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Deciphering the different phases of preclinical inflammatory bowel disease

Nature Reviews Gastroenterology & Hepatology volume 21, pages 86–100 (2024)Cite this article

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Abstract

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory disease (IMID) of the gastrointestinal tract and includes two subtypes: Crohn’s disease and ulcerative colitis. It is well-recognized that IBD is associated with a complex multifactorial aetiology that includes genetic predisposition and environmental exposures, with downstream dysregulation of systemic immune function and host–microbial interactions in the local environment in the gut. Evidence to support the notion of a multistage development of IBD is growing, as has been observed in other IMIDs such as rheumatoid arthritis and systemic lupus erythematosus. With the rising worldwide incidence of IBD, it is increasingly important to understand the complex interplay of pathological events during the different stages of disease development to enable IBD prediction and prevention strategies. In this article, we review comprehensively the current evidence pertaining to the preclinical phase of IBD, including at-risk, initiation and expansion phases. We also discuss the framework of preclinical IBD, expanding on underlying pathways in IBD development, future research directions and IBD development in the context of other IMIDs.

Key points

  • Available evidence pertaining to the preclinical phase of inflammatory bowel disease (IBD) has expanded substantially, providing a foundation for understanding the development of IBD.

  • The development of IBD seems to evolve from at-risk individuals through several distinct subphases, including disease initiation and disease expansion approximately 2 years prior to diagnosis.

  • Observed changes within the preclinical phase of IBD include dysregulation of the adaptive and innate immune systems of the intestine, as well as compositional changes in the gut microbiome, increased intestinal permeability, and changes in the glycome and clinical parameters.

  • The specific temporal order of events within preclinical disease initiation are presently hard to decipher, owing to limited availability of longitudinal prediagnostic samples globally.

  • Longitudinal studies linking data from several relevant data sources are needed to elucidate the pathways, molecular interplays and order of events in the development of IBD.

  • Disease development in IBD seemingly shares many general features with that of other immune-mediated inflammatory diseases (such as rheumatoid arthritis), making studies focused on comparing preclinical development between diseases of great relevance.

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Fig. 1: Proposed model of disease development in IBD based on current evidence.
Fig. 2: Proposed chronology of events starting from the prenatal period leading to IBD diagnosis and potential opportunities for preventive intervention.

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Acknowledgements

The authors thank J. Gregory, Certified Medical Illustrator, Icahn School of Medicine at Mount Sinai, for the original versions of the illustrations. M.A. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK129762-02). T.J. is funded by a centre of excellence grant from the Danish National Research Foundation (DNRF148); the foundation had no role in the Review.

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Authors and Affiliations

  1. Center for Molecular Prediction of Inflammatory Bowel Disease, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark

    Jonas J. Rudbaek, Manasi Agrawal & Tine Jess

  2. Section for Biomarkers, Immunology and Antibodies, Department for Congenital Disorders, Statens Serum Institut, Copenhangen, Denmark

    Jonas J. Rudbaek

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

    Manasi Agrawal, Joana Torres, Saurabh Mehandru & Jean-Frederic Colombel

  4. Department of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal

    Joana Torres

  5. Division of Gastroenterology, Hospital da Luz, Lisbon, Portugal

    Joana Torres

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

    Joana Torres

  7. Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark

    Tine Jess

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  1. Jonas J. Rudbaek
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  2. Manasi Agrawal
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Contributions

All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. J.J.R., M.A. and J.T. researched data for the article. J.J.R., M.A. and J.T. wrote the article.

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Correspondence to Tine Jess.

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Competing interests

S.M. has received research grants from Genentech and Takeda; payment for lectures from Genentech, Morphic and Taleda; and consulting fees from Arena Pharmaceuticals, Ferring, Morphic and Takeda. J.-F.C. has received research grants from AbbVie, Janssen Pharmaceuticals and Takeda; has received payment for lectures from AbbVie, Amgen, Allergan, Ferring Pharmaceuticals, Shire and Takeda; has received consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix and Vifor; and holds stock options in Intestinal Biotech Development. J.T. has received research grants from AbbVie and Janssen Pharmaceuticals; has received advisory board fees from AbbVie, Janssen Pharmaceuticals, Pfizer and BMS; and has received speaker fees from AbbVie, Janssen Pharmaceuticals and Pfizer. J.J.R., M.A. and T.J. declare no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks Luc Biedermann, Iago Rodriguez-Lago and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

ASCA

Antibodies targeting mannan molecules on the fungus Saccharomyces cerevisiae.

Autoantibodies

Antibodies targeting molecules produced by an indivdual’s own cells, also known as self-antigens.

Commensal antigens

Antigens derived from commensals, which are microorganisms that derive benefit from a host without aiding or causing harm to the host.

Dysbiosis

An imbalance in the composition of the microbial community that is associated with adverse health outcomes.

Faecal calprotectin

An intracellular neutrophilic protein commonly measured in faecal samples as a way to determine the degree of intestinal inflammation.

IMIDs

Immune-mediated inflammatory diseases (IMIDs) comprise a diverse spectrum of diseases, which share commonalities in their inflammatory nature and similar genetic, environmental and immunological factors.

Immune tolerance

The state of unresponsiveness of the immune system to molecules produced by the host to prevent damage to healthy tissues.

Metabolome

The complete spectrum and number of metabolites present within an organism, tissue or cell.

Microbiome

The collection of genetic material from all the microorganisms present in a specific environment.

Penetrating complications

Fistulas or abscesses formed in the intestinal wall as a result of chronic uncontrolled inflammation.

Preclinical disease

The part of disease development prior to clinical onset of the disease.

Self-antigen

An antigen produced by an indivdual’s cells that elicits an immune response by that indivdual’s own immune cells leading to production of self-reactive antibodies known as autoantibodies, often as a consequence of breaking of immune tolerance.

Stricturing complications

The narrowing of a part of the intestine as a consequence of scar tissue in the intestinal wall, often as a result of chronic inflammation.

Subclinical inflammation

An inflammatory condition that does not yet give rise to clinically apparent symptoms in the individual.

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Rudbaek, J.J., Agrawal, M., Torres, J. et al. Deciphering the different phases of preclinical inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 21, 86–100 (2024). https://doi.org/10.1038/s41575-023-00854-4

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