Introduction
Inflammatory bowel disease (IBD) is a chronic, debilitating disorder of the gastrointestinal (GI) tract comprising two main subtypes: Crohn’s disease (CD) and ulcerative colitis (UC).1 Both conditions are rising in incidence and prevalence globally, with approximately 1% of the UK population currently living with IBD.2–4 The biological mechanisms underlying disease pathogenesis and progression remain poorly understood but are thought to involve an inappropriate immune response to unidentified environmental triggers in genetically susceptible individuals.56 The clinical course of IBD is highly heterogeneous, and the disease is, as yet, incurable. Some individuals follow relatively indolent trajectories, while others require multiple biologics or targeted small-molecule therapies, develop complications, undergo surgery or experience repeated hospitalisations, with a substantial impact on quality of life and healthcare costs.7–9 There is therefore no ‘one-size-fits-all’ approach to effective disease management.
The biological mechanisms responsible for this heterogeneity, along with robust predictive biomarkers of disease course and drug response, remain elusive.1011 Although a wider range of therapeutic options is now available than ever before, and earlier use of biologics or targeted small-molecule therapies is increasingly adopted, effective, individualised treatment decisions at diagnosis remain a major clinical challenge.1012 Primary non-response rates to first-line biologic therapies remain as high as 40%, with a similar proportion experiencing secondary loss of response within the first year.811 Prior exposure to one agent can also diminish the likelihood of success with subsequent treatments.813 Collectively, these factors underscore the urgent unmet need for improved prognostication and precision treatment strategies early in the disease course.
Growing molecular insights into IBD indicate that disease development and heterogeneity are driven by complex interactions between environmental exposures and multiple biological domains. These span the genome, transcriptome, proteome, metabolome and microbiome. Consequently, systems biology approaches that integrate multi-omic data longitudinally at the individual patient level have been proposed as the foundation for future precision medicine strategies in IBD.614
A current limitation of most existing multi-omic IBD cohorts is that they recruit patients after diagnosis and following exposure to one or more therapies, complicating interpretation about causative biology versus downstream consequences of chronic inflammation and/or treatment.14–18 Studies of newly diagnosed and treatment-naïve IBD have demonstrated microbial perturbation and mucosal and blood transcriptomic signatures at disease onset, with potential diagnostic and prognostic relevance.19–23 Treatment-naïve paediatric IBD studies have also identified ileal host transcriptomic and host-microbial signatures at diagnosis, with baseline molecular features associated with subsequent complicated disease.24–26 Important gaps remain, including the predominance of 16S rRNA sequencing in the new-onset IBD microbiome literature, with comparatively limited treatment-naïve shotgun metagenomic sequencing data.1920 In addition, few large adult suspected-IBD cohorts combine pre-treatment biosampling at scale with longitudinal clinical phenotyping and integrated multi-omic profiling.1427–29
Open-IBD, a longitudinal multi-omics inception cohort in IBD, directly addresses these gaps through a multicentre UK study recruiting individuals with suspected IBD at the point of referral, prior to initiation of IBD-specific therapy. Participants undergo systematic, standardised biosampling alongside detailed collection of clinical, demographic, environmental and patient-reported outcome (PRO) data from diagnosis through up to 4 years of follow-up. This design enables characterisation of early-stage treatment-naïve IBD, evaluation of early treatment response and consideration of natural-history biomarkers.
Participants recruited with suspected IBD but ultimately not diagnosed with IBD will form a symptomatic non-IBD control cohort. Inclusion of this group is a key methodological strength of Open-IBD, providing a real-world, clinically relevant comparator rather than relying on healthy controls alone. Prior treatment-naïve IBD studies including both symptomatic and healthy control groups have shown that symptomatic controls may resemble patients with IBD more closely than healthy controls, supporting the value of clinically relevant comparator cohorts.2230 This design will support identification of features distinguishing IBD from alternative causes of GI symptoms, with the potential to improve the clinical translatability of multi-omic findings and optimise future diagnostic and triage pathways.
Open-IBD is being conducted at a pivotal moment in the evolving treatment landscape of IBD, characterised by increasing biosimilar availability, a broadened range of first-line therapeutic options and earlier adoption of biologics or targeted small-molecule therapies.10123132 By describing treatment-naïve biology at diagnosis, the cohort aims to inform prognostic modelling, first-line therapeutic decision-making, and enable biomarker and therapeutic target discovery in early-stage IBD.
Study objectives and aims
The primary objective of the Open-IBD cohort study is to establish a deeply phenotyped, prospective, treatment-naïve inception cohort of adults with suspected IBD, enabling integrated longitudinal multi-omic analyses in those subsequently diagnosed with IBD.
The overarching aims of the Open-IBD cohort are to:
Methods and analysis
Study design
Open-IBD is a prospective, observational, inception cohort study recruiting adults with a suspected diagnosis of IBD. Up to 2000 participants with a high clinical suspicion of IBD will be enrolled and undergo a baseline assessment. With an anticipated IBD diagnosis rate of approximately 50% from those recruited, the cohort aims to enrol 1000 participants with confirmed IBD and up to 1000 symptomatic non-IBD controls.
Participants with a confirmed diagnosis of IBD will be followed for up to 48 months with detailed longitudinal clinical data collected alongside stool, blood and intestinal biopsy samples, PRO measures and dietary intake (figure 1). An approximately 1:1 ratio of CD to UC/IBD-unclassified (IBD-U) is expected. Participants not diagnosed with IBD will undergo clinical record review only at 3, 12, 24, 36 and 48 months after baseline.
Open-IBD is intentionally designed as a pragmatic inception cohort within NHS suspected-IBD diagnostic pathways, prioritising pre-treatment biosampling, rich clinical and sampling metadata, and sufficient scale to support downstream project-specific analyses.
Study setting
Participants will be recruited from seven NHS secondary and tertiary care providers across the UK. The participating clinical sites are: The Newcastle upon Tyne Hospitals NHS Foundation Trust, Cambridge University Hospitals NHS Foundation Trust, NHS Lothian, Royal Devon University Healthcare NHS Foundation Trust, Barts Health NHS Trust, Guy’s and St Thomas’ NHS Foundation Trust and St George’s University Hospitals NHS Foundation Trust.
Study status and timeline
Recruitment commenced in March 2025 and is ongoing across participating sites. Recruitment is anticipated to be completed in 2029. Participants will be followed for up to 48 months after baseline.
Study population
Adults aged 16 years or older who are undergoing investigation for a possible diagnosis of IBD and have not yet received IBD-specific treatment are eligible for recruitment. IBD-specific treatment is defined as treatment commenced for suspected or confirmed IBD, including oral or rectal corticosteroids, 5-aminosalicylates, biologics, JAK inhibitors or sphingosine-1-phosphate receptor modulators. Open-IBD will predominantly recruit participants prior to treatment initiation who are being referred from primary care for hospital outpatient assessment.
However, due to the importance of understanding disease biology in those presenting with severe IBD and the practical challenges of obtaining treatment-naïve samples from these patients, hospital inpatients with suspected new-onset IBD may be included despite limited treatment exposure. Full inclusion and exclusion criteria are detailed in figure 2.
Coexisting immune-mediated inflammatory diseases, and corticosteroids, immunomodulators, biologics or targeted small molecule therapies prescribed for non-IBD indications, are not exclusion criteria. These participants will be included to reflect the real-world suspected-IBD population in which Open-IBD is embedded. These medication exposures will be recorded in detail, including indication and timing relative to biosampling.
Patient identification and consent
Most potential participants will be identified through screening of gastroenterology referrals from primary and secondary care for patients presenting with symptoms or test results suggestive of IBD, for example, elevated faecal calprotectin, positive faecal immunochemical testing (FIT) or imaging evidence of intestinal inflammation. Additional routes of identification include screening of endoscopy or outpatient clinic lists, as well as routine outpatient consultations and inpatient admissions. No single protocol-mandated faecal calprotectin, FIT, imaging or clinical prediction threshold is used to define suspected IBD across all sites.
Potential participants are identified according to local NHS referral and diagnostic pathways.
Recruitment to the IBD cohort will be maximised by employing a clinically enriched recruitment strategy rather than strict consecutive enrolment. Patients considered to have a high pre-test probability of IBD will be recruited in the pre-diagnosis phase. This approach supports the inception study design and the aim of collecting treatment-naïve biosamples.
This will also facilitate recruitment of a well-matched, symptomatic control cohort.
Recruitment metrics and cohort composition will be monitored prospectively, including site-level recruitment, referral routes, demographic characteristics and diagnostic distribution to identify potential sources of selection bias. Where imbalances are identified, these data will inform targeted site support and refinement of recruitment processes, with the aim of improving cohort representativeness where feasible.
Consent will predominantly be taken electronically using a Research Electronic Data Capture (REDCap) online database. Paper consent forms will be available if required. Strategies for participant identification, approach, recruitment and review are outlined in online supplemental figure 1.
Study visits and diagnostic classification
Study visits will be coordinated to coincide with routine clinical appointments where possible. Several participating sites have established dedicated combined clinical-research outpatient clinics to enable the integrated delivery of standard clinical care alongside the systematic collection of research data, questionnaires and biosamples.
At the baseline visit, detailed clinical data will be collected, including participant demographics, presenting symptoms, pre-diagnosis healthcare interactions, comorbidities, previous surgeries, environmental exposures, socioeconomic status, family history, early-life factors and available laboratory results. Concomitant medications, including those with potential relevance to inflammatory or microbial profiles, such as proton pump inhibitors, antibiotics and non-steroidal anti-inflammatory drugs, will also be recorded, including indication and timing relative to biosampling. Baseline clinical disease activity indices will be collected for both CD (Harvey-Bradshaw Index) and UC (Partial Mayo Score), alongside Rome IV criteria for relevant differential diagnoses.3334 Reviewing clinicians will also be asked to estimate the likelihood of an IBD diagnosis based on pre-endoscopy clinical assessment.
Diagnostic classification will use standard NHS clinical assessments by the clinical care team, incorporating available clinical, biochemical, endoscopic, histological and radiological information. No single investigation will be used in isolation to define disease classification, and the research protocol does not mandate a fixed minimum combination of investigations. The basis for IBD diagnoses will be recorded, including the investigations contributing to the final clinical diagnosis.
Participants diagnosed with IBD will enter the IBD cohort and have further study visits and clinical record reviews (figure 1). Longitudinal data collected in this cohort will include disease phenotype, treatment exposure and response, disease activity indices and healthcare utilisation.
Participants not diagnosed with IBD during their baseline investigations will enter the symptomatic non-IBD cohort and will not have further study visits. Instead, interval clinical record reviews will be performed to identify alternative diagnoses and assess for subsequent development of IBD. Participants initially diagnosed with IBD whose diagnosis is subsequently revised to non-IBD will be reclassified into the symptomatic non-IBD cohort.
Participants initially classified as non-IBD who subsequently receive an IBD diagnosis will not enter the longitudinal IBD study visit and sampling schedule but will continue to undergo scheduled clinical record review.
Participants will provide biosamples as detailed in box 1 and complete study questionnaires as detailed in box 2.
Endoscopy
Baseline sampling of the GI tract will be performed during NHS diagnostic endoscopy procedures undertaken as part of standard clinical care. This will primarily involve colonoscopy or flexible sigmoidoscopy but may also include enteroscopy or oesophagogastroduodenoscopy, where clinically indicated. Additional biopsies for research purposes will be collected during these procedures.
The number and anatomical locations of biopsies will vary according to endoscopic findings. Where feasible, paired biopsies will be obtained from both inflamed and uninflamed ileal and colonic mucosa (box 1).
At baseline, both the Simplified Endoscopic Score for Crohn’s Disease and the Ulcerative Colitis Endoscopic Index of Severity will be recorded by the performing endoscopist as part of prospective data capture.3536 To capture clinical disease activity at the time of endoscopy, a 1-day retrospective PRO-2 score (for both CD and UC) will be collected, describing symptoms on the day prior to bowel preparation. This endoscopy-aligned measure is intended to supplement, rather than replace, longitudinal symptom assessments collected at study visits.
Participants with a confirmed IBD diagnosis will be invited to undergo a repeat colonoscopy at 12 months for disease assessment and collection of repeat intestinal biopsy samples. Biopsies will be preferentially taken from the same anatomical regions sampled at baseline to enable paired comparisons.
Study samples
All samples will be collected, processed, stored and transferred using standardised protocols across clinical sites to ensure consistency and high-quality multi-omic data generation. Downstream assays will be performed according to project-specific scientific priorities, funding, sample availability, sample quality and assay feasibility. Not all assays will be performed for every participant or at every timepoint.
Where analyses compare participants with IBD and symptomatic non-IBD controls, baseline non-IBD samples will be selected according to the relevant research question and prespecified analysis plan. Collection dates and storage information will be recorded for each sample type to enable consideration of sampling intervals in downstream analyses.
Stool samples
One stool sample will be collected at each visit according to predefined instructions provided to participants. Participants will collect approximately 15–20 mL of stool from a single defecation event and aliquot samples into three separate tubes for faecal calprotectin measurement and for stabilisation of nucleic acids and metabolites at room temperature, enabling microbiome and metabolome assessment (box 1). DNA extraction will be performed prior to metagenomic shotgun sequencing.
Every effort will be made to obtain stool samples prior to the commencement of bowel cleansing preparation for endoscopic procedures. Where this is not possible, stool samples will be collected 2 weeks after endoscopy to minimise the confounding effect of bowel cleansing on the gut microbiome.3738 In exceptional circumstances, where participants are expected to commence IBD-specific treatment before the 2-week period has elapsed, stool collection within the 2-week window is permitted.
Participants will post stool samples directly to the Newcastle University Biobank using prepaid, pre-addressed packaging.3940 Participant collection date and laboratory receipt date will be recorded. On receipt, OMNIgene•GUT and OMNImet•GUT stool samples will be transferred to –80°C for long-term storage. Unbuffered stool samples will be immediately transferred for central faecal calprotectin measurement.
Any remaining sample will be stored for potential future assays as per box 1. Available clinical faecal calprotectin results, obtained locally, will be recorded separately as part of routine clinical metadata.
Blood samples
Blood samples will be collected at all study visits (box 1). At baseline, blood sampling may occur at the baseline study visit or on the day of diagnostic endoscopy, provided sampling occurs before initiation of IBD-specific treatment. Peripheral blood mononuclear cells (PBMCs) will be isolated, and plasma will be separated from whole blood at clinical sites.
Samples will be cryopreserved locally in accordance with standardised protocols, with plasma stored at −80°C and PBMCs stored at −150°C or in liquid nitrogen. Samples will be shipped periodically in batches from clinical sites to the Wellcome Sanger Institute for centralised storage and downstream processing, including whole genome sequencing, single-cell transcriptomics and metabolomic and proteomic data generation.
Intestinal biopsy samples
Samples for single-cell RNA sequencing will be processed locally according to standardised cryopreservation protocols and stored at −150°C or in liquid nitrogen, while samples for 16S rRNA sequencing will be stored in AllProtect Tissue Reagent (QIAGEN) at −80°C. FFPE samples will be processed according to local NHS laboratory standard operating procedures. Samples will be transferred in batches for central storage and/or data generation, including single-cell transcriptomics, mucosal microbiome 16S rRNA gene sequencing and spatial transcriptomics.
Outcome measures
Open-IBD is a prospective treatment-naïve inception cohort study collecting a broad array of clinical metadata, PRO measures and biosamples to enable integrated multi-omic analyses and the development of predictive models of disease course and treatment response. As such, no single primary clinical endpoint is specified, reflecting the exploratory and discovery-focused nature of the cohort. Instead, a comprehensive range of outcomes will be captured to enable integrative analyses linking clinical features and multi-omic signatures.
Measured outcomes are summarised in box 3. Definitions of treatment response outcomes for participants commencing IBD therapies, including biologics or targeted small molecules, during follow-up are aligned with the IBD-RESPONSE cohort study (online supplemental box 1).18
Sample size calculation
In the absence of a single prespecified primary hypothesis or outcome, a conventional power calculation for a single endpoint is not appropriate. Open-IBD is designed as a prospective inception cohort and biorepository to support multiple exploratory, mechanistic and prognostic analyses. The planned sample size of 2000 adults referred with suspected IBD is therefore pragmatic and informed by the study’s overarching aims.
This sample size is anticipated to enable:
The proposed cohort size is comparable to, or larger than, that of several previously published inception cohorts and is considered sufficient to support the exploratory and discovery-focused aims of the study.26–2941 In addition, Open-IBD is distinguished by deep clinical phenotyping and longitudinal multi-omic analyses, supported by a rich biorepository of linked blood, stool and biopsy samples. Power considerations for individual analyses will be addressed within study-specific statistical analysis plans developed for each research question.
Data analysis plan
Multiple datasets will be generated by project collaborators, including longitudinal clinical data, PRO measures and multi-omic datasets. Analyses will be conducted and reported according to study-specific statistical analysis plans tailored to individual research questions, with governance provided by the Open-IBD Scientific Oversight Committee.
Primary analytical approaches will include:
Clinical and operational variables with potential relevance to specific analyses, including comorbidities such as coexisting immune-mediated inflammatory diseases, medication exposures, referral route, clinical site, disease phenotype and severity, timing of biosampling relative to treatment initiation and recorded alternative diagnoses within the symptomatic non-IBD cohort, will be described and considered in project-specific analysis plans. Depending on the research question, these variables may be included as covariates or used to define comparator groups, exclusions or subgroup/sensitivity analyses where appropriate.
Relevant technical metadata, including sample type, processing date, storage duration, assay batch, sequencing run and analytical platform, will be recorded where applicable. Batches will be formed according to sample availability and longitudinal data-generation timelines. Standard operating procedures and automated platform pipelines will be used to process samples consistently across sites and minimise technical bias between batches.
Quality-control workflows and statistical analyses will incorporate relevant technical covariates, including batch effects, as required by each assay and analysis.
For high-dimensional omic analyses, multiple-testing correction, including false-discovery-rate control, will be applied where appropriate. Missing data will be described for each analysis where relevant, including the extent and pattern of missingness across clinical variables, PRO measures, biosamples and omic datasets. The approach to missing data will be prespecified in project-specific statistical analysis plans and may include, for example, complete-case analysis, multiple imputation, inverse probability weighting or model-based approaches, depending on the variable, outcome, missingness mechanism and analysis objective.
Results will be reported in accordance with relevant reporting guidelines, including Strengthening the Reporting of Observational Studies in Epidemiology for observational analyses and Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis for prediction modelling.4243
Sequencing data will be made available via managed access at the European Genome-Phenome archive and other relevant online platforms. Results from analyses will be made available via the Open Targets platform (https://platform.opentargets.org/) following publication. Access to clinical feature data will be available on request, subject to approval from the Open-IBD Scientific Oversight Committee.
Patient and public involvement and engagement
The Open-IBD protocol development has been supported by a Lived Experience Advisory Panel (LEAP) comprising people living with IBD, convened through open application via the patient charity Crohn’s & Colitis UK. The LEAP has been integral to the design and delivery of Open-IBD from project conception and will continue to advise throughout recruitment, analysis and dissemination.
The LEAP materially informed multiple aspects of the study, including the method and timing of potential participant approach, the acceptability and burden of questionnaires, prioritisation of specific symptoms, outcomes and covariates important to patients, strategies to improve engagement and retention, ensuring appropriate ethnic representation and co-developing eventual dissemination plans. LEAP members co-authored participant information sheets and formally presented their recommendations to research teams on participant communication and recruitment strategies. A detailed description of the fundamental role of patient and public involvement and engagement in shaping Open-IBD has been published separately.44
Ethics and dissemination
Ethical approval for the study was obtained from the Wales Research Ethics Committee 1 (REF 24/WA/0338). All participants provide informed consent before enrolment and before any research-specific data or biosample collection. The study will be conducted in accordance with the Research Governance Framework and will follow the registered UK Clinical Research Collaboration Newcastle Clinical Trials Unit Standard Operating Procedures, ensuring compliance with the principles of Good Clinical Practice as defined by the International Council for Harmonisation (ICH) E6(R3) and the ethical principles outlined in the Declaration of Helsinki.
In line with the study Sponsor, The Newcastle upon Tyne Hospitals NHS Foundation Trust, research data policy, datasets will be kept for at least 5 years after the date they were last accessed.
The Open-IBD study will follow the Open Targets data sharing policy, where pre-publication data will be made available to Open Targets partners (https://www.opentargets.org/partners). The Open-IBD datasets will be available via managed access conditions to ensure data is used in line with the consent provided by the Open-IBD research participants. Anonymised clinical and scientific data may also be made available via other repositories and can be made available via data-sharing request on completion of the study.
The Chief Investigators, Sponsor, Open Targets, Scientific Oversight Committee and research team members are committed to ensuring that the research findings are shared. Findings will be written up and submitted to a peer-reviewed scientific journal. Findings will be presented by the study team at national and international conferences, and lay summaries of the study findings will be disseminated to the study participants and members of the national patient group, Crohn’s & Colitis UK.
Supplementary material