IBD prediction and prevention. In this Review, we discuss current advances, emerging challenges and future prospects in exploiting the power of the mucosal glycocalyx and the glycome as master coordinators of the immunoregulatory networks in IBD from the preclinical phase to established diagnosis. We discuss the clinical utility of the glycome as a serological biomarker with diagnostic, prognostic and predictive value, and as a potential new target for preventive intervention strategies in IBD.

Key points

  • The mucosal glycocalyx is a fundamental physical and biological barrier that shields the surface of the gut mucosa, guaranteeing epithelial barrier integrity.

  • Glycan-encoded information is recognized by a variety of glycan-binding proteins on immune cells, establishing powerful glycan-mediated immunoregulatory circuits for preserving gut homeostasis.

  • Changes in mucosal glycocalyx affect the gut permeability and the microbiota composition associated with gut dysbiosis.

  • Changes in mucosa glycosylation activate pro-inflammatory pathways culminating in intestinal inflammation.

  • Changes in glycome are detected in blood, in plasma glycoproteins and circulating antibodies (IgG), acting as biomarkers that track with disease onset and progression.

  • Targeting mucosa glycosylation through metabolic supplementation with glycans can preserve gut homeostasis with an effect in preventing the transition from health to intestinal inflammation.

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Fig. 1: Gut mucosal glycocalyx in health and inflammation.
Fig. 2: Glycans as master triggers of the transition from health to intestinal inflammation.

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Acknowledgements

S.S.P. acknowledges funding from the European Union (GlycanTrigger, grant agreement number 101093997; GlycanSwitch, grant agreement number 101071386). The views and opinions expressed here are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency. S.S.P. also acknowledges funding from the US Department of Defense, US Army Medical Research Acquisition Activity and FY18 Peer-Reviewed Medical Research Program Investigator-Initiated Research Award (award number W81XWH1920053); and funding from the European Crohn’s and Colitis Organisation (ECCO) Pioneer Award 2021, the International Organization for the study of Inflammatory Bowel Disease (IOIBD), the Portuguese Group of Study on IBD (GEDII), Mizutani Foundation for Glycoscience (Grant 250007) and the Portuguese Foundation for Science and Technology (FCT; 2023.16654.ICDT). J.-F.C. and J.T. acknowledge funding from the Innovative Health Initiative Joint Undertaking (IHI JU) under grant agreement no. 101194780 (INTERCEPT). The IHI JU receives support from the European Union’s Horizon Europe Research and Innovation Programme and COCIR, EFPIA, Europa Bío, MedTech Europe, Vaccines Europe, Ludger Ltd, Celltrion Inc. and Prometheus Laboratories Inc. J.-F.C. and J.T. also acknowledge funding from the European Union (GlycanTrigger, grant agreement number 101093997). Views and opinions expressed here are, however, those of the author(s) only and do not necessarily reflect those of the aforementioned parties. Neither of the aforementioned parties can be held responsible for them. The authors acknowledge J. Gregory, Senior Medical Illustrator at Mount Sinai, for her outstanding artwork prepared for this review.

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Authors and Affiliations

  1. i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal

    Salomé S. Pinho

  2. ICBAS – School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal

    Salomé S. Pinho

  3. Faculty of Medicine, University of Porto, Porto, Portugal

    Salomé S. Pinho

  4. Gastroenterology Division, Hospital da Luz, Lisbon, Portugal

    Joana Torres

  5. Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal

    Joana Torres

  6. Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

    Joana Torres

  7. Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jean-Frederic Colombel

Authors
  1. Salomé S. Pinho
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  2. Joana Torres
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  3. Jean-Frederic Colombel
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Contributions

All authors researched data for the article. All authors contributed substantially to discussion of the content. All authors wrote the article. S.S.P. reviewed and/or edited the manuscript before submission.

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Correspondence to Salomé S. Pinho.

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Nature Reviews Gastroenterology & Hepatology thanks Shinichiro Shinzaki, Jennifer Brazil and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

GlycanTrigger Project: https://glycantrigger.eu/

Glossary

Glycan mimicry

Similarity of glycan structures between microorganisms and host cells. Microorganisms can engage in glycan mimicry by expressing glycan structures similar to those of the host to evade immune detection and, therefore, colonize and infect the host. Glycan mimicry can also underlie the inability of the host immune system to distinguish self from non-self glycans, leading to the loss of immunological tolerance and autoimmune reactions.

Glycan-binding proteins

Proteins expressed or secreted by host cells (immune cells, epithelial cells, endothelial cells) that specifically recognize and bind to carbohydrate structures (glycans), being important in immune regulation.

Glycans

Complex carbohydrate structures composed of at least two monosaccharides linked together, attached to proteins or lipids. N-linked glycans are carbohydrate chains attached to the nitrogen atom of asparagine residues in proteins. O-linked glycans are carbohydrate chains attached to the oxygen atom of serine or threonine residues in proteins.

Glycome

The complete repertoire of glycan structures (free or attached to proteins and lipids) expressed or secreted by a cell, tissue or organism. It contains a large amount of important biological information that adds to the information provided by the genome and proteome. It contributes to biological diversity and to speciation.

Gut mucosal glycocalyx

A dense gel-like layer, composed of a diverse repertoire of glycan structures attached to glycoproteins, glycolipids and mucins that coats the apical surface of epithelial cells of gut mucosa. It functions as a protective shield, promoting epithelial barrier integrity and regulating interactions between the host immune system and the microbiota.

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Pinho, S.S., Torres, J. & Colombel, JF. Mucosal glycans: key drivers of the development of inflammatory bowel disease and a potential new therapeutic target. Nat Rev Gastroenterol Hepatol (2026). https://doi.org/10.1038/s41575-025-01164-7

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