Preclinical IBD: the key to the future is (probably) behind us

In the meantime, our understanding of the mechanisms underlying the development of IBD have improved significantly. It is now clear that IBD leads to cumulative damage in the bowel wall, and that this is associated with significant disability and decreased quality of life. However, those events occurring at the very onset of the pathogenic process have not yet been clearly elucidated. Improving our understanding of these early events would enable us to identify the main triggers of the inflammatory process and the drivers that lead to a chronic and persistent immunological response. More importantly, it would also reveal which targets will offer greater benefit when treating the disease early, and potentially could even make possible the application of preventive measures in subjects at risk.

 

In recent years, international collaborative initiatives have provided many significant clinical and basic data and this new evidence has been received with great interest. The Seventh Scientific Workshop of ECCO on Precision Medicine consequently addressed the topic of prediction and prevention of IBD [2]. The panel of international experts established definitions, reviewed the current evidence and proposed what should be considered by future work in this field (Figure 1). For instance, various studies have now demonstrated that events during the first years of life , such as smoking, infections and antibiotic use, can increase susceptibility to IBD development [3]. In addition, it has been demonstrated that certain immunological, clinical and healthcare consequences are already present in the years before diagnosis, even during the period without detectable disease in terms of gastrointestinal symptoms [4–6].

Figure 1. Overview of the stages during the preclinical period of IBD (adapted from Torres et al. [2])

The concept of preclinical IBD and its staging

The most widely accepted definition of preclinical IBD includes all the events and findings occurring before the clinical onset of disease [2]. Many different studies involving analysis of serological and proteomic panels [4, 7–11], metabolomic features [12], microbiome signatures [13] and faecal markers [14] have built a robust body of evidence showing that is already present years before diagnosis, and these findings have been linked to certain altered cellular pathways [4]. Overall, the collective evidence nicely demonstrates how a systemic yet subclinical immune process can be present for a long time in asymptomatic subjects (disease initiation phase), confirming such unique opportunity for earlier disease identification.

The next phase (i.e. disease expansion) involves progression of the pathogenic process within the bowel wall and at the mucosal level. Identification of this pathogenic process might seem (very) complicated at first sight, but the introduction of regional and nationwide colorectal cancer screening programmes has shown that it is possible to detect mucosal damage associated with IBD in asymptomatic subjects after a positive faecal occult blood test [15–17]. Interestingly, this subclinical inflammation is also linked with an overall increase in the burden on healthcare resources, including primary care visits and steroid use [5]. This context provides an opportunity to analyse how an altered interaction between the host, environmental factors and gut microbiota evolves and leads to the initial lesions, even before a person describes the initial manifestations.

Several studies have evaluated the preclinical period and some are still ongoing, so more results can be expected in the near future [18, 19]. Here we highlight some of these studies:

PREDICTS (PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects)

This is a nested case-control study of subjects with incident IBD, including 1000 cases of CD, 1000 cases of UC and 500 healthy controls from the Defense Medical Surveillance System [20]. This is the main database from the US Armed Forces and contains clinical information from over 10 million members who have served in the armed forces since 1990. Up to four serum samples obtained biennially have been obtained from cases and controls.

This repository has led to the discovery of many of the most relevant findings in the field of preclinical IBD, including proteomic markers [4] and a range of serologic markers, such as antimicrobial antibodies [4] and anti-GM-CSF antibodies [9]. Most of the evidence relates to CD patients, and the immune process underlying UC remains partially undiscovered. However, recent data from this team of investigators have demonstrated that certain anti-integrin antibodies towards integrin αvβ6 are also present before the onset of UC [7]. Further investigations are ongoing from this cohort and we all are expecting more results from these researchers.

CCC GEM (Crohn’s and Colitis Canada Genetic, Environmental, Microbial) cohort

This study, led by Crohn’s and Colitis Canada, involves a prospective cohort including asymptomatic first-degree relatives of CD patients aged between 6 and 35 years. After excluding any digestive symptoms and previous gastrointestinal disease, these subjects have been followed up every six months (https://www.gemproject.ca/). Highly interesting findings have been obtained from a range of analyses comparing the characteristics of first-degree relatives who have developed CD and those who have remained asymptomatic (without IBD) during follow-up.

These researchers have demonstrated different aspects of the subclinical inflammatory process that develops prior to diagnosis in this selected at-risk population. In a cohort of 1420 first-degree relatives who were followed up for a median of 7.8 years, they nicely showed how disruption of gut barrier integrity can be detected through an increase in intestinal permeability years before diagnosis, and this link remained significant even if the test was performed more than three years before CD diagnosis [21]. Additionally, more recent data have shown that the altered gut barrier function is linked to a different gut microbiome and a proteomic signature [10, 22]. Interestingly, these researchers have also replicated the findings from the PREDICTS group showing that antimicrobial antibodies are present in these patients, so they could be included as additional biomarkers [23]. In view of these findings, we may conclude that the in-depth evaluation of first-degree relatives within the CCC GEM project will definitely increase our knowledge about the initial processes prior to disease onset.

POP-IBD

The POP-IBD study group is a collaborative enterprise involving researchers from St George's University of London, Imperial College London, University College London and King's College London. The group conducts population-based studies in the field of IBD, and among these it is worthwhile to highlight those concerning the presence of gastrointestinal symptoms and psychiatric comorbidity before IBD diagnosis. These researchers have described an excess prevalence of digestive symptoms over the ten years preceding IBD diagnosis [24]. Also, the association of these symptoms with depression increased the risk of both UC and CD, by 47% and 41%, respectively [25]. Their clinical perspective in approaching the preclinical period through population-based studies is of great value and will help in determining those individuals who are at higher risk of developing IBD and will need early referral to specialised clinics.

PREDICT (Center for Molecular Prediction of Inflammatory Bowel Disease)

The Center for the Molecular Prediction of Inflammatory Bowel Disease (PREDICT) is a national centre of excellence at Aalborg University, Copenhagen, Denmark. The purpose of PREDICT is to study and unravel the cause and prognosis of IBD. Based on unique patient samples from the Danish National Biobank combined with longitudinal nationwide register data, PREDICT examines genetics, epigenetics, antibodies, inflammatory markers, metabolomics and microbiomes in thousands of patients prior to development of IBD. PREDICT has built a data infrastructure with nationwide registry data and biological data from biobank samples. Data from biobank samples include GWAS (genome-wide association study) data on >9000 patients with IBD and inflammatory markers on neonatal blood spots from >400 individuals who later developed IBD; in addition, metabolomics studies are currently being conducted on 4000 prediagnostic IBD serum samples.

Recently PREDICT showed that patients with IBD have higher use of almost every medication ten years prior to IBD diagnosis, indicating multiorgan involvement of IBD [6]. Also, the centre has described increased use of antibiotics prior to development of IBD [26] and has found that patients with IBD are at increased risk of anxiety and depression both before and after the diagnosis of IBD [27]. The PREDICT data infrastructure represents a unique and well-powered framework which will be leveraged for further investigations of the prediagnostic phase of IBD.

EARLY cohort

The Spanish IBD Working Group on Crohn’s Disease and Ulcerative Colitis (GETECCU) has just launched this prospective study, which will recruit 350 patients with an incidental diagnosis of IBD during colorectal cancer screening at 25 sites in Spain and compare them with two control cohorts (ClinicalTrials.gov: NCT05698745). Apart from describing the clinical, endoscopic and microscopic characteristics of these patients, the study will combine this information with multi-omic data including transcriptomic, proteomic, genetic, microbiome, serological and single-cell RNA sequencing data. The results from this study will provide detailed information about the disease expansion phase and, particularly, about the prognosis and potential disease stratification of subjects who will develop symptomatic disease and more aggressive phenotypes.

Main limitations of current evidence and looking into the future

Despite international consortiums and the available datasets, there are still some areas that will need to be clarified regarding the preclinical period. The main current limitation is the paucity of reports describing biomarkers and immune processes involved in the development of UC. Most data come from the GEM cohort and the IBD Character initiative that have demonstrated some faecal and circulating proteomic signatures in this setting [11, 14]. Another weakness of currently available reports is the scarcity of data on multi-omic analysis combining different techniques, which would help in understanding how all the layers involved in disease pathogenesis interact [18, 19]. Also, samples from different sources and tissues will increase our possibilities of finding new biomarkers and the triggers, in particular during the disease initiation and expansion phases. Nevertheless, the available evidence is of great value and is expected to drive further research that will change our understanding of IBD in the near future.

In conclusion, evaluation of the events preceding IBD diagnosis is an evolving and exciting area of research, where recent data have shown that the subclinical inflammatory process is detectable many years before diagnosis, similar to other immune-mediated inflammatory diseases. Research in this field will help us in multiple ways, including identification of individuals at risk, stratification according to risk of disease progression, further improvement of the beneficial effect of disease intervention strategies and even development of disease prevention approaches.

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