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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).
Torres, J. et al. Crohn’s disease. Lancet 389, 1741–1755 (2017).
Ungaro, R. C. et al. Ulcerative colitis. Lancet 289, 1756–1770 (2017).
Chang, J. T. Pathophysiology of inflammatory bowel diseases. N. Engl. J. Med. 383, 2652–2664 (2020).
Ng, S. C. et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390, 2769–2778 (2017).
Frazzei, G. et al. Preclinical autoimmune disease: a comparison of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and type 1 diabetes. Front. Immunol. 13, 899372 (2022).
Greenblatt, K. H. et al. Preclinical rheumatoid arthritis and rheumatoid arthritis prevention. Curr. Opin. Rheumatol. 32, 289–296 (2020).
Robertson, J. M. & James, J. A. Preclinical systemic lupus erythematosus. Rheum. Dis. Clin. North Am. 40, 621–635 (2014).
Israeli, E. et al. Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease. Gut 54, 1232–1236 (2005).
Torres, J. et al. Results of the Seventh Scientific Workshop of ECCO: Precision Medicine in IBD — Prediction and Prevention of Inflammatory Bowel Disease. J. Crohns Colitis 15, 1443–1454 (2021).
De Lange, K. M. et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat. Genet. 49, 256–261 (2017).
Graham, D. B. & Xavier, R. J. Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature 578, 527–539 (2020).
Agrawal, M. et al. Early life exposures and the risk of inflammatory bowel disease: systematic review and meta-analyses. EClinicalMedicine 36, 100884 (2021). Comprehensive systemic review and meta-analysis collecting the available knowledge of early life risk factors and showing the importance of the early life period in the risk of later IBD development.
Piovani, D. et al. Environmental risk factors for inflammatory bowel diseases: an umbrella review of meta-analyses. Gastroenterology 157, 647–659.e4 (2019).
Halme, L. et al. Family and twin studies in inflammatory bowel disease. World J. Gastroenterol. 12, 3668–3672 (2006).
Jess, T. et al. Disease concordance, zygosity, and NOD2/CARD15 status: follow-up of a population-based cohort of Danish twins with inflammatory bowel disease. Am. J. Gastroenterol. 100, 2486–2492 (2005).
Orholm, M. et al. Familial occurrence of inflammatory bowel disease. N. Engl. J. Med. 324, 84–88 (1991).
Liu, J. Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979–986 (2015). Large trans-ancestry study that not just discovers new genetic risk loci, but also shows that some genetic heterogeneity is present between divergent populations in some of the risk loci.
Van Limbergen, J. et al. Advances in IBD genetics. Nat. Rev. Gastroenterol. Hepatol. 11, 372–385 (2014).
Barker, D. J. P. The origins of the developmental origins theory. J. Intern. Med. 261, 412–417 (2007).
Colebatch, A. N. & Edwards, C. J. The influence of early life factors on the risk of developing rheumatoid arthritis. Clin. Exp. Immunol. 163, 11–16 (2011).
Haupt-Jørgensen, M. et al. Maternal antibiotic use during pregnancy and type 1 diabetes in children – a national prospective cohort study. Diabetes Care 41, e155–e157 (2018).
Al Nabhani, Z. & Eberl, G. Imprinting of the immune system by the microbiota early in life. Mucosal Immunol. 13, 183–189 (2020).
Agrawal, M. et al. Early-life mebendazole exposure increases the risk of adult-onset ulcerative colitis: a population-based cohort study. Am. J. Gastroenterol. 117, 2025–2032 (2022).
Agrawal, M. et al. Maternal antibiotic exposure during pregnancy and risk of IBD in offspring: a population-based cohort study. Gut 72, 804–805 (2023).
Elten, M. et al. Ambient air pollution and the risk of pediatric-onset inflammatory bowel disease: a population-based cohort study. Environ. Int. 138, 105676 (2020).
Elten, M. et al. Residential greenspace in childhood reduces risk of pediatric inflammatory bowel disease: a population-based cohort study. Am. J. Gastroenterol. 116, 347–353 (2021).
Lee, S. H. et al. Peri-natal exposure to parental Crohn’s disease is associated with impaired gut barrier, microbiome composition differences and increased risk of Crohn’s disease [abstract OP29]. J. Crohns Colitis 17 (Suppl. 1), i40–i47 (2023).
Nair, N. et al. Association between early-life exposures and inflammatory bowel diseases, based on analyses of deciduous teeth. Gastroenterology 159, 383–385 (2020). An interesting study showing the usefulness of an unconventional sample type (deciduous teeth) to investigate environmental exposures and risk of IBD.
Torres, J. et al. Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice. Gut 69, 42–51 (2020).
Kim, E. S. et al. Longitudinal changes in fecal calprotectin levels among pregnant women with and without inflammatory bowel disease and their babies. Gastroenterology 160, 1118–1130.e3 (2021).
Soon, I. S. et al. The relationship between urban environment and inflammatory bowel disease: a systematic review and meta-analysis [abstract 1265]. Am. J. Gastroenterol. 105, S465 (2010).
Lo, C. H. et al. Ultra-processed foods and risk of Crohn’s disease and ulcerative colitis: a prospective cohort study. Clin. Gastroenterol. Hepatol. 20, e1323–e1337 (2022).
Narula, N. et al. Association of ultra-processed food intake with risk of inflammatory bowel disease: prospective cohort study. BMJ 374, n1554 (2021).
Chen, J. et al. Intake of ultra-processed foods is associated with an increased risk of Crohn’s disease: a cross-sectional and prospective analysis of 187 154 participants in the UK Biobank. J. Crohns Colitis 17, 535–552 (2022).
Axelrad, J. E. et al. Systematic review: gastrointestinal infection and incident inflammatory bowel disease. Aliment. Pharmacol. Ther. 51, 1222–1232 (2020).
Cosnes, J. et al. Gender differences in the response of colitis to smoking. Clin. Gastroenterol. Hepatol. 2, 41–48 (2004).
Karczewski, J. et al. The effect of cigarette smoking on the clinical course of inflammatory bowel disease. Prz. Gastroenterol. 9, 153–159 (2014).
Mahid, S. S. et al. Smoking and inflammatory bowel disease: a meta-analysis. Mayo Clin. Proc. 81, 1462–1471 (2006).
Torres, J. et al. Risk factors for developing inflammatory bowel disease within and across families with a family history of IBD. J. Crohns Colitis 17, 30–36 (2023).
Faye, A. S. et al. Antibiotic use as a risk factor for inflammatory bowel disease across the ages: a population-based cohort study. Gut 72, 663–670 (2023).
Ananthakrishnan, A. N. et al. Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn disease ulcerative colitis: a cohort study. Ann. Intern. Med. 156, 350–359 (2012).
Sanmarco, L. M. et al. Identification of environmental factors that promote intestinal inflammation. Nature 611, 801–809 (2022).
Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92–96 (2015).
Steenland, K. et al. A cohort incidence study of workers exposed to perfluorooctanoic acid (PFOA). Occup. Environ. Med. 72, 373–380 (2015).
Steenland, K. et al. Ulcerative colitis and perfluorooctanoic acid (PFOA) in a highly exposed population of community residents and workers in the Mid-Ohio Valley. Environ. Health Perspect. 121, 900–905 (2013).
Lochhead, P. et al. Plasma concentrations of perfluoroalkyl substances and risk of inflammatory bowel diseases in women: a nested case control analysis in the Nurses’ Health Study cohorts. Environ. Res. 207, 112222 (2022).
Porter, C. K. et al. Cohort profile of the PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects (PREDICTS) study: rationale, organization, design, and baseline characteristics. Contemp. Clin. Trials Commun. 14, 100345 (2019).
Nishida, A. et al. Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin. J. Gastroenterol. 11, 1–10 (2018).
Manichanh, C. et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 55, 205–211 (2006).
Walker, A. W. et al. High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol. 11, 7 (2011).
Johansson, M. E. V. et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63, 281–291 (2014).
Zeissig, S. et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut 56, 61–72 (2007).
Lassen, K. G. et al. Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc. Natl Acad. Sci. USA 111, 7741–7746 (2014).
Breugelmans, T. et al. Aberrant mucin expression profiles associate with pediatric inflammatory bowel disease presentation and activity. Inflamm. Bowel Dis. 29, 589–601 (2023).
Uniken Venema, W. T. et al. Single-cell RNA sequencing of blood and ileal T cells from patients with Crohn’s disease reveals tissue-specific characteristics and drug targets. Gastroenterology 156, 812–815.e22 (2019).
Uzzan, M. et al. Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity. Nat. Med. 28, 766–779 (2022).
van Unen, V. et al. Identification of a disease-associated network of intestinal immune cells in treatment-naive inflammatory bowel disease. Front. Immunol. 13, 893803 (2022).
Turpin, W. et al. Increased intestinal permeability is associated with later development of Crohn’s disease. Gastroenterology 159, 2092–2100.e5 (2020). This prospective study, which was performed in pre-Crohn’s disease FDRs and healthy FDRs, is the first to our knowledge to show that abnormal intestinal permeability seems to be present prior to onset of Crohn’s disease.
Galipeau, H. J. et al. Novel fecal biomarkers that precede clinical diagnosis of ulcerative colitis. Gastroenterology 160, 1532–1545 (2021). This study shows that functional changes in the intestinal environment, in the form of increased proteolytic activity, which is associated with changes in the microbial composition, can be found several years prior to the onset of ulcerative colitis in FDRs.
Kevans, D. et al. Determinants of intestinal permeability in healthy first-degree relatives of individuals with Crohn’s disease. Inflamm. Bowel Dis. 21, 879–887 (2015).
Söderholm, J. D. et al. Different intestinal permeability patterns in relatives and spouses of patients with Crohn’s disease: an inherited defect in mucosal defence? Gut 44, 96–100 (1999).
Leclercq, S. et al. Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects. Brain. Behav. Immun. 26, 911–918 (2012).
Turpin, W. et al. Analysis of genetic association of intestinal permeability in healthy first-degree relatives of patients with Crohn’s disease. Inflamm. Bowel Dis. 25, 1796–1804 (2019).
Nighot, M. et al. Matrix metalloproteinase MMP-12 promotes macrophage transmigration across intestinal epithelial tight junctions and increases severity of experimental colitis. J. Crohns Colitis 15, 1751–1765 (2021).
Leibovitzh, H. et al. Immune response and barrier dysfunction-related proteomic signatures in preclinical phase of Crohn’s disease highlight earliest events of pathogenesis. Gut 72, 1462–1471 (2023). This study combines findings of disease-associated serum protein markers with markers of subclinical inflammation, humoral response to microbial antigens and intestinal barrier properties, therefore giving insight into the links between these different pathways.
Mills, R. H. et al. Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity. Nat. Microbiol. 7, 262–276 (2022).
Carroll, I. M. & Maharshak, N. Enteric bacterial proteases in inflammatory bowel disease – pathophysiology and clinical implications. World J. Gastroenterol. 19, 7531–7543 (2013).
Ruseler-van Embden, J. G. H. & Van Lieshout, L. M. C. Increased proteolysis and leucine aminopeptidase activity in faeces of patients with Crohn’s disease. Digestion 40, 33–40 (1988).
Hedin, C. R. et al. Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn’s disease and their unaffected siblings. Gut 63, 1578–1586 (2014).
Hedin, C. et al. Siblings of patients with Crohn’s disease exhibit a biologically relevant dysbiosis in mucosal microbial metacommunities. Gut 65, 944–953 (2016).
Jacobs, J. P. et al. A disease-associated microbial and metabolomics state in relatives of pediatric inflammatory bowel disease patients. Cell. Mol. Gastroenterol. Hepatol. 2, 750–766 (2016).
Raygoza Garay, J. A. et al. Gut microbiome composition is associated with future onset of Crohn’s disease in healthy first-degree relatives. Gastroenterology 165, 670–681 (2023). To our knowledge, the first study showing an association between preclinical changes in the microbial composition and later Crohn’s disease onset.
Dong, Z. J., Lv, W. Q., Zhang, C. Y. & Chen, S. Correlation analysis of gut microbiota and serum metabolome with Porphyromonas gingivalis-induced metabolic disorders. Front. Cell Infect. Microbiol. 12, 858902 (2022).
Liu, G. et al. Gut dysbiosis impairs hippocampal plasticity and behaviors by remodeling serum metabolome. Gut Microbes 14, 2104089 (2022).
Gallagher, K. et al. Metabolomic analysis in inflammatory bowel disease: a systematic review. J. Crohns Colitis 15, 813–826 (2021).
Hua, X. et al. Inflammatory bowel disease is associated with prediagnostic perturbances in metabolic pathways. Gastroenterology 164, 147–150.e2 (2023).
Lee, S. H. et al. Anti-microbial antibody response is associated with future onset of Crohn’s disease independent of biomarkers of altered gut barrier function, subclinical inflammation, and genetic risk. Gastroenterology 161, 1540–1551 (2021).
Mortha, A. et al. Neutralizing anti-granulocyte macrophage-colony stimulating factor autoantibodies recognize post-translational glycosylations on granulocyte macrophage-colony stimulating factor years before diagnosis and predict complicated Crohn’s disease. Gastroenterology 163, 659–670 (2022). A comprehensive study showing that autoantibodies targeting GM-CSF are elevated up to 6 years before Crohn’s disease onset, and furthermore these autoantibodies specifically target an altered post-translational glycosylation on GM-CSF, thereby suggesting that changes in glycosylation might be associated with disease development.
Livanos, A. E. et al. Anti-integrin αvβ6 autoantibodies are a novel biomarker that antedate ulcerative colitis. Gastroenterology 164, 619–629 (2023). This study in two independent cohorts is the first to show that autoantibodies targeting integrin αvβ6 are associated with later disease onset of ulcerative colitis, and that the presence of these antibodies can predict later disease onset.
Van Schaik, F. D. M. et al. Serological markers predict inflammatory bowel disease years before the diagnosis. Gut 62, 683–688 (2013).
Torres, J. et al. Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis. Gastroenterology 159, 96–104 (2020). This large retrospective case–control study with longitudinal sampling identified a panel of protein markers and serum antibodies that are predictive of Crohn’s disease development within 5 years.
Choung, R. S. et al. Serologic microbial associated markers can predict Crohn’s disease behaviour years before disease diagnosis. Aliment. Pharmacol. Ther. 43, 1300–1310 (2016).
Choung, R. S. et al. Preclinical serological signatures are associated with complicated Crohn’s disease phenotype at diagnosis. Clin. Gastroenterol. Hepatol. https://doi.org/10.1016/j.cgh.2023.01.033 (2023).
Choi, M. Y. & Costenbader, K. H. Understanding the concept of pre-clinical autoimmunity: prediction and prevention of systemic lupus erythematosus: identifying risk factors and developing strategies against disease development. Front. Immunol. 13, 890522 (2022).
Gravallese, E. M. & Firestein, G. S. Rheumatoid arthritis – common origins, divergent mechanisms. N. Engl. J. Med. 388, 529–542 (2023).
Melinder, C. et al. Physical fitness in adolescence and subsequent inflammatory bowel disease risk. Clin. Transl. Gastroenterol. 6, e121–e128 (2015).
Lochhead, P., Khalili, H., Ananthakrishnan, A. N., Richter, J. M. & Chan, A. T. Association between circulating levels of C-reactive protein and interleukin-6 and risk of inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 14, 818–824.e6 (2016).
Bergemalm, D. et al. Systemic inflammation in preclinical ulcerative colitis. Gastroenterology 161, 1526–1539.e9 (2021).
Reily, C. et al. Glycosylation in health and disease. Nat. Rev. Nephrol. 15, 346–366 (2019).
Kudelka, M. R. et al. Intestinal epithelial glycosylation in homeostasis and gut microbiota interactions in IBD. Nat. Rev. Gastroenterol. Hepatol. 17, 597–617 (2020).
Zhou, X. et al. Antibody glycosylation in autoimmune diseases. Autoimmun. Rev. 20, 102804 (2021).
Hafenscheid, L. et al. N-linked glycans in the variable domain of IgG anti-citrullinated protein antibodies predict the development of rheumatoid arthritis. Arthritis Rheumatol. 71, 1626–1633 (2019).
Alves, I. et al. Host-derived mannose glycans trigger a pathogenic γδ T cell/IL-17a axis in autoimmunity. Sci. Transl. Med. 15, eabo1930 (2023).
Pham, M. et al. Subclinical intestinal inflammation in siblings of children with Crohn’s disease. Dig. Dis. Sci. 55, 3502–3507 (2010).
Thjodleifsson, B. et al. Subclinical intestinal inflammation: an inherited abnormality in Crohn’s disease relatives? Gastroenterology 124, 1728–1737 (2003).
Montalto, M. et al. Fecal calprotectin in first-degree relatives of patients with ulcerative colitis. Am. J. Gastroenterol. 102, 132–136 (2007).
Taylor, K. M. et al. Genetic and inflammatory biomarkers classify small intestine inflammation in asymptomatic first-degree relatives of patients with Crohn’s disease. Clin. Gastroenterol. Hepatol. 18, 908–916.e13 (2020).
Torres, J. Prediction of inflammatory bowel disease: a step closer? Gastroenterology 158, 278–279 (2020).
Cohen N. A., et al. Trends in biochemical parameters, healthcare resource and medication use in the 5 years preceding IBD diagnosis: a Health Maintenance Organization Cohort Study. Dig. Dis. Sci. 38, 414–422 (2023).
Vadstrup, K. et al. Cost burden of Crohn’s disease and ulcerative colitis in the 10-year period before diagnosis – a Danish register-based study from 2003–2015. Inflamm. Bowel Dis. 26, 1377–1382 (2020).
Rodríguez-Lago, I. et al. Characteristics and progression of preclinical inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 16, 1459–1466 (2018).
Rodríguez-Lago, I. et al. Early microscopic findings in preclinical inflammatory bowel disease. Dig. Liver Dis. 52, 1467–1472 (2020).
Rodríguez-Lago, I. et al. Subclinical bowel inflammation increases healthcare resources utilization and steroid use before diagnosis of inflammatory bowel disease. United European Gastroenterol. J. 11, 9–18 (2023). Retrospective case–control study showing that individuals who later develop IBD have elevated usage of steroids and increased health-care utilization 3 and 5 years before diagnosis of disease.
Blackwell, J. et al. Prevalence and duration of gastrointestinal symptoms before diagnosis of inflammatory bowel disease and predictors of timely specialist review: a population-based study. J. Crohns Colitis 15, 203–211 (2021).
Bonfils, L. et al. Medication use is increased in the decade prior to IBD diagnosis: a nationwide cohort study [abstract DOP62]. Presented at the 18th Congress of the European Crohn’s and Colitis Organisation. https://www.ecco-ibd.eu/publications/congress-abstracts/item/dop62-medication-use-is-increased-in-the-decade-prior-to-ibd-diagnosis-a-nationwide-cohort-study.html (2023). A large population-based study showing that usage of a broad spectrum of medication types is increased in the 10 years leading up to disease onset in patients with IBD.
Puente, A. D. et al. The incidence of rheumatoid arthritis is predicted by rheumatoid factor titer in a longitudinal population study. Arthritis Rheum. 31, 1239–1244 (1988).
Nielen, M. M. J. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).
Sokolove, J. et al. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS ONE 7, e35296 (2012).
Lu, R. et al. Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies. J. Autoimmun. 74, 182–193 (2016).
James, J. A. et al. Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients. EBioMedicine 42, 76–85 (2019).
Ercan, A. et al. Aberrant IgG galactosylation precedes disease onset, correlates with disease activity, and is prevalent in autoantibodies in rheumatoid arthritis. Arthritis Rheum. 62, 2239–2248 (2010).
Kinashi, Y. & Hase, K. Partners in leaky gut syndrome: intestinal dysbiosis and autoimmunity. Front. Immunol. 12, 673708 (2021).
Herold, K. C. et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N. Engl. J. Med. 381, 603–613 (2019).
Keam, S. J. Teplizumab: first approval. Drugs 83, 439–445 (2023).
Frazzei, G. et al. Prevention of rheumatoid arthritis: a systematic literature review of preventive strategies in at-risk individuals. Autoimmun. Rev. 22, 103217 (2023).
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.
Author information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
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.
Peer review
Peer review information
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.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41575-023-00854-4