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Innovations in IBD Therapy: The Story of TL1A - from Discovery to Potential Future Care (F. Hoffmann-La Roche Ltd) (Complete Session)

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Innovations in IBD Therapy: The Story of TL1A - from Discovery to Potential Future Care (F. Hoffmann-La Roche Ltd) (Complete Session)

Jean-Frédéric Colombel 1, Beatriz Gros 2, Remo Panaccione 3

Affiliations

1 Icahn School of Medicine at Mount Sinai, USA, United States of America

2 Hospital Universitario Reina Sofia, Cordoba, Spain

3 University of Calgary, Calgary, Canada

Summary

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This symposium reviewed the 22-year development of TL1A inhibitors for IBD, from cytokine discovery in 2002 to positive phase 2 trial results in 2024, with phase 3 programmes now recruiting in ulcerative colitis and Crohn's disease.

TL1A is a cytokine that amplifies immune responses when intestinal barrier damage occurs, expressed in antigen-presenting cells and binding to death receptor 3 on immune cells including ILCs and T cells.
The speaker stated that three anti-TL1A therapies have reported positive phase 2 trials in ulcerative colitis showing significance over placebo across clinical and endoscopic endpoints with large placebo-adjusted treatment differences and no safety signals observed during induction and maintenance.
Genetic polymorphisms in TNFSF15 linked to higher TL1A production may serve as predictive biomarkers, with the speaker noting that biomarker-positive patients in one trial had numerically greater treatment effects than all-comer patients.
The speaker described TL1A inhibition as addressing multiple IBD features including inflammation, tissue remodelling, and potentially fibrosis, while maintaining immune homeostasis without over-immunosuppression.
Multiple phase 3 trials in ulcerative colitis and Crohn's disease are recruiting, with the speaker stating some trials are ahead of schedule and top-line results expected between 2026 and 2028.
The speakers discussed potential future applications beyond IBD including idiopathic pulmonary fibrosis, hidradenitis suppurativa, and spondyloarthropathy, though positioning relative to existing therapies will depend on phase 3 outcomes and remains uncertain.

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Abstract

Publisher

F. Hoffmann La Roche

Event

UEG Week Berlin 2025

Session

Innovations in IBD Therapy: The Story of TL1A - from Discovery to Potential Future Care (F. Hoffmann-La Roche Ltd)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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PREDICTORS OF BIOLOGICS/JAKI USE, SURGERIES, AND HOSPITALISATIONS IN A NEWLY DIAGNOSED COHORT OF IBD PATIENTS: LONG-TERM OUTCOMES FROM THE NATIONWIDE EPIDEMIBD STUDY OF GETECCU

María Dolores Martín-Arranz

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Elena Verdu

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Smart choices in systemic HCC therapy

Anna Saborowski 1

Affiliations

1 Hannover Medical School, Hannover, Germany

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Abstract

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Digestive Oncology Hepatobiliary

Session

Hepatocellular carcinoma: All you need to know

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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PREDICTORS OF BIOLOGICS/JAKI USE, SURGERIES, AND HOSPITALISATIONS IN A NEWLY DIAGNOSED COHORT OF IBD PATIENTS: LONG-TERM OUTCOMES FROM THE NATIONWIDE EPIDEMIBD STUDY OF GETECCU

María Dolores Martín-Arranz

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Elena Verdu

UEG Presentation

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The treatment

Judith Wellens 1

Affiliations

1 University Hospitals Leuven, Leuven, Belgium

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Abstract

Event

UEG Week Berlin 2025

Topics

IBD Primary Care

Session

When IBD and IBS experts collaborate for optimal diagnosis and treatment of IBD with IBS-like symptoms

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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PREDICTORS OF BIOLOGICS/JAKI USE, SURGERIES, AND HOSPITALISATIONS IN A NEWLY DIAGNOSED COHORT OF IBD PATIENTS: LONG-TERM OUTCOMES FROM THE NATIONWIDE EPIDEMIBD STUDY OF GETECCU

María Dolores Martín-Arranz

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Elena Verdu

UEG Presentation

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Surgical navigation

Suzanne S. Gisbertz 1

Affiliations

1 Amsterdam UMC, Amsterdam, Netherlands

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Abstract

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Endoscopy Nurses Oesophagus Surgery

Session

What's new in early oesophageal cancer in 2025?

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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PREDICTORS OF BIOLOGICS/JAKI USE, SURGERIES, AND HOSPITALISATIONS IN A NEWLY DIAGNOSED COHORT OF IBD PATIENTS: LONG-TERM OUTCOMES FROM THE NATIONWIDE EPIDEMIBD STUDY OF GETECCU

María Dolores Martín-Arranz

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Elena Verdu

UEG Presentation

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Who is at risk?

Matt Rutter 1

Affiliations

1 University Hospital North Tees NHS Dept. of Gastroenterology - Gastroenterology, University Hospital, Stockton-on-Tees, United Kingdom

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Abstract

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Endoscopy IBD Surgery

Session

Endoscopy, cancer and IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Anna Saborowski

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Judith Wellens

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Matt Rutter

PREDICTORS OF BIOLOGICS/JAKI USE, SURGERIES, AND HOSPITALISATIONS IN A NEWLY DIAGNOSED COHORT OF IBD PATIENTS: LONG-TERM OUTCOMES FROM THE NATIONWIDE EPIDEMIBD STUDY OF GETECCU

María Dolores Martín-Arranz

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Elena Verdu

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

PREDICTORS OF BIOLOGICS/JAKI USE, SURGERIES, AND HOSPITALISATIONS IN A NEWLY DIAGNOSED COHORT OF IBD PATIENTS: LONG-TERM OUTCOMES FROM THE NATIONWIDE EPIDEMIBD STUDY OF GETECCU

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PREDICTORS OF BIOLOGICS/JAKI USE, SURGERIES, AND HOSPITALISATIONS IN A NEWLY DIAGNOSED COHORT OF IBD PATIENTS: LONG-TERM OUTCOMES FROM THE NATIONWIDE EPIDEMIBD STUDY OF GETECCU

Ana Garre Vázquez 1, Andrea Núñez Ortiz 2, Saioa Rubio Iturria 3, María Teresa Diz-Lois Palomares 4, Sabino Riestra 5, Horacio Alonso-Galán 6, Estela Fernández-Salgado 7, Rocío Ferreiro-Iglesias 8, Milagros Vela Gonzalez 9, Ángel Ponferrada-Díaz 10, Eugenia Sánchez Rodríguez 11, Vicent Hernández 12, Lara Arias García 13, Jesús Barrio 14, Jose Maria Huguet 15, Daniel Ginard 16, Montserrat Rivero 17, Maria Isabel Vera Mendoza 18, Inmaculada Alonso-Abreu 19, JOSE MANUEL BENITEZ CANTERO 20, Mariam Aguas 21, Iago Rodríguez-Lago 22, Xavier Calvet 23, Luis Fernández-Salazar 24, Ana Echarri Piudo 25, María Teresa Arroyo-Villarino 26, Mercè Navarro 27, Pablo Vega 28, Monica Sierra 29, ELENA OTILIA GUERRA DEL RIO CÁRDENES 30, Raquel Vicente Lidón 31, María José Casanova 1, Pablo Navarro Cortés 32, Jone Ortiz de zarate 33, Pilar Varela Trastoy 34, Katerina Spicakova 35, Ana Gutiérrez-Casbas 36, María Dolores Martín-Arranz 37, Concepcion Piñero 38, Alvaro Hernández Martínez 39, Emilio a Torrella Cortes 40, Jose Miguel Marrero Monroy 41, Rufo Lorente Poyatos 42, Lidia Martí Romero 43, Orencio Bosch 44, José María Duque-Alcorta 45, Montserrat Aceituno 46, HIPÓLITO FERNÁNDEZ 47, Javier P. Gisbert 1, María Chaparro 1

Affiliations

1 Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain

2 Hospital Universitario Virgen del Rocío, Sevilla, Spain

3 Hospital Universitario de Navarra, Pamplona, Spain

4 Hospital Universitario A Coruña, A Coruña, Spain

5 Hospital Universitario Central de Asturias and ISPA, Oviedo, Spain

6 Hospital Universitario Donostia and Instituto Biogipuzkoa, San Sebastián, Spain

7 Complexo Hospitalario Universitario de Pontevedra, Instituto de Investigación Sanitaria Galicia Sur, Pontevedra, Spain

8 , Complexo Hospitalario Universitario de Santiago and Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain

9 Complejo Hospitalario Universitario Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain

10 Hospital Universitario Infanta Leonor, Madrid, Spain

11 Hospital Ramón y Cajal, Madrid, Spain

12 Hospital Álvaro Cunqueiro, Estrutura Organizativa de Xestión Integrada de Vigo, Vigo, Spain

13 Hospital Universitario de Burgos, Burgos, Spain

14 Hospital Universitario Rio Hortega, Valladolid, Spain

15 Consorcio Hospital General Universitario de Valencia, Valencia, Spain

16 Hospital Universitari Son Espases, Palma de Mallorca, Spain

17 Hospital Universitario Marqués de Valdecilla and IDIVAL, Santander, Spain

18 Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

19 Hospital Universitario de Canarias (H.U.C.), Santa Cruz de Tenerife, Spain

20 Hospital Universitario Reina Sofia and IMIBIC, Cordoba, Spain

21 Hospital Universitari i Politecnic La Fe, Valencia, Spain

22 Hospital de Galdakao-Usansolo, Vizcaya, Spain

23 Hospital de Sabadell, Institut Universitari Parc Taulí, Universitat Autònoma de Barcelona, CIBEREHD., Sabadell, Spain

24 Hospital Clínico Universitario de Valladolid, Valladolid, Spain

25 Complejo Hospitalario Universitario de Ferrol, A Coruña, Spain

26 Hospital Clínico Universitario “Lozano Blesa”, IIS Aragón and CIBERehd, Zaragoza, Spain

27 Hospital de Sant Joan Despí Moisès Broggi, Barcelona, Spain

28 Complexo Hospitalario Universitario de Ourense, Ourense, Spain

29 Complejo Asistencial Universitario de León, León, Spain

30 Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas, Spain

31 Hospital Universitario Miguel Servet, Zaragoza, Spain

32 Hospital Clínico Universitario de Valencia, Universitat de València, Valencia, Spain

33 Hospital Universitario de Basurto, Bilbao, Spain

34 Hospital de Cabueñes, Gijón, Spain

35 Hospital Universitario de Araba, Vitoria, Spain

36 Hospital General Universitario Dr. Balmis and CIBERehd, Alicante, Spain

37 Hospital Universitario de La Paz, Instituto de Investigación Biomédica de La Paz, Universidad Autónoma de Madrid, Madrid, Spain

38 Hospital Universitario de Salamanca, Salamanca, Spain

39 Complejo Hospitalario de Especialidades Torrecárdenas, Almería, Spain

40 Hospital General Universitario J.M. Morales Meseguer, Murcia, Spain

41 Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain

42 Hospital General Universitario de Ciudad Real, Ciudad real, Spain

43 Hospital Francesc De Borja de Gandía, Valencia, Spain

44 Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain

45 Hospital San Agustín, Aviles, Spain

46 Hospital Universitari Mutua Terrasa and CIBEREHD, Terrassa, Spain

47 Hospital San Pedro, Logroño, Spain

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Abstract

Introduction

Factors influencing the exposure to targeted therapies (biologics/JAKi), intestinal resections and hospitalisations in newly diagnosed IBD patients have been scarcely studied.

Aims & Methods

Aim: To identify predictive factors of exposure to biologics/JAKi, surgeries, and hospitalisations within the first five years in IBD patients.
Methods: Prospective, population-based, nationwide registry. Adult patients diagnosed with IBD [Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)] during 2017 in the 17 Spanish regions were included. Patients who consented were followed-up for 5 years after diagnosis. Multivariate analyses were performed to identify the predictive factors for biologics/JAKi use, surgeries, and hospitalisations. To this end, only abdominal surgeries were analysed, and early treatment with immunomodulators or biologics/JAKi drugs were considered if these had been prescribed within the first six months of diagnosis.

Results

A total of 1,526 patients diagnosed with CD and 1,633 with UC were included. Regarding the predictors of exposure to biologics/JAKi treatments, we observed that younger age, more aggressive phenotype of CD and greater extent of UC were associated with a higher risk of exposure (table 1). Furthermore, smoking was associated with a higher likelihood of exposure to biologics/JAKi drugs in patients with CD (HR=1.33, 95%CI=1.11-1.60) while in UC patients it was associated with a lower risk (HR=0.56, 95%CI=0.35-0.89). Concerning surgeries (table 1), early treatment with immunomodulators was associated with a lower risk in patients with CD (HR=0.33, 95%CI=0.22-0.49), whereas early use of biologics/JAKi drugs was associated with a higher likelihood of surgery in patients with UC (HR=11.86, 95%CI=4.62-30.42). Finally, the exposure to biologics/JAKi drugs was associated with a lower risk of hospital admissions both in patients with CD (HR=0.37, 95%CI=0.24-0.56) and UC (HR=0.45, 95%CI=0.22-0.91) (table 1).

Table 1: Predictors of biologics/JAKi use (A), surgeries (B) and hospitalisations (C) in patients with Corhn´s disease (CD) and ulcerative colitis (UC)

A	CD Age Family history of IBD Smoker Behaviour disease B1 (inflammatory) B2 (stricturing) B3 (fistulising) Perianal	HR (95% CI) 0.99 (0.98-1.00) 1.29 (1.06-1.57) 1.26 (1.06-1.50) Ref 1.89 (1.50-2.39) 2.35 (1.79-3.10) 1.86 (1.47-2.35)	P-value <0.001 0.010 0.002 <0.001 <0.001 <0.001
	UC Age Smoker Extension Proctitis Left-side colitis Pancolitis	0.99 (0.99-1.00) 0.56 (0.35-0.89) Ref 2.33 (1.62-3.36) 5.02 (3.59-7.03)	0.047 0.015 <0.001 <0.001
B	CD Behaviour disease B1 (inflammatory) B2 (stricturing) B3 (fistulising) Exposure to biologics/JAKi before surgery No exposure to treatment Exposure to treatment Early exposure to treatment Exposure to Immunomodulators before surgery No exposure to treatment Exposure to treatment Early exposure to treatment	HR (95% CI) Ref 5.52 (3.62-8.42) 8.68 (5.55-13.58) Ref 0.73 (0.45-1.78) 1.29 (0.84-1.98) Ref 0.23 (0.11-0.46) 0.33 (0.22-0.49)	P-value <0.001 <0.001 0.197 0.245 <0.001 <0.001
	UC Extension Proctitis Left-side colitis Pancolitis Exposure to biologics/JAKi before surgery No exposure to treatment Exposure to treatment Early exposure to treatment Exposure to Immunomodulators before surgery No exposure to treatment Exposure to treatment Early exposure to treatment	HR (95% CI) Ref 2.00 (0.53-7.53) 2.33 (0.64-8.45) Ref 2.70 (0.93-7.87) 11.86 (4.62-30.42) Ref 0.50 (0.16-1.58) 0.89 (0.37-2.15)	P-value 0.311 0.199 0.068 <0.001 0.238 0.973
C	CD Smoker Behaviour disease B1 (inflammatory) B2 (stricturing) B3 (fistulising) Exposure to biologics/JAKi before hospitalisation No exposure to treatment Exposure to treatment Early exposure to treatment Exposure to Immunomodulators before hospitalisation No exposure to treatment Exposure to treatment Early exposure to treatment	HR (95% CI) 1.31 (1.09-1.57) Ref 1.69 (1.33-2.15) 1.63 (1.27-2.09) Ref 0.37 (0.24-0.56) 0.48 (0.32-0.72) Ref 0.39 (0.25-0.60) 0.59 (0.44-0.79)	P-value 0.004 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
	UC Extension Proctitis Left-side colitis Pancolitis Exposure to biologics/JAKi before hospitalisation No exposure to treatment Exposure to treatment Early exposure to treatment Exposure to Immunomodulators before hospitalisation No exposure to treatment Exposure to treatment Early exposure to treatment	HR (95% CI) Ref 4.02 (1.62-3.36) 10.77 (0.67-8.65) Ref 0.45 (0.22-0.91) 0.63 (0.19-2.07) Ref 0.67 (0.34-1.31) 0.77 (0.38-1.57)	P-value <0.001 <0.001 0.027 0.444 0.245 0.475

Conclusion

The exposure to biologics/JAKi drugs is mediated by the more aggressive phenotype of CD, greater extent of UC, and younger patient age. The use of biologics/JAKi drugs, as currently practiced, is associated with a lower risk of hospitalisations but does not reduce the need for surgery, even when administered early. There is an unmet need for more accurate identification of patients who require these treatments to modify the natural course of the disease.

Disclosure

SR has received support for conference attendance, speaker fees, research support, and consulting fees from AbbVie, Adacyte, Faes Pharma, Ferring, Tillots, Galapagos, Janssen, Pfizer, and Lilly.
RF has received support for conference attendance, and research support from AbbVie, Faes Pharma, Ferring, Janssen, Pfizer, Takeda, and Galapagos.
RC: has received support from Janssen, Johnson&Johnson, Ferring, Abbvie, Falk, Pfizer y Galápagos.
AN: has received financial support for travelling and educational activities from Pfizer, Abbvie, Takeda, Janssen, Tillotts Pharma and Ferring.
JPG has served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Hospira, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Vifor Pharma.
MC has served as a speaker, or has received research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma.

Event

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

Predicting clinical outcomes in IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

Smart choices in systemic HCC therapy

Anna Saborowski

The treatment

Judith Wellens

Surgical navigation

Suzanne S. Gisbertz

Who is at risk?

Matt Rutter

PREDICTORS OF BIOLOGICS/JAKI USE, SURGERIES, AND HOSPITALISATIONS IN A NEWLY DIAGNOSED COHORT OF IBD PATIENTS: LONG-TERM OUTCOMES FROM THE NATIONWIDE EPIDEMIBD STUDY OF GETECCU

María Dolores Martín-Arranz

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Elena Verdu

UEG Presentation

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TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

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TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Kyle Jackson 1, Heather Galipeau 2, Amber Hann 2, Marco Constante 2, Megan Zangara 3, Alexandra Fuentas 2, Chiko Shimbori 2, Premysl Bercik 2, Brian Coombes 3, Zeinab Hosseinidoust 1, Elena Verdu 2

Affiliations

1 McMaster University, Hamilton, Canada|||Farncombe Family Digestive Health Research Institute, Hamilton, Canada

2 Farncombe Family Digestive Health Research Institute, Hamilton, Canada

3 McMaster University, Hamilton, Canada

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Abstract

Introduction

Current therapies for inflammatory bowel disease (IBD) suppress inflammation rather than inhibiting underlying microbial drivers. Treatment failures of frontline interventions, including corticosteroids, can lead to dose escalation and risk of adverse effects.^1,2 Bacteria with pro-inflammatory potential, like adherent-invasive Escherichia coli (AIEC), have been postulated as a possible microbial driver in Crohn’s disease (CD), however, targeting these bacteria with precision in IBD remains challenging.^3,4 Most antibiotics have broad-spectrum activity and disturb the background microbiome, which may exacerbate inflammation.⁵ Attention has shifted towards bacteriophages, yet their underlying mechanisms of treating IBD, and how they may work as an adjunctive therapy, remains elusive.

Aims & Methods

We aimed to assess whether and how phage therapy, specific for a CD-associated bacterium, reduces colitis severity using gnotobiotic mouse models.
In vitro kill curves and biofilm challenges were used to identify lytic phage candidates. Adult germ-free C57BL/6 mice were colonized with altered Schaedler-flora (ASF) and E. coli NRG857c (NRG), a CD-associated isolate. After 3 weeks, mice were treated with an NRG-specific lytic phage (1x10⁹ PFU/dose; daily or TIW) or vehicle (PBS) for 2 weeks (n=6/group) and then exposed to 1 cycle of dextran sulfate sodium (2%; DSS) in drinking water. PBS-treated mice (n=6) not exposed to DSS served as controls. Phage treatment was also tested in a spontaneous model of colitis using C57BL/6NTac-Il10^em8Tac (IL-10^-/-) mice, treated weekly. Mice were monitored daily for weight, stool consistency, and occult blood. Fecal contents were cultured to determine bacterial load, and the expression of NRG fimS was quantified using qPCR as an assessment of virulence. At endpoint, colon tissues were collected for histological and immunohistochemistry analysis to quantify colitis severity and NRG infiltration, respectively. Additional C57BL/6 mice were colonized and treated as previously described. During colitis induction, mice received a low-dose of budesonide (2μg/day)⁶ (n=5) or vehicle (n=5) until endpoint. Mice were monitored daily for disease activity and colon tissues were collected for histological analysis. HPLC was used to determine active budesonide levels.

Results

HER259 was identified as a lytic phage against CD-associated AIEC NRG. In ASF and NRG colonized mice, HER259 reduced clinical symptoms (p< 0.001, p< 0.001) and histological scores (p< 0.0001, p< 0.001) in chemical induced and spontaneous colitis, respectively. A 1-log reduction in NRG bacterial load was observed in HER259-treated mice (p< 0.001). Reisolated NRG exhibited a reduced FimS ON/OFF ratio (p-value < 0.01). Immunohistochemistry revealed reduced infiltration of NRG into the lamina propria following HER259 treatment, with greater accumulation in the epithelium. HER259 treatment increased the efficacy of a sub-therapeutic dosing regimen of budesonide (p< 0.001), which was independent of microbial-based drug metabolism as determined by HPLC.

Conclusion

Our results demonstrate that lytic phage targeting a CD-associated bacterium attenuates colitis in two gnotobiotic mouse models. The intervention did not lead to complete eradication of the disease-driving agent, but instead modulated bacterial virulence mechanisms and enhanced responses to corticosteroid therapy. The data suggests that alternative mechanisms should be considered when translating phage therapy to treat IBD in clinical trials.

References

1. Yan, Y. et al. Commensal bacteria promote azathioprine therapy failure in inflammatory bowel disease via decreasing 6-mercaptopurine bioavailability. Cell Rep Med 4, 101153 (2023).
2. Nagayama, M., Gogokhia, L. & Longman, R. S. Precision microbiota therapy for IBD: premise and promise. Gut Microbes 17, 2489067 (2025).
3. Darfeuille-Michaud, A. et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology 127, 412–421 (2004).
4. A, D.-M. et al. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn’s disease. Gastroenterology 115, 1405–1413 (1998).
5. Nelson, R. L., Suda, K. J. & Evans, C. T. Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults. Cochrane Database Syst Rev 3, (2017).
6. Bercik, P. et al. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139, (2010).

Event

UEG Week Berlin 2025

Topics

Gut Microbiota IBD

Submission format

Abstract

Session

New tales of the gut microbiome: From profiling to new therapies

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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