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THE IMPACT OF ETRASIMOD ON THE TRANSCRIPTOME IN COLON BIOPSIES USING RNA-SEQ: DATA FROM ELEVATE UC 52 AND ELEVATE UC 12 PHASE 3 CLINICAL TRIALS

Britta Siegmund 1,2, Rathi D Ryan 3, Catherine M. Crosby 4, Maria T. Abreu 5, Severine Vermeire 6, Iris Dotan 7,8, Keren M Rabinowitz 7,9, Xiang Guo 10, H Kiyomi Komori 11, Martina Goetsch 12, John C. Woolcott 10, Silvio Danese 13

Affiliations

1 Charité – Universitätsmedizin Berlin, Berlin, Germany

2 Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

3 Pfizer Inc, South San Francisco, United States

4 Pfizer Inc, La Jolla, San Diego, United States

5 University of Miami Miller School of Medicine, Miami, United States

6 University Hospitals Leuven, Leuven, Belgium

7 Rabin Medical Center, Petah Tikva, Israel

8 Tel Aviv University, Faculty of Medical and Health Sciences, Tel Aviv, Israel

9 Felsentstein Medical Research Centre, Medical and Health Sciences, Tel Aviv, Israel

10 Pfizer Inc, Collegeville, United States

11 Formerly Arena Pharmaceuticals, a wholly-owned subsidiary of Pfizer Inc, New York, United States

12 Pfizer AG, Zürich, Switzerland

13 IRCCS San Raffaele Hospital and Vita Salute San Raffaele University, Milan, Italy

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Abstract

Introduction

Etrasimod is an oral, once-daily (QD), selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). S1P₁ receptor modulation is believed to reversibly sequester lymphocytes¹; its impact on UC intestinal tissue is unknown.

Aims & Methods

We characterised the impact of etrasimod in inflamed colonic biopsy tissue using ribonucleic acid sequencing (RNA-seq) to examine transcriptional-level impacts on disease, in terms of mucosal barrier inflammatory pathways and immune cell populations. In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (pts) aged 16–80 years with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg QD or placebo (PBO). Etrasimod treatment effects were characterised by RNA-seq at Week 12 vs baseline (both trials), and in responders achieving clinical remission vs nonresponders. CytoPro (CytoReason) was used for colon-specific cell type deconvolution analysis and single sample Geneset Enrichment Analysis was used for pathway analysis.

Results

At baseline in ELEVATE UC 52/ELEVATE UC 12, colon biopsy samples were available for 245/166 pts receiving etrasimod and 114/84 pts receiving PBO. There were significant reductions in T cell subsets (CD4+, CD8+, helper [Th]1 and Th17), plasma/mature B cell subsets and innate immune cell subsets (monocytes, macrophages, dendritic cells and natural killer cells) in the colon of pts receiving etrasimod (false discovery rate [FDR] < 0.05]); significant changes were not seen among pts receiving PBO. There were also reductions in inflammatory fibroblasts and increases in epithelial cells in the colon of pts receiving etrasimod but not PBO. The change in immune cell populations for responders vs nonresponders at Week 12 was similar to that for etrasimod Week 12 vs baseline. At Week 12, several inflammatory pathways were reduced in responders vs nonresponders to etrasimod; IL-17 signalling was among the most affected (both trials). Nonimmune pathways related to mucosal healing were significantly increased in Week 12 responders.

Conclusion

Decreases in activated immune cell subset and inflammatory signalling pathway changes in responders to etrasimod suggest reductions in local inflammation may contribute to remission and mucosal healing. RNA-seq with cell type deconvolution and pathway analysis contributes to the understanding of etrasimod’s mechanism of action.

References

Scott FL et al. Br J Pharmacol 2016; 173: 1778–1792.

Disclosure

BS has received lecture fees from AbbVie, CED Service GmbH, Chiesi, Dr. Falk, Forga Software, Galapagos, IBD Passport, Janssen, Materia Prima, Pfizer Inc and Lilly; consultancy fees from AbbVie, Arena Pharma, Boehringer Ingelheim, BMS, Celgene, CT-Scout, Endpoint Health, Galpagos, Gilead Sciences, Janssen, Landos, Lilly, Pfizer Inc, PredictImmune and PsiCro. RDR is an employee of and holds stock options with Pfizer Inc. CMC, XG and JCW are employees and shareholders of Pfizer Inc. MTA has received consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celsius, Eli Lilly, Gilead, Janssen, Microba Life Sciences, Pfizer, Prometheus, Prometheus Bioscience, Takeda and UCB Biopharma. SV has received lecture/speaker fees from AbbVie, Dr. Falk Pharma, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda and Tillotts; consultancy/advisory fees from AbbVie, AbolerIS Pharma, Alimentiv, Arena , AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillots Pharma AG and Zealand Pharma; grant/research support from AbbVie, MSD, Pfizer Inc, Galapagos, Janssen and Takeda. ID has received consultancy fees, research grants or honoraria from Abbott, AbbVie, Altman, Arena, Athos, Cambridge Healthcare, Celgene/BMS, Celltrion, Falk Pharma, DSM, Ferring, Food Industries Organisation, Galapagos, Genentech/Roche, Gilead, GSK, Hospital for Sick Children, Integra Holdings, Iterative Scopes, Janssen, Mediahuset, Medscape, Neopharm, Nestle, Peer voice, Pfizer, Rafa Laboratories, Sangamo, Sublimity, Takeda, Wilbio. KMR has received grant/research support from Bristol Myers Squibb. HKK has received consultancy fees from Kinevant Sciences and is an employee/shareholder for Uniquity Bio. MG is an employee and shareholder of Pfizer AG. SD has received lecture/speaker fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer and Takeda; consultancy/advisory fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead Sciences, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer Inc, Roche, Sandoz, Takeda, TiGenix, UCB, and Vifor; holds directorship/ownership for Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele.

Conference

UEG Week Vienna 2024

Topics

IBD

Submission format

Abstract

Session

IBD (Posters)

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

More Like This:

INTEGRATING MUCOSAL TRANSCRIPTOMIC AND MICROBIAL SIGNATURES TO DEFINE COMPREHENSIVE DISEASE CONTROL IN ULCERATIVE COLITIS AT MOLECULAR RESOLUTION

Philip Rosenstiel

EFFICACY AND SAFETY OF DUVAKITUG MAINTENANCE THERAPY IN PATIENTS WITH CROHN’S DISEASE (CD): RESULTS FROM THE PHASE 2B RELIEVE UCCD LONG-TERM EXTENSION STUDY

Walter Reinisch

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

TOWARD PRECISION THERAPY IN ULCERATIVE COLITIS: GENOTYPE-BASED SINGLE-NUCLEOTIDE POLYMORPHISM (SNPS) SIGNATURES PREDICT DEEP RESPONSE TO USTEKINUMAB - A POST-HOC ANALYSIS OF THE UNIFI TRIAL

Subrata Ghosh

AI-DRIVEN PROBE CONFOCAL LASER ENDOMICROSCOPY ENABLES AUTOMATED ASSESSMENT OF INTESTINAL BARRIER IMPAIRMENT IN IBD

Valery Naranjo

DEFINING THE CELLULAR GUT MUCOSAL ORIGINS OF PRECLINICAL CIRCULATING PROTEIN SIGNATURES IN INFLAMMATORY BOWEL DISEASE

E.A.M. (Noortje) Festen

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INTEGRATING MUCOSAL TRANSCRIPTOMIC AND MICROBIAL SIGNATURES TO DEFINE COMPREHENSIVE DISEASE CONTROL IN ULCERATIVE COLITIS AT MOLECULAR RESOLUTION

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INTEGRATING MUCOSAL TRANSCRIPTOMIC AND MICROBIAL SIGNATURES TO DEFINE COMPREHENSIVE DISEASE CONTROL IN ULCERATIVE COLITIS AT MOLECULAR RESOLUTION

Finn Hinrichsen 1,2, Joana P. Bernardes 1, Víctor A. López-Agudelo 1, Neha Mishra 1, Lina Wehkamp 1,2, Florian Tran 1,2, Konrad Aden 1,2, Stefan Schreiber 1,2, Philip Rosenstiel 1,2

Affiliations

1 University Hospital Schleswig-Holstein UKSH, Kiel, Kiel, Germany

2 University Hospital Schleswig-Holstein UKSH, Campus Kiel, Kiel, Germany

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Abstract

Introduction

In the last decennary treatment goals in ulcerative colitis (UC) have progressed beyond simple symptom relief toward achieving deeper, multidimensional forms of remission. This evolution has led to a critical re-evaluation of traditional single endpoints in accurately reflecting disease activity and therapeutic response. A recent Delphi consensus introduced the concept of comprehensive disease control (CDC) in UC, by integrating clinical, endoscopic, and patient-reported outcomes to characterize a state of true disease quiescence. We proposed that this stringent combination of endpoints might correspond to a distinct molecular signature indicating minimal residual inflammation. To test this, we analyzed mRNA and mucosa-associated microbiota signatures in a cohort of UC patients across different remission states.

Aims & Methods

A total of 211 colonic biopsies were obtained from 173 UC patients at Kiel University Hospital between 2010 and 2020. Bulk mRNA sequencing and mucosal 16S rRNA profiling were conducted. Patients were classified according to established remission domains: Biomarker Remission: CRP < 5mg/dL and leukocytes 2.5-9/nL; Clinical Remission: Partial Mayo Score 0-1; Histological Remission: Nancy Index 0-1; Endoscopic Remission: Endoscopic Mayo Score 0. Individuals meeting all 4 criteria were designated as achieving CDC. To identify molecular features predictive of CDC, we applied an iterative random forest model using an 80% training and 20% testing split.

Results

Microbial and transcriptomic profiles mirrored inflammation gradients. Analyses revealed overlapping but distinct signatures across remission domains, exemplified by enrichment of Dorea formicigenerans in endoscopic, histological, and clinical -but not biomarker- remission. None of the 31 CDC patients CDC required IBD-related hospitalization or surgery over 2 years, highlighting CDC as a clinically meaningful state of profound disease inactivity. Linear mixed modeling showed differential abundance of IBD-associated taxa Lachnoclostridium and Lachnospiraceae FC020 in CDC. Transcriptomic profiling revealed a molecular gradient between CDC and non-CDC patients, with enrichment of fatty acid metabolism and suppression of immune programs. A random forest classifier identified 19 transcriptomic markers predictive of CDC (AUC 0.856), including known IBD-associated genes (CXCL1, KRT7, SLC6A14, ESRRA, FGFR3, ITPKA) and novel markers (ATP5PBP8, CHPT1, CPVL-AS2, CTDSPL, GRIK2, MAZ, MCM9, MED7, RIMKLA, RND1, TIGD5, TMEM115, ZDHHC23).

Conclusion

CDC reflects a biologically profound state of disease quiescence in UC, extending to both the molecular and microbial landscape of the intestinal mucosa. The observed molecular gradient suggests a continuum of mucosal healing and highlights the potential for objective biomarkers capable of quantifying minimal residual disease activity. Importantly, such molecular signatures might help identify patients with low disease activity who are in a molecularly inactive state of disease, even if they do not fulfill all Comprehensive Disease Control criteria. External validation of this molecular signature will determine its prognostic value for long-term clinical outcomes.

Disclosure

Hinrichsen, Finn: Received travel support from Pfizer.
P. Bernardes, Joana: I have no conflict of interest to declare
Lopez Agudelo, Victor Alonso: No conflicts
Mishra, Neha: none
Welz, Lina: Received support from Celltrion for independent reporting from scientific congresses.
Tran, Florian: Grant: Sanofi/Regeneron Personal Fees: Speaker’s fees: Abbvie, Bristol-Myers-Squibb, Celltrion Healthcare, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, J & J, Sanofi, Takeda Consulting honoraria: AbbVie, J & J, Takeda Non-financial Support: Sanofi for statistical analysis
Aden, Konrad: Personal Fees: Lecture fee: Takeda, Janssen, Lilly, Abbvie
Consulting fee: Takeda, Jannsen, Lilly, Guidepoint
Schreiber, Stefan Wolfgang: Personal Fees: AbbVie, Alfasigma, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Celltrion, Falk, Ferring, Fresenius Kabi, Galapagos, Gilead, IMAB, Janssen, Lilly, MSD, Mylan, Novartis, Pfizer, Protagonist, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance
Rosenstiel, Philip: stock ownership Gerion

Event

UEG Week Barcelona 2026

Topics

Mechanisms & Personalised Medicine Immunology IBD

Submission format

Abstract

Session

Immunologic pathways of disease and drug response in IBD

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

More Like This:

INTEGRATING MUCOSAL TRANSCRIPTOMIC AND MICROBIAL SIGNATURES TO DEFINE COMPREHENSIVE DISEASE CONTROL IN ULCERATIVE COLITIS AT MOLECULAR RESOLUTION

Philip Rosenstiel

EFFICACY AND SAFETY OF DUVAKITUG MAINTENANCE THERAPY IN PATIENTS WITH CROHN’S DISEASE (CD): RESULTS FROM THE PHASE 2B RELIEVE UCCD LONG-TERM EXTENSION STUDY

Walter Reinisch

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

TOWARD PRECISION THERAPY IN ULCERATIVE COLITIS: GENOTYPE-BASED SINGLE-NUCLEOTIDE POLYMORPHISM (SNPS) SIGNATURES PREDICT DEEP RESPONSE TO USTEKINUMAB - A POST-HOC ANALYSIS OF THE UNIFI TRIAL

Subrata Ghosh

AI-DRIVEN PROBE CONFOCAL LASER ENDOMICROSCOPY ENABLES AUTOMATED ASSESSMENT OF INTESTINAL BARRIER IMPAIRMENT IN IBD

Valery Naranjo

DEFINING THE CELLULAR GUT MUCOSAL ORIGINS OF PRECLINICAL CIRCULATING PROTEIN SIGNATURES IN INFLAMMATORY BOWEL DISEASE

E.A.M. (Noortje) Festen

UEG Presentation

New

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EFFICACY AND SAFETY OF DUVAKITUG MAINTENANCE THERAPY IN PATIENTS WITH CROHN’S DISEASE (CD): RESULTS FROM THE PHASE 2B RELIEVE UCCD LONG-TERM EXTENSION STUDY

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EFFICACY AND SAFETY OF DUVAKITUG MAINTENANCE THERAPY IN PATIENTS WITH CROHN’S DISEASE (CD): RESULTS FROM THE PHASE 2B RELIEVE UCCD LONG-TERM EXTENSION STUDY

Vipul Jairath 1, Alessandro Armuzzi 2,3, Silvio Danese 4, Bruce E. Sands 5, Bogdan Ratiu-Duma 6, Phillip Levine 7, Rajendra Singh 8, Nicholas Gross 8, Ken Abrams 9, Walter Reinisch 10

Affiliations

1 Department of Medicine, Schulich School of Medicine & Dentistry I Western University, Room A10-219, University Hospital, London, Canada

2 Department of Biomedical Sciences, Humanitas University, Milan, Italy

3 IBD Center, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy

4 IRCCS Ospedale San Raffaele - University Vita-Salute, Milan, Italy

5 Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, United States

6 Teva Pharmaceuticals S.R.L, Bucharest, Romania

7 Sanofi, Cambridge, United States

8 Teva Branded Pharmaceutical Products R&D, Inc., West Chester, United States

9 Teva Branded Pharmaceutical Products R&D LLC., Parsippany, United States

10 Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

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Abstract

Introduction

Duvakitug is an anti-TL1A monoclonal antibody selected for its preferential inhibition of TL1A-DR3 signaling over DcR3 binding.¹ In the RELIEVE UCCD phase 2b induction study, duvakitug demonstrated significant evidence for endoscopic response vs placebo in patients with moderately to severely active CD at week 14.² Efficacy, safety and tolerability of duvakitug in patients who continued into the 44-week maintenance phase of the RELIEVE UCCD long-term extension (LTE) study are presented here.

Aims & Methods

This was a phase 2b, randomized, double-blind study without placebo control. Patients were eligible to enter the maintenance phase if they achieved clinical remission/response (CDAI) after 14 weeks of induction treatment, at which point they were re-randomized 1:1 to receive subcutaneous duvakitug 450 mg or 900 mg every 4 weeks. Efficacy analysis included duvakitug-treated patients who entered directly into the maintenance phase (total exposure of 58 weeks). The safety analysis included all patients who received ≥1 dose of duvakitug during the maintenance phase. Maintenance outcomes were assessed at week 44. The primary efficacy endpoint was endoscopic response (SES-CD). Secondary efficacy endpoints included clinical response and remission (CDAI). Safety and tolerability were assessed by adverse event (AE) reporting and laboratory monitoring.

Results

The CD efficacy analysis set included 58 patients (27 [450 mg]; 31 [900 mg]); the safety analysis set included 103 patients (50 [450 mg]; 53 [900 mg]). Demographics and baseline characteristics were generally similar between dose groups. At week 44, endoscopic response was achieved by 41% (450 mg) and 55% (900 mg) of patients receiving duvakitug (Table). High rates of clinical response and remission were observed in patients receiving 450 mg and 900 mg (Table). Treatment-emergent AEs occurred in 35 (70%) of patients receiving 450 mg and 41 (77%) receiving 900 mg. Most AEs were mild to moderate in severity, and the most common were upper respiratory infections. AEs leading to discontinuation occurred in 3 (6%) patients in each dose group.

Conclusion

Duvakitug maintenance therapy demonstrated high rates of endoscopic response and clinical response and remission at week 44 (total exposure of 58 weeks) in patients with moderately to severely active CD who had responded to duvakitug induction therapy. Duvakitug appeared to demonstrate a dose response. No new safety concerns observed. These findings support duvakitug maintenance therapy as a potentially effective and durable treatment option for patients with CD, which is being further evaluated in phase 3.

Table: Endoscopic and clinical outcomes following duvakitug treatment (week 14 of induction and week 44 of maintenance phase)
	*Week 14 induction¹*		Week 44 maintenance (58 weeks’ exposure)
	*Duvakitug 450mg* *q2w* *N=46*	*Duvakitug 900mg* *q2w* *N=46*	Duvakitug 450mg q4w N=27	Duvakitug 900mg q4w N=31
Primary endpoint: Endoscopic response, n (%)	12 (26)	22 (48)	11 (41) [95% CI: 25, 62]	17 (55) [95% CI: 39, 75]
Secondary endpoints:
Clinical remission (CDAI), n (%)	23 (50)	25 (54)	22 (81) [95% CI: 65, 95]	26 (84) [95% CI: 68, 96]
Clinical response (CDAI), n (%)	28 (61)	28 (62)*	22 (81) [95% CI: 63, 94]	27 (87) [95% CI: 70, 96]
Endoscopic response defined as ≥50% improvement in SES-CD; clinical remission defined as CDAI score <150; clinical response defined as ≥100 point decrease from baseline in CDAI score. CI, confidence interval. *n=45. 1. Jairath et al. J Crohns Colitis 2025;19:i77–8;doi: 10.1093/ecco-jcc/jjae190.0039A.

References

Clarke et al. MAbs 2018;10:664–77; doi: 10.1080/19420862.2018.1440164.
Jairath et al. J Crohn's Colitis 2025;19:i77–8; doi: 10.1093/ecco-jcc/jjae190.0039A.

Disclosure

Duvakitug is being developed in partnership by Teva and Sanofi.
VJ: consulting/advisory board fees from Abbvie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, AstraZeneca, Attovia, Blackbird Labs, BMS, Boehringer Ingleheim, Biomebank, Cabaletta, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Equillium Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Janssen, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Palisade Bio, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Throne Scientific, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma; payment for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Pfizer, Takeda, Tillotts; and participation on Data Safety Monitoring Board or Advisory Board for Abbvie, Takeda, Janssen, Fresenius Kabi, Gilead, Roche.
AA: Consulting fees: AbbVie, Abivax, Alfa Sigma, Astra Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Eli Lilly, Enthera, Ferring, Galapagos, Gilead, Giuliani, Johnson & Johnson, Lionhealth, MSD, Nestlé, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sanofi, Sandoz, Takeda, Teva Pharmaceuticals, and Tillots Pharma; Speaker’s fees: AbbVie, Abivax, AG Pharma, Alfa Sigma, Biogen, Bristol-Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Johnson & Johnson, Lionhealth, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Teva Pharmaceuticals; Research support: Biogen, MSD, Takeda, Pfizer; non-financial support: AbbVie, Johnson & Johnson, MSD, Pfizer, Takeda.
SD: consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor; and lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, Takeda.
BES: reports consulting fees from AbbVie, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Celltrion, Ensho Therapeutics, Enthera, Enveda Biosciences, Equillium, Evommune, Ferring, Fzata, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Immunyx Therapeutics, Index Pharmaceuticals, Innovation Pharmaceuticals, Kaleido, Kallyope, Merck & Co., Microba, Microbiotica, Mitsubishi Tanabe Pharma, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Palisade Bio, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biotherapeutics, Sanofi, Sorriso Pharmaceuticals, Surrozen, Target RWE, Teva, TLL Pharmaceutical, TR1X, Union Therapeutics; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees, and other support from Bristol Myers Squibb, Janssen/J & J Innovative Medicine, Pfizer, Takeda; research grants and consulting fees from Theravance Biopharma; and consulting fees, stock, and stock options from Ventyx Biopharma.
BR-D, RS, NG, KA: Teva employees.
PL: employee of Sanofi – may hold stock and/or stock options in the company.
WR: served as speaker for AbbVie, Celltrion, Ferring, Galapagos, Janssen, Merck Sharp & Dohme, Pfizer, Roche, Sobi, Takeda; as a consultant for AbbVie, Amgen, AOP Orphan, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead, Index Pharma, Janssen, Medahead, Microbiotica, Pfizer, Takeda, Teva; served as an advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Janssen, Pfizer, Teva; and has received research funding from AbbVie, Janssen, Sandoz, Sanofi, Takeda.

Event

UEG Week Barcelona 2026

Topics

Mechanisms & Personalised Medicine IBD

Submission format

Abstract

Session

Looking into the future: Novel therapeutics in IBD (Part 2)

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

More Like This:

INTEGRATING MUCOSAL TRANSCRIPTOMIC AND MICROBIAL SIGNATURES TO DEFINE COMPREHENSIVE DISEASE CONTROL IN ULCERATIVE COLITIS AT MOLECULAR RESOLUTION

Philip Rosenstiel

EFFICACY AND SAFETY OF DUVAKITUG MAINTENANCE THERAPY IN PATIENTS WITH CROHN’S DISEASE (CD): RESULTS FROM THE PHASE 2B RELIEVE UCCD LONG-TERM EXTENSION STUDY

Walter Reinisch

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

TOWARD PRECISION THERAPY IN ULCERATIVE COLITIS: GENOTYPE-BASED SINGLE-NUCLEOTIDE POLYMORPHISM (SNPS) SIGNATURES PREDICT DEEP RESPONSE TO USTEKINUMAB - A POST-HOC ANALYSIS OF THE UNIFI TRIAL

Subrata Ghosh

AI-DRIVEN PROBE CONFOCAL LASER ENDOMICROSCOPY ENABLES AUTOMATED ASSESSMENT OF INTESTINAL BARRIER IMPAIRMENT IN IBD

Valery Naranjo

DEFINING THE CELLULAR GUT MUCOSAL ORIGINS OF PRECLINICAL CIRCULATING PROTEIN SIGNATURES IN INFLAMMATORY BOWEL DISEASE

E.A.M. (Noortje) Festen

UEG Presentation

New

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BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

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BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

E.A.M. (Noortje) Festen 1, Paola Pibiri 2, Roy Oelen 2, Werna T. C. Uniken Venema 3, Emilia Bigaeva 1, Monique G.P. Van der Wijst 2, Maria Paraskevopoulou 4, Klaas Nico Faber 2

Affiliations

1 UMCG, Groningen, Netherlands

2 University Medical Center Groningen, Groningen, Netherlands

3 Zuyderland Medisch Centrum, Leuven, Belgium

4 Takeda Pharmaceuticals, Acton, United States

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Abstract

Introduction

Ulcerative colitis (UC) and Crohn’s disease (CD) share chronic intestinal inflammation but differ in clinical behavior and treatment response. Although single-cell RNA sequencing (scRNA-seq) studies have advanced understanding of IBD biology, limited sample sizes have hindered robust comparison of shared versus disease-specific mechanisms. We therefore performed a large-scale meta-analysis of gut mucosal scRNA-seq datasets to define common inflammatory architecture and divergent immune programs in UC and CD.

Aims & Methods

Gut mucosal scRNA-seq datasets from two CD and two UC cohorts were integrated using a standardized computational workflow for preprocessing, harmonization, and downstream analysis. Cell-type annotation, differential abundance and gene expression analyses, pathway enrichment, and cell–cell communication inference were performed to compare inflamed and non-inflamed tissue within each disease and identify shared versus disease-specific programs.

Results

We generated disease-specific atlases comprising more than 405,000 cells from approximately 190 patients with CD and 313,000 cells from approximately 72 patients with UC. Across both diseases, inflammation followed a shared remodeling program marked by epithelial cell loss, expansion of immune populations, and activation of immune-related pathways. Despite this common inflammatory framework, immune execution diverged by disease. In CD, CD8+ T cells declined in inflamed tissue, whereas in UC they expanded together with other immune subsets. B cells showed a similar contrast, with enrichment of innate and stress-response pathways in CD versus adaptive and humoral immune programs in UC. Monocytes added further specificity, with strong enrichment of JAK-STAT signaling observed only in UC. Consistently, cell-cell communication analysis indicated stronger adaptive immune interactions in UC than in CD.

Conclusion

UC and CD share a common inflammation-associated tissue remodeling program, but diverge in the immune pathways and cellular interactions that dominate the inflamed mucosa. These findings provide a systems-level framework for understanding IBD heterogeneity and may help prioritize phenotype-specific therapeutic targets.

References

1. Martin, J. C. et al. Single-Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy. Cell 178, 1493-1508.e20 (2019).
2. Smillie, C. S. et al. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 178, 714-730.e22 (2019).
3. Jaeger, N. et al. Single-cell analyses of Crohn’s disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions. Nat. Commun. 12, 1921 (2021).
4. Calviño-Suárez, C. et al. Exploration of JAK/STAT pathway activation in ulcerative colitis reveals sex-dependent activation of JAK2/STAT3 in the inflammatory response. Front. Immunol. 16, 1609740 (2025).

Event

UEG Week Barcelona 2026

Topics

Gut Microbiota Mechanisms & Personalised Medicine Immunology IBD

Submission format

Abstract

Session

New insights into IBD mechanisms

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

More Like This:

INTEGRATING MUCOSAL TRANSCRIPTOMIC AND MICROBIAL SIGNATURES TO DEFINE COMPREHENSIVE DISEASE CONTROL IN ULCERATIVE COLITIS AT MOLECULAR RESOLUTION

Philip Rosenstiel

EFFICACY AND SAFETY OF DUVAKITUG MAINTENANCE THERAPY IN PATIENTS WITH CROHN’S DISEASE (CD): RESULTS FROM THE PHASE 2B RELIEVE UCCD LONG-TERM EXTENSION STUDY

Walter Reinisch

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

TOWARD PRECISION THERAPY IN ULCERATIVE COLITIS: GENOTYPE-BASED SINGLE-NUCLEOTIDE POLYMORPHISM (SNPS) SIGNATURES PREDICT DEEP RESPONSE TO USTEKINUMAB - A POST-HOC ANALYSIS OF THE UNIFI TRIAL

Subrata Ghosh

AI-DRIVEN PROBE CONFOCAL LASER ENDOMICROSCOPY ENABLES AUTOMATED ASSESSMENT OF INTESTINAL BARRIER IMPAIRMENT IN IBD

Valery Naranjo

DEFINING THE CELLULAR GUT MUCOSAL ORIGINS OF PRECLINICAL CIRCULATING PROTEIN SIGNATURES IN INFLAMMATORY BOWEL DISEASE

E.A.M. (Noortje) Festen

UEG Presentation

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TOWARD PRECISION THERAPY IN ULCERATIVE COLITIS: GENOTYPE-BASED SINGLE-NUCLEOTIDE POLYMORPHISM (SNPS) SIGNATURES PREDICT DEEP RESPONSE TO USTEKINUMAB - A POST-HOC ANALYSIS OF THE UNIFI TRIAL

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TOWARD PRECISION THERAPY IN ULCERATIVE COLITIS: GENOTYPE-BASED SINGLE-NUCLEOTIDE POLYMORPHISM (SNPS) SIGNATURES PREDICT DEEP RESPONSE TO USTEKINUMAB - A POST-HOC ANALYSIS OF THE UNIFI TRIAL

Marietta Iacucci 1, Santanu Das 1, Irene Zammarchi 1, Cecilia Lina Pugliano 1, Subrata Ghosh 1

Affiliations

1 University College Cork, Cork, Ireland

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Abstract

Introduction

Despite advances in treat-to-target strategies, a substantial proportion of ulcerative colitis (UC) patients fail to achieve endoscopic and histological remission [1]. This gap reflects the complex biological heterogeneity underlying UC pathogenesis and the limitations of current one-size-fits-all treatment algorithms. The absence of validated biomarkers predicting response to biologic therapy remains a major barrier to precision treatment selection. Pharmacogenetic studies captured by SNPs may help explain inter-individual heterogeneity in therapeutic response [2,3]. We aimed to identify SNPs signatures predictive of response to Ustekinumab in patients with moderate-to-severe UC enrolled in the Phase 3 UNIFI clinical trial [4].

Aims & Methods

Genome-wide data from 654 participants with moderate-to-severe UC were processed and analysed using PLINK v1.9 [5]. The binary genotype files generated were subjected to standard quality control (QC) parameters, including sample call rate filtering followed by variant call, minor allele frequency (MAF), and Hardy-Weinberg equilibrium (HWE) filtering. Genome-wide association analyses (GWAS) evaluated SNPs associated with Clinical remission (Mayo ≤2), endoscopic improvement and remission (Mayo endoscopic score [MES] 1 and 0, respectively), histological improvement and remission (Geboes score <3.1 and <2B.0, respectively), and mucosal healing (endoscopic and histological remission) at maintenance week 44. A multimodal logistic regression model, adjusted for relevant covariates, was applied. The threshold for identifying Single Nucleotide Polymorphism (SNP) was considered at 1 X 10^-5(suggestive threshold) for further downstream interpretations.

Results

QC filtered data generated a total of 1,528,830 variants retained for downstream analyses with an overall genotype rate of 0.9993. Table 1 summarise the identified SNPs with corresponding therapeutic outcomes. GWAS analysis with treatment response phenotypes demonstrated associations with 41 SNPs (9 protective, 32 risk‑increasing) for clinical remission, 25 SNPs for endoscopic improvement (23 protective, 2 risk‑increasing), and 5 protective SNPs for histological improvement. Additionally, SNPs signatures were associated with endoscopic remission (10 SNPs; 8 protective, 2 risk‑increasing), histological remission (4 risk‑increasing SNPs), and mucosal healing (14 SNPs; 8 protective, 6 risk‑increasing). Notably, several loci mapped to immune regulatory genes, including RGS1 and IL7R [6], suggesting a mechanistic link between host immunogenetic variation and response to IL-12/23 pathway inhibition.

Table 1: Summary of therapeutic outcomes with corresponding identified SNPs

Therapeutic outcomes	N of patients	N of associated SNPs	Genes involved in SNPs	Biological Significance
Clinical remission (Mayo ≤2)	344 (52.92%)	41 (9 protective, 32 risk-increasing)	RGS1, HLA‑DQA1 region, MAPT locus, IL7R, FHIT	Immune system regulation (T cell activation, lymphocyte trafficking), DNA damage response and epithelial integrity, microtubule stability
Endoscopic improvement (MES 1)	216 (33.23%)	25 (23 protective and 2 risk increasing)	RGS1 and genes of unknown functions	Immune system regulation (lymphocyte trafficking)
Histological improvement (Geboes < 3.1)	237 (36.46%)	5 (all protective)	RGS1	Immune system regulation (lymphocyte trafficking)
Endoscopic remission (MES 0)	123 (18.92 %)	10 (8 protective 2 risk-increasing)	MAPT locus, RGS1, C12orf65, SLC4A10	Immune system regulation (T cell activation, lymphocyte trafficking, microtubule stability, regulatory function)
Histological remission (Geboes < 2B.0)	194 (29.84%)	4 (all risk increasing)	RGS1, FHIT, Il7R	Immune system regulation (T cell activation, lymphocyte trafficking), microtubule stability, DNA damage response and epithelial integrity
Mucosal healing (endoscopic and histological remission)	102 (15.69 %)	14 (8 protective 6 risk-increasing)	MAPT locus, RGS1, C12orf65, SLC4A10, FHIT, Il7R	Immune system regulation (T cell activation, lymphocyte trafficking), microtubule stability, DNA damage response and epithelial integrity, regulatory function

Conclusion

Genome-wide SNPs signatures identify patients more likely to achieve a deep response to Ustekinumab, supporting the feasibility of genetically guided biologic selection in UC. These findings represent a step towards precision therapy in IBD. Further integration with multi-Omics data is ongoing to refine this predictive framework.

References

[1] Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology. 2021;160(5):1570-1583. doi:10.1053/j.gastro.2020.12.031
[2] Plaza J, Mínguez A, Bastida G, et al. Genetic Variants Associated with Biological Treatment Response in Inflammatory Bowel Disease: A Systematic Review. Int J Mol Sci. 2024;25(7):3717. 2024. doi:10.3390/ijms25073717
[3] van der Werf J, Fleming NI. Are single nucleotide polymorphisms underutilized for guiding treatment of inflammatory bowel disease?. Immunol Cell Biol. 2025;103(6):551-562. doi:10.1111/imcb.70029
[4] Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2019;381(13):1201-1214. doi:10.1056/NEJMoa1900750
[5] Chang C. C., Chow C. C., Tellier L. C., et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015; 4(1), s13742-015.
[6] Fercoq F. & Carlin L. M. “Mind the GAP”: RGS1 hinders antitumor lymphocytes. Nature Immunology. 2021; 22(7), 802-804.

Event

UEG Week Barcelona 2026

Topics

Gut Microbiota Mechanisms & Personalised Medicine IBD

Submission format

Abstract

Session

One patient, multiple futures: Predicting outcomes in IBD

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

More Like This:

INTEGRATING MUCOSAL TRANSCRIPTOMIC AND MICROBIAL SIGNATURES TO DEFINE COMPREHENSIVE DISEASE CONTROL IN ULCERATIVE COLITIS AT MOLECULAR RESOLUTION

Philip Rosenstiel

EFFICACY AND SAFETY OF DUVAKITUG MAINTENANCE THERAPY IN PATIENTS WITH CROHN’S DISEASE (CD): RESULTS FROM THE PHASE 2B RELIEVE UCCD LONG-TERM EXTENSION STUDY

Walter Reinisch

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

TOWARD PRECISION THERAPY IN ULCERATIVE COLITIS: GENOTYPE-BASED SINGLE-NUCLEOTIDE POLYMORPHISM (SNPS) SIGNATURES PREDICT DEEP RESPONSE TO USTEKINUMAB - A POST-HOC ANALYSIS OF THE UNIFI TRIAL

Subrata Ghosh

AI-DRIVEN PROBE CONFOCAL LASER ENDOMICROSCOPY ENABLES AUTOMATED ASSESSMENT OF INTESTINAL BARRIER IMPAIRMENT IN IBD

Valery Naranjo

DEFINING THE CELLULAR GUT MUCOSAL ORIGINS OF PRECLINICAL CIRCULATING PROTEIN SIGNATURES IN INFLAMMATORY BOWEL DISEASE

E.A.M. (Noortje) Festen

UEG Presentation

New

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AI-DRIVEN PROBE CONFOCAL LASER ENDOMICROSCOPY ENABLES AUTOMATED ASSESSMENT OF INTESTINAL BARRIER IMPAIRMENT IN IBD

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AI-DRIVEN PROBE CONFOCAL LASER ENDOMICROSCOPY ENABLES AUTOMATED ASSESSMENT OF INTESTINAL BARRIER IMPAIRMENT IN IBD

Marietta Iacucci 1,2, Irene Zammarchi 1, Ilan Carretero 3, Pablo Meseguer 3, Cecilia Lina Pugliano 1, Giovanni Santacroce 1, Rocio Del Amor 3,4, Ujwala Chaudhari 5, Bisi Bode Kolawole 5, Rory Crotty 6, Brian Hayes 6, Subrata Ghosh 1, Enrico Grisan 5, Valery Naranjo 3,4

Affiliations

1 University College Cork, Cork, Ireland

2 University of Calgary, Calgary, Canada

3 Universitat Politècnica de València, Valencia, Spain

4 Artikode Intelligence S.L., Valencia, Spain

5 London South Bank University, London, United Kingdom

6 Cork University Hospital, Cork, Ireland

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Abstract

Introduction

Barrier healing is emerging as a key therapeutic target in Inflammatory bowel disease (IBD), and is increasingly associated with improved long-term outcomes than endoscopic and histological remission alone. However, objective and reproducible assessment of barrier integrity remains challenging. Probe-based confocal laser endomicroscopy (pCLE) enables real-time structural and functional assessment of epithelial and vascular barrier features, including villi and crypt architecture, goblet cells, fluorescein leakage and vessel architecture. However, its interpretation remains complex and highly operator-dependent, limiting reproducibility and widespread application. ¹. We aimed to develop and validate an artificial intelligence (AI)-driven pCLE system for automated standardised assessment of epithelial and vascular barrier impairment (BI) in IBD.

Aims & Methods

A total of 297 high-quality pCLE videos from IBD patients undergoing colonoscopy in two tertiary centers (University College Cork, Ireland and University of Calgary, Canada) were considered. Experienced endoscopists assessed the presence of overall barrier and feature-specific impairment according to a previously developed pCLE-scoring system ², providing a reference standard for AI. 196 videos from the Calgary cohort were used to train and validate the framework (using cross-validation) and 101 videos from the Cork cohort were considered for external validation.
An AI algorithm was developed to predict pCLE-based overall- and feature-level BI using a weakly supervised learning paradigm that exclusively employs video-level scoring. First, frame-level representations were extracted with a DINOv2 foundation model³. Later, a multiple instance learning (MIL) model aggregates frame-features into a global representation to produce the predicted score of the video⁴. The model’s diagnostic performance to predict overall, epithelial, vascular and feature-level impairment was evaluated.

Results

Overall, 297 videos from 141 IBD patients were considered. BI was detected in 187/297 (63.0%) videos, including 68/101 (67.3%) in Cork and 119/196 (60.7%) in the Calgary cohort.
Table 1 details the diagnostic performance of the model. The AI algorithm achieved remarkable performance in both the development and validation cohorts, with 71.4% (95% 63.3-79.5) and 89.7% (95% CI 82.3-97.1) sensitivity, 71.4% (95% CI 61.3-81.5) and 39.4% (95% CI 22.7-56.1) specificity, 71.4% (95% CI 65.1-77.8) and 73.3% (95% CI 64.6-81.9) accuracy, and 0.77 and 0.72 AUC for detecting overall BI at the video level. Performance remained consistent for most epithelial and vascular components, although slightly lower for villi/crypts architecture and goblet cells, likely reflecting the more challenging assessment of these features with pCLE.

	Overall BI	Epithelial BI	Vascular BI	Villi/ crypts architecture	Goblet cells	Vessel architecture	Fluorescein leakage
Development cohort (N=196)
AUC % (95% CI)	0.77	0.74	0.77	0.80	0.78	0.78	0.77
F1 score % (95% CI)	75.2 (68.8-81.6)	74.2 (67.5-80.9)	75.3 (68.7-81.9)	68.6 (59.0-78.0)	76.5 (70.0-83.0)	63.5 (54.1-72.7)	76.5 (70.2-82.8)
Accuracy % (95% CI)	71.4 (65.1-77.8)	70.9 (64.4-77.3)	70.9 (64.4-77.3)	78.1 (72.3-83.9)	74.0 (67.9-80.1)	68.9 (62.4-75.4)	72.5 (66.2-78.6)
Validation cohort (N=101)
AUC % (95% CI)	0.72	0.71	0.75	0.58	0.73	0.79	0.74
F1 score % (95% CI)	81.9 (72.4-89.6)	69.6 (60.0-79.2)	79.2 (70.9-87.3)	47.9 (35.2-60.6)	53.1 (42.1-64.1)	75.9 (66.2-85.6)	77.7 (69.8-85.6)
Accuracy % (95% CI)	73.3 (64.6-81.9)	59.4 (49.8-68.9)	70.3 (61.4-79.2)	50.5 (40.8-60.2)	47.5 (42.1-64.1)	72.3 (63.6-81.0)	69.3 (60.4-78.2)

Table. Diagnostic performance of the AI algorithm to predict barrier impairment on pCLE videos.

Conclusion

Our AI-driven pCLE enables automated, standardised in vivo assessment of epithelial and vascular barrier features, offering an objective, reproducible tool to monitor barrier healing as a novel therapeutic endpoint in IBD.

References

1. Iacucci M, Jeffery L, Acharjee A, et al. Computer-Aided Imaging Analysis of Probe-Based Confocal Laser Endomicroscopy With Molecular Labeling and Gene Expression Identifies Markers of Response to Biological Therapy in IBD Patients: The Endo-Omics Study. Inflamm Bowel Dis. 2023;29(9):1409-1420. doi:10.1093/ibd/izac233
2. Iacucci M, Majumder S, Zammarchi I, et al. Automated real-time imaging of intestinal barrier integrity and molecular profiling for early outcome prediction in inflammatory bowel disease - Endo-Histo-Barrier-Omics study. J Crohns Colitis.
3. Oquab M, Darcet T, Moutakanni T, et al. DINOv2: Learning Robust Visual Features without Supervision. Published online February 2, 2024.
4. Carretero I, Meseguer P, et al. Time-aware semantic prototypes for weakly-supervised endomicroscopy video classification. Published online April, 2026.

Event

UEG Week Barcelona 2026

Topics

Colorectal IBD

Submission format

Abstract

Session

IBD diagnostics: In search of optimal implementation

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

More Like This:

INTEGRATING MUCOSAL TRANSCRIPTOMIC AND MICROBIAL SIGNATURES TO DEFINE COMPREHENSIVE DISEASE CONTROL IN ULCERATIVE COLITIS AT MOLECULAR RESOLUTION

Philip Rosenstiel

EFFICACY AND SAFETY OF DUVAKITUG MAINTENANCE THERAPY IN PATIENTS WITH CROHN’S DISEASE (CD): RESULTS FROM THE PHASE 2B RELIEVE UCCD LONG-TERM EXTENSION STUDY

Walter Reinisch

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

TOWARD PRECISION THERAPY IN ULCERATIVE COLITIS: GENOTYPE-BASED SINGLE-NUCLEOTIDE POLYMORPHISM (SNPS) SIGNATURES PREDICT DEEP RESPONSE TO USTEKINUMAB - A POST-HOC ANALYSIS OF THE UNIFI TRIAL

Subrata Ghosh

AI-DRIVEN PROBE CONFOCAL LASER ENDOMICROSCOPY ENABLES AUTOMATED ASSESSMENT OF INTESTINAL BARRIER IMPAIRMENT IN IBD

Valery Naranjo

DEFINING THE CELLULAR GUT MUCOSAL ORIGINS OF PRECLINICAL CIRCULATING PROTEIN SIGNATURES IN INFLAMMATORY BOWEL DISEASE

E.A.M. (Noortje) Festen

UEG Presentation

New

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DEFINING THE CELLULAR GUT MUCOSAL ORIGINS OF PRECLINICAL CIRCULATING PROTEIN SIGNATURES IN INFLAMMATORY BOWEL DISEASE

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DEFINING THE CELLULAR GUT MUCOSAL ORIGINS OF PRECLINICAL CIRCULATING PROTEIN SIGNATURES IN INFLAMMATORY BOWEL DISEASE

Lisa Aboosy 1, Paola Pibiri 1, Antonio da Costa de Pina 1, Emilia Bigaeva 1, Naomi Karmi 1, Roy Oelen 1, Sofie de Jong 1, Rali Aleksandrova 1, Arno R. Bourgonje 1, Rinse K. Weersma 1, E.A.M. (Noortje) Festen 1

Affiliations

1 University Medical Center Groningen, Groningen, Netherlands

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Abstract

Introduction

The research paradigm in inflammatory bowel disease (IBD) is shifting toward biomarker-based prediction and early detection before clinical onset. Circulating protein signatures can identify individuals at risk of IBD years before diagnosis, supporting the existence of a preclinical phase¹. However, the cellular origin of these proteins remains unclear, limiting interpretation of whether they reflect early disease biology, subclinical mucosal inflammation or other processes.

Aims & Methods

To investigate the cellular origin of preclinical circulating protein signatures in IBD, genes encoding a selected set of previously reported Crohn’s disease (CD) and ulcerative colitis (UC) circulating protein signatures were mapped onto in-house UMCG single-cell RNA-sequencing datasets from CD, UC, and healthy controls (HC)¹. CD proteins included CXCL9, IL6, MMP10, CCL20, MDK, CXCL17, DNER, GPNMB, and CX3CL1, while UC proteins included STAMBP, SIRT2, SCAMP3, ADAM8, GZMB, ABL1, CCL11, CD5, TNFRSF6B, MMP10, CDKN1A, and CXCL9. CD data were derived from terminal ileum (159 biopsies; 151 patients; 96 female; mean age 46 years), while UC data were derived from colon (78 biopsies; 53 patients; 28 female; mean age 41 years). Colonic biopsies from HC (n=5) served as controls. Cells were annotated into 51 (CD) and 54 (UC/HC) cell types using published references^2-4. For each protein-encoding gene, cell types with highest average expression were identified and differential expression between inflamed and non-inflamed tissue was assessed using the Wilcoxon rank-sum test with Benjamini-Hochberg correction (adjusted P<0.05).

Results

Across IBD, genes encoding preclinical proteins were predominantly expressed in intestinal mucosal immune cells, whereas in HC expression was mainly localized to stromal subsets. In CD, highest average expression was observed in Th17 tissue-resident memory cells, activated dendritic cells (DC), and inflammatory and resident macrophages. Six of nine CD-associated biomarkers (CXCL9, IL6, DNER, MDK, GPNMB, MMP10) showed significant differential expression between inflamed vs. non-inflamed tissue, with strongest associations for IL6 in inflammatory macrophages (adjusted P (P)=2.15x10^-¹⁴), MMP10 in transitional stromal 3(C3⁺) cells (P=1.93x10^-5) and CXCL9 in activated DCs (P=1.03x10^-4). In UC, highest average expression was likewise observed across immune subsets, including DCs, cycling T- and B-cells, inflammatory monocytes, natural killer cells (NK), CD8⁺IL17⁺ T-cells, plasmacytoïd DCs, and macrophages. Nine of twelve UC-associated biomarkers (STAMBP, SCAMP3, ADAM8, GZMB, ABL1, CCL11, CD5, CDKN1A, CXCL9) showed significant inflammation‑associated differences, with strongest associations for CCL11 in WNT2B⁺Fos^-lo1 fibroblasts (P=9.87x10^-47), CDKN1A in inflammatory monocytes (P=3.50x10^-11) and GZMB in NKs (P=1.39x10^-8). In HCs, highest average expression was mainly observed in stromal subsets including RSPO3⁺ and WNT2B⁺Fos^-lo1 fibroblasts, endothelial, microvascular and glial cells. TNFRSF6B remained undetectable across all gut mucosal subsets.

Conclusion

Transcripts from previously identified circulating proteins in CD and UC are predominantly expressed by gut mucosal immune cells. Several show inflammation-associated expression differences, suggesting these proteins reflect local mucosal inflammatory activity in established IBD. Transcripts without such differences may arise from alternative cell states or tissue not captured in gut mucosa. These findings provide biological context for preclinical IBD protein signatures and help interpret the processes they may represent.

References

1. Grännö, O. et al. (2025) Gastroenterology. https://doi.org/10.1053/j.gastro.2024.11.006
2. Smillie, C. S. et al. (2019) Cell. https://doi.org/10.1016/j.cell.2019.06.029
3. Martin, J. C. et al. (2019) Cell. https://doi.org/10.1016/j.cell.2019.08.008
4. Elmentaite, R. et al. (2020) Cell. https://doi.org/10.1016/j.devcel.2020.11.010

Disclosure

Sample processing was performed by Takeda.

Event

UEG Week Barcelona 2026

Topics

Mechanisms & Personalised Medicine Immunology IBD

Submission format

Abstract

Session

Abstract session: Hot topics in IBD

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

More Like This:

INTEGRATING MUCOSAL TRANSCRIPTOMIC AND MICROBIAL SIGNATURES TO DEFINE COMPREHENSIVE DISEASE CONTROL IN ULCERATIVE COLITIS AT MOLECULAR RESOLUTION

Philip Rosenstiel

EFFICACY AND SAFETY OF DUVAKITUG MAINTENANCE THERAPY IN PATIENTS WITH CROHN’S DISEASE (CD): RESULTS FROM THE PHASE 2B RELIEVE UCCD LONG-TERM EXTENSION STUDY

Walter Reinisch

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

TOWARD PRECISION THERAPY IN ULCERATIVE COLITIS: GENOTYPE-BASED SINGLE-NUCLEOTIDE POLYMORPHISM (SNPS) SIGNATURES PREDICT DEEP RESPONSE TO USTEKINUMAB - A POST-HOC ANALYSIS OF THE UNIFI TRIAL

Subrata Ghosh

AI-DRIVEN PROBE CONFOCAL LASER ENDOMICROSCOPY ENABLES AUTOMATED ASSESSMENT OF INTESTINAL BARRIER IMPAIRMENT IN IBD

Valery Naranjo

DEFINING THE CELLULAR GUT MUCOSAL ORIGINS OF PRECLINICAL CIRCULATING PROTEIN SIGNATURES IN INFLAMMATORY BOWEL DISEASE

E.A.M. (Noortje) Festen