The Israeli IBD Research Nucleus: collaborative advancements in Israeli IBD research

Review methods

We conducted a narrative, consortium-authored review of scientific advancements, translational findings, and patient-related programs. A pre-defined inclusion criterion included studies arising from IIRN-associated infrastructure or multicenter collaborations in the core IIRN research domains. These were synthesized into a conjoint report demonstrating how projects from the different centers merged and evolved throughout the years. We profiled past and present IIRN members to illustrate the disciplines that accounted for the diversity of our collaboration. We note key challenges, failures, and lessons.

To enumerate the number of peer-reviewed publications written as part of the IIRN work throughout the years, we performed a structured bibliometric search using the Scopus database (Elsevier). Two complementary search strategies were applied: (1) Core IIRN publications—we queried studies explicitly affiliated with the IIRN and authored by the predefined core investigators, representing the five participating centers; (2) IIRN-related collaborative outputs—we conducted a broader search of IBD-related publications authored by the same group of investigators between 2015 and 2025, using title/abstract keywords of IIRN domains and author identifiers. Articles were screened and classified as IIRN-related if they reflected multicenter collaboration, use of IIRN infrastructure, or were conceptually derived from IIRN cohorts and research programs. Full queries are provided in the Supplemental Methods.

A nationwide epidemiological data backbone

The epidemiological group of the IIRN (epi-IIRN), Israel’s nationwide IBD cohort, leverages a unique healthcare data infrastructure, in which each resident has a personal ID that connects the four national payers’ HMOs EMRs, thereby covering 98% of the population. This infrastructure enables a population-based, unselected sampling to support research across epidemiology, management, imaging, outcomes, and risk prediction; Israel’s demographics, including Jewish and Arab communities alongside immigrants, create a unique setting to parse genetics, environment, and acculturation. Epi-IIRN’s signal achievement that laid foundation to subsequent scientific research was the uniting of all four national HMOs into a single, population-scale de-identified database and providing a highly accurate algorithm to identify IBD, based on validation and curation by all IIRN centers.

The epi-IIRN platform yielded key studies that demonstrated how IBD prevalence has nearly doubled since 2005, with Crohn’s disease (CD) surpassing ulcerative colitis (UC), alongside heterogeneous trends across age groups and populations. ³ Findings suggest an epidemiologic transition influenced by environmental and socioeconomic factors, ¹⁷ with rising pediatric incidence. ⁴ Risk stratification reflects genetic susceptibility, early-life exposures, and socioeconomic context,^18,19 while longitudinal data suggest preclinical disease signals years before diagnosis. ²⁰ Patients with IBD also exhibit increased risk for autoimmune comorbidities.^21–23 We illustrated how treatment patterns have shifted toward earlier biologic use with more selective immunomodulator strategies,^24–27 yet found that some disease complications remain despite therapeutic advances,^28,29 and identified key predictors of worse outcomes.^30–33 Collaboration between adult and pediatric gastroenterologists enabled representation of pediatric populations with age-spanning analyses.

Prospective cohorts with granular multi-level data

A key feature of the IIRN is the recruitment of patients with well-defined phenotypes and longitudinal follow-up at prespecified time points, enabling comprehensive multi-level assessment of clinical data, inflammatory, and exploratory markers. This approach has resulted in several medium-sized, center-specific cohorts, with complementary recruitment strategies and limited overlap. Examples include an inception cohort of patients with newly diagnosed CD demonstrating short- and long-term clinical outcomes, microbial shifts, effects of dietary patterns, and the importance of multidisciplinary care in a real world setting^6–8; a cohort of patients with CD in remission defining remission depths and suggesting therapeutic interventions to mitigate risk of flare^11,34–36; a cohort of patients initiating therapy with anti-TNF with prospective therapeutic drug monitoring (TDM)^13,37–40; and a cohort of patients with mild-to-moderate CD demonstrating factors associated with a higher psychosocial burden, and the effects of a mindfulness-based cognitive behavioral interventions to modify CD outcomes.^{15,16,41–43}

Each of these cohorts had a main clinical plan and follow-up term, and its biomarker analyses enabled the addition of mechanistic insights spanning a whole spectrum of CD: from diagnosis, to flare, to remission. Collectively, these complementary cohorts aimed to capture the longitudinal journey of patients with CD.

Empowering MDT approach

The care for patients with IBD extends beyond the gastroenterologist, a notion shared and promoted by IIRN centers, advancing the MDT approach that spans adult and pediatric gastroenterology, colorectal surgery, dermatology, obstetrics/gynecology, pediatrics, IBD nursing, dietetics, and psychosocial care. Emerging real-world evidence from other cohorts has also highlighted the importance of metabolic comorbidities in IBD, including associations between type 2 diabetes and worse outcomes in CD, further reinforcing the need for broader systemic and MDT assessment of the metabolic intake and status of patients with IBD. ⁴⁴ Concordantly, several studies conducted by the IIRN suggested that coordinated MDT care is associated with improved clinical outcomes, including reduced readmissions ⁴⁵ and improved short-term outcomes in newly diagnosed CD. ⁴⁶ Joint clinics, including IBD-Derma, ⁴⁷ pregnancy, ⁴⁸ and transition programs, ⁴⁹ provided structured frameworks for addressing the patient’s journey across various stages of their disease. Diet-related research and implementation within the IIRN have been distributed across centers, a step that established nutrition as a scalable MDT-anchored therapeutic domain. Additional MDT interventions, such as psychological therapies and physical exercise, have demonstrated a shift in the microbial taxa among patients with CD. ⁴³

MDT integration also enabled prospective evaluation of modifiable factors, particularly diet and psychosocial interventions. Patients with early CD who adhered to the Mediterranean diet had a more favorable outcome, with lower inflammatory markers, less dysbiotic microbiome, and changes in fecal metabolites. ⁶ These findings align with growing international evidence supporting diet as a key modifiable component of IBD management, and in conjunction with microbiome-directed approaches. ⁵⁰

Guiding diagnosis, prognostication, and remission using novel imaging

One of the key challenges in IBD is selecting appropriate tools for diagnosis, disease monitoring, and assessment of remission. Several IIRN studies addressed the role of different imaging modalities in these settings. Comparative work between video-capsule endoscopy (VCE) and magnetic resonance enterography^9,51–53 suggested that VCE may provide higher sensitivity in detecting proximal small-bowel disease, with potential prognostic impact. A validated VCE score was suggested, and the prognostic value of a non-passed patency capsule was highlighted.^34,36 These observations were subsequently integrated into an IIRN collaborative randomized trial, the CURE-CD trial, in which a VCE-guided treat-to-target was superior to continued standard care in the prevention of clinical relapse over 24 months. ¹¹ These studies prompted the addition of CD monitoring as an indication for VCE reimbursement by all HMOs.

IIRN studies supported the feasibility of gastroenterologist-performed IUS ⁵⁴ and further explored practical strategies for disease monitoring and prognostication. ⁵⁵ Subsequent collaborative efforts contributed to international recommendations regarding IUS response criteria and operator competency.^56,57

Overall, these advances turned various tests into shared SOPs and actionable targets in the IIRN centers, implemented in real-world care and national-level decisions.

Biologic therapy: Mechanisms, immunogenicity, and biomarkers

TDM and immunogenicity were other major domains within the IIRN.^12,58–60 Specifically, we assessed the formation of anti-drug antibodies (ADA) to anti-TNF agents, mechanistic clues based on mucosal and peripheral blood drug levels and ADA, ways for their modification,^13,37–40 and drug levels and ADA relation to disease outcomes and prediction of early response to treatment.^39,61,62 Harnessing the epidemiological power of the epi-IIRN, we translated laboratory findings regarding the influence of antibiotics on ADA formation into a clinical trial, demonstrating how different antibiotics might be related to ADA formation.^14,63 These studies shed light on our understanding of biologic therapies’ mechanisms and supported the integration of TDM and drug dosing as a part of common clinical practice.

Holistic approach and the psychosocial burden of IBD

As part of the IIRN comprehensive assessment and MDT-guided intervention in IBD, particularly CD, the role of psychosocial factors in disease activity and quality of life was explored. The contribution of stress, life experiences, and social support to disease burden was highlighted showing that adverse life events and family dynamics were associated with higher psychological distress and poorer quality of life,^64,65 whereas perceived social support was associated with lower psychological distress and lower disease activity. ⁶⁶ These findings align with broader, international evidence that has demonstrated a substantial psychiatric burden among patients with IBD, further supporting the integration of psychological assessment into routine IBD care. ⁶⁷

To this end, we examined disease-specific coping mechanisms, somatization, and their relationship to disease severity to further support integration of psychological assessment and intervention into routine management.^68,69 More recent international perspectives expanded this by highlighting the importance of IBD-related trauma, suggesting that disease course and complications may themselves become important contributors to long-term psychological burden. ⁷⁰ Reflection of these processes was demonstrated in several epi-IIRN-based studies reporting substantial burden of depression and anxiety disorders in pediatric-onset IBD and their modifying factors, ⁷¹ as well as fatigue in adults. ⁷² In a multicenter, randomized controlled trial, we evaluated a structured cognitive-behavioral and mindfulness-based intervention with daily exercise (COBMINDEX) in patients with active CD. ¹⁵ The intervention was associated with improvement in quality of life and patient-reported outcomes,^16,42 as well as changes in selected microbiome features. ⁴³

Taken together, proactive screening and structured management of psychological burden, as well as incorporation of mental health experts in the IBD MDT, are important implications of IIRN output.

Stepping into the future with artificial intelligence and deep learning

Over time, the IIRN was expanded to include emerging conceptual domains, including artificial intelligence and machine learning. Specifically, predictive models using longitudinal clinical and laboratory data for detecting patients with CD pre-diagnosis^20,73 were applied in the epi-IIRN database, and prompt-learning and natural language processing were used to structure radiology reports.^74–76 Deep learning models were also applied for the detection of small-bowel ulcers on VCE, demonstrating the potential to shorten reading time, with grading of ulcer severity and the detection of strictures.^77–79 The integrated work pipeline of the IIRN that spans across these varied topics is illustrated in Figure 1.

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Figure 1.

Pipeline work of the IIRN.

The footprint of collaboration: Measuring the IIRN impact

The IIRN spans five centers, but its contribution relies on the people who have contributed to its founding and ongoing works over the years. This network includes physicians across different disciplines, basic and translational scientists, nurses, dietitians, social workers and psychologists, bioinformaticians, and research coordinators. Annual scientific meetings were held 1–2 yearly, enabling discussion of projects, sharing ideas, preliminary findings, and feedback. Scientific output was reflected in multiple publications, with 90 documents as core IIRN outputs between 2015 and 2025 and 2169 citations (Figure 2). IIRN-related collaborative or infrastructure-based studies included 165 publications with 4281 citations.

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Figure 2.

Annual number of peer-reviewed publications arising from IIRN work.

Overcoming limitations, challenges, and lessons learned

Coordinating a national consortium of leading centers over a decade posed several challenges. Early on, moving beyond ad hoc collaboration toward true co-design required building trust, shared priorities, and aligned research and care pathways. Data sharing represented a major constraint, given institutional interests, data-protection policies, and alongside regulatory barriers for establishing multicenter and national cohorts such as the epi-IIRN. The IIRN approach to such challenges was to preserve each center’s unique cohorts and platforms, enabling scientific insights, while fostering interaction cross-referral, validation, and mutual contribution. This comes at a cost of limited harmonization in outcome measures and exploratory assessments across heterogeneous cohorts.

These challenges were addressed through transparent governance, a steering committee with decision-making authority, and targeted, data-sharing pipelines activated when indicated scientifically. Sustained coordination efforts ultimately strengthened the scalability and translational impact of IIRN outputs. Facing and overcoming these challenges enabled our joint effort to produce tangible achievements and to look forward, not without its own lessons. We believe that these challenges may be encountered in similar efforts to bridge over different centers while attempting to conduct comprehensive research, which will focus on a complex disease such as IBD. We therefore summarize our main approaches and lessons for each domain in Table 2.

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Table 2.

Main lessons from the IIRN experience in developing a national IBD research network.

Domain	Challenge	IIRN approach	Main lesson
Governance	Inter-institutional collaboration	Steering committee with center representation	Define leadership, decision rules, and distribution of credit
Funding	Sustaining long-term collaboration	Central philanthropic support for center-specific projects	Ensure management and infrastructure funding, beyond individual projects
Data sharing	Privacy, ownership, regulation	Targeted data-sharing pipelines	Consider the benefits and limitations of individualization vs joint cohort inception
Multidisciplinary team	Different local resources	Dietitians, nurses, psychologists, and surgeons integrated variably	Build around available strengths, not identical models
Standardization	Heterogeneous definitions, protocols, and approaches	Ongoing discussion, refinement of operating procedures	Standardize approaches, outcomes, and measurable milestones
Implementation	Evidence does not automatically change care	Local implementation, national-level discussions, reimbursement advocacy	Progress from evidence generation to measuring implementation as a trajectory of impact
Sustainability	Personnel turnover	Consortium management coordinators; joint scientific meetings	Create continuity and “consortium organizational memory”
Failures and limitations	Some projects may not become multicenter	Selective collaboration	Not all projects necessitate full-network activation

IBD, inflammatory bowel disease; IIRN, Israeli IBD Research Nucleus.