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THE RESISTANT MICROBIOME: INSIGHTS FROM POUCHITIS AND HEALTHY ILEAL POUCHES

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Introduction

Chronic pouchitis is a common complication following ileal pouch-anal anastomosis (IPAA), with limited effective treatment options.¹ Antibiotics remain the first-line therapy; however, in cases of chronic pouchitis, prolonged antibiotic use contributes to increased antimicrobial resistance within the ileal pouch microbiome.² Fecal microbiota transplantation (FMT) has been proposed as a means of restoring microbial balance. Nevertheless, randomized placebo-controlled trials have demonstrated that, although FMT can alter the microbiome, it does not confer clinical benefits compared to placebo.^3–5

Aims & Methods

Given the lack of efficacy of FMT using stool from healthy donors, the present study aims to characterize the microbiome of a healthy ileal pouch and to evaluate the impact of high antibiotic exposure in patients with chronic pouchitis.
In this cohort study, stool samples were collected from four groups: patients with a normally functioning IPAA, patients with chronic pouchitis, patients with ulcerative colitis, and healthy controls. Microbiome composition and antibiotic resistance genes were analyzed across these groups. Fecal samples underwent metagenomic sequencing, and metagenome-assembled genomes (MAGs) were reconstructed. For Escherichia coli MAGs, the antibiotic resistance gene (ARG) profiles and plasmid content were specifically examined.

Results

This study included 197 participants. A clear pattern emerged in the microbial composition, revealing that reduced alpha diversity is directly associated with declining gut function and clinical health. Both species richness and Shannon diversity were lowest in patients with chronic pouchitis and highest in healthy individuals, with intermediate levels observed in the other groups. Notably, the ileal pouch microbiome of many chronic pouchitis patients was dominated by E. coli. Given the potential clinical implications of high E. coli abundance, we further investigated the ARG profiles and plasmid content of E. coli MAGs. E. coli MAGs from chronic pouchitis patients exhibited a significantly higher frequency of single nucleotide polymorphisms (SNPs) associated with resistance to fluoroquinolones—an antibiotic uniformly used among this patient group—compared to MAGs from the normally functioning IPAA and healthy control cohorts. Furthermore, E. coli MAGs from chronic pouchitis patients harbored a greater number of plasmids, with an increased presence of plasmid-borne ARGs conferring resistance to antibiotics commonly administered in this group, relative to the other cohorts.

Conclusion

These findings demonstrate that the composition of the ileal pouch microbiome—both in chronic pouchitis and normally functioning IPAA—differs significantly from that of individuals with normal gut physiology. This suggests that the microbiome of a normally functioning IPAA may serve as a more appropriate baseline for comparative studies than the healthy gut microbiome. Additionally, our results indicate that antibiotic use exerts increased selective pressure on E. coli strains carrying antibiotic resistance genes, directly correlating with the types of antibiotics administered.

References

1. Hata K, Ishihara S, Nozawa H, et al. Pouchitis after ileal pouch-anal anastomosis in ulcerative colitis: Diagnosis, management, risk factors, and incidence. Dig Endosc 2017;29:26–34.
2. Shen B, Kochhar GS, Rubin DT, et al. Treatment of pouchitis, Crohn’s disease, cuffitis, and other inflammatory disorders of the pouch: consensus guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterol Hepatol 2021;7:69–95.
3. Herfarth H, Barnes EL, Long MD, et al. Combined Endoscopic and Oral Fecal Microbiota Transplantation in Patients with Antibiotic-Dependent Pouchitis: Low Clinical Efficacy due to Low Donor Microbial Engraftment. Inflamm Intest Dis 2019;4:1–6.
4. Karjalainen EK, Renkonen-Sinisalo L, Satokari R, et al. Fecal Microbiota Transplantation in Chronic Pouchitis: A Randomized, Parallel, Double-Blinded Clinical Trial. Inflamm Bowel Dis 2021;27:1766–1772.
5. Kousgaard SJ, Cold F, Halkjær SI, et al. The effect of non-pooled multi-donor faecal microbiota transplantation for inducing clinical remission in patients with chronic pouchitis: Results from a multicentre randomised double-blinded placebo-controlled trial (MicroPouch). J Crohn’s Colitis 2024;18:1753–1766.

THE RESISTANT MICROBIOME: INSIGHTS FROM POUCHITIS AND HEALTHY ILEAL POUCHES

Sabrina Kousgaard 1, Alberte Holm Møllekær 2, Sebastian Mølvang Dall 2, Lone Larsen 3, Mads Albertsen 2, Ole Thorlacius-Ussing 4

1 Aalborg University Hospital, Aalborg, Denmark|||Aalborg University Hospital, Aalborg, Denmark

2 Aalborg University, Aalborg, Denmark

3 Aalborg University Hospital, Aalborg, Denmark|||Aalborg University, Copenhagen, Denmark

4 Aalborg University Hospital, Aalborg, Denmark

Event

UEG Week Berlin 2025

Topics

Colorectal Gut Microbiota Mechanisms & Personalised Medicine IBD

Submission format

Abstract

Session

Dissecting the microbiome in gut inflammation

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Presidential address

Matthias Löhr 1

1 Karolinska Institutet, Stockholm, Sweden

Event

UEG Week Berlin 2025

Topics

Immunology

Session

Opening Plenary

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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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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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).

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

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

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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Building a bile duct: What can structural tissue patterning tell us about liver disease?

Luke Boulter 1

1 University of Edinburgh, Edinburgh, United Kingdom

Event

UEG Week Berlin 2025

Topics

Hepatobiliary Mechanisms & Personalised Medicine

Session

The art of making clinical research precise: Narrowing the gap between the bench and bedside

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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The usefulness of target trial emulations to enhance the field of Gastroenterology

Louise Emilsson 1

1 County Council of Värmland, Värmlands, Sweden

Event

UEG Week Berlin 2025

Topics

Mechanisms & Personalised Medicine Standards & Guidelines

Session

The art of making clinical research precise: Options for study design

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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DUAL MODULATION OF GPBAR1/RORΓT ATTENUATES CHOLESTATIC INFLAMMATION VIA IL-23/IL-17 PATHWAY REGULATION IN MURINE MODEL OF PSC

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Introduction

Primary sclerosing cholangitis (PSC) is a progressive autoimmune cholestatic liver disease often associated with inflammatory bowel disease (IBD), particularly ulcerative colitis [1]. In PSC, reduced expression and function of the bile acid receptor GPBAR1 (TGR5) in cholangiocytes is associated with a dysfunctional gut–liver immune axis and impaired resolution of inflammation [2,3]. Parallelly, the transcription factor RORγt in Th17 cells sustains IL-17 perpetuating IL-23-driven intestinal [4] and liver inflammation [5]. While GPBAR1 mediates anti-inflammatory responses to secondary bile acids, RORγt governs Th17 differentiation and cytokine secretion. Recent clinical studies have demonstrated that IL-23 inhibitors, such as risankizumab [6] and mirikizumab [7], are effective in treating IBD, highlighting the significance of the IL-23/IL-17 axis. GPBAR1/RORγt dual simultaneous modulation represents a novel strategy to counteract the fibrotic and inflammatory environment characteristic of PSC.

Aims & Methods

We evaluated the therapeutic efficacy of PBT002, a dual GPBAR1 agonist and RORγt inverse agonist, in modulating immune and fibrotic pathways in PSC. Transcriptomic distribution of target genes was assessed using publicly available single-cell RNA-sequencing datasets from healthy human livers [8]. Differential gene expression was validated in two independent cohorts of patients with PSC and PBC, and further confirmed in an external validation cohort (GSE159676). Functional studies were performed in vitro using primary human cholangiocytes (NHC), immortalized hepatic stellate cells (LX-2), primary monocyte-derived macrophages and CD4+ T lymphocytes. In vivo efficacy was assessed in Abcb4^⁻/⁻ mice treated with PBT002 (10 mg/kg/day) for 12 weeks.

Results

Single-cell transcriptomic analysis revealed that IL-17 and IL-23 cytokines are predominantly expressed by immune cells, whereas their receptors (IL23R, IL17RA, IL17RC, IL17RE) are enriched in epithelial cells, including hepatocytes and cholangiocytes. Deconvolution analysis of liver bulk transcriptomes from PSC and PBC cohorts showed features of immune exhaustion, with a mild upregulation of pro-inflammatory markers and IL-17 receptor subunits, along with prominent overexpression of PD-L1, a known pro-fibrotic mediator. In vitro, exposure of hepatic stellate cells, macrophages, and CD4+ T cells to supernatants from inflamed cholangiocytes induced strong activation, which was reversed by PBT002 treatment. In vivo, PBT002 significantly reduced hepatocellular damage, as shown by decreased serum ALT, AST, ALP, and bilirubin levels. Histological analyses revealed marked reductions in periductal inflammation and liver fibrosis. Gene expression profiling confirmed significant downregulation of M1 and Th17-associated genes (Rorc, Il17f, Il22, Il23a) in colon and liver. Bile acid profiling showed restoration of key GPBAR1 agonists and RORγt antagonists (DCA, 3-oxo-DCA, allo-LCA), while microbiota analysis demonstrated increased abundance of protective taxa (e.g., Blautia, Sutterellaceae), inversely associated with disease severity.

Conclusion

PBT002 exerts potent immunomodulatory effects in experimental PSC by rebalancing M1/M2 and Th17/Treg homeostasis through dual GPBAR1 activation and RORγt inhibition. These effects correlate with restoration of bile acid and microbiota profiles, confirming the key role of the microbiota–bile acid–immune axis in PSC and supporting PBT002’s clinical development for immune-mediated cholangiopathies, particularly in PSC-IBD overlap.

References

1. Fiorucci, S. et al. Bile Acids-Based Therapies for Primary Sclerosing Cholangitis: Current Landscape and Future Developments. Cells 13, (2024).
2. Di Giorgio, C. et al. Liver GPBAR1 Associates With Immune Dysfunction in Primary Sclerosing Cholangitis and Its Activation Attenuates Cholestasis in Abcb4-/- Mice. Liver Int. Off. J. Int. Assoc. Study Liver 45, e16235 (2025).
3. Reich, M. et al. Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J. Hepatol. 75, 634–646 (2021).
4. Biagioli, M. et al. Development of dual GPBAR1 agonist and RORγt inverse agonist for the treatment of inflammatory bowel diseases. Pharmacol. Res. 208, 107403 (2024).
5. Garcia Moreno, A. S. et al. IL-17 signaling in primary sclerosing cholangitis patient-derived organoids. Hepatol. Commun. 8, (2024).
6. Louis, E. et al. Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials. JAMA 332, 881–897 (2024).
7. D’Haens, G. et al. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N. Engl. J. Med. 388, 2444–2455 (2023).
8. Andrews, T. S. et al. Single-Cell, Single-Nucleus, and Spatial RNA Sequencing of the Human Liver Identifies Cholangiocyte and Mesenchymal Heterogeneity. Hepatol. Commun. 6, 821–840 (2022).