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DISSEMINATED TUBERCULOSIS AFTER INFLIXIMAB USE IN A PATIENT WITH CROHN'S DISEASE

Kelson Batista 1, DANIELLE Queiroz Bonilha 1, Hugo Brandao Araujo 1, Diego Delgado 1, Julia Manara Martins 1, amanda clevelario 1, Ciro Montes 1, Cristiane Kibune Nagasako 1

Affiliations

1 State University of Campinas, Campinas, Brazil

Summary

AI Generated

A 40-year-old woman with Crohn's disease developed disseminated tuberculosis three months after switching from adalimumab to infliximab despite negative pre-treatment screening.

The patient presented with systemic decline, weight loss, cough, and neurological signs including left-sided weakness, hyperreflexia, dysmetria, and gait ataxia three months after starting infliximab.
Chest CT showed multiple centrilobular micronodules with tree-in-bud pattern in upper lobes, and brain MRI revealed a 13 mm peripherally enhancing brainstem lesion with central necrosis in the right pons and midbrain.
Disseminated tuberculosis was diagnosed based on clinical presentation, epidemiological context, and anti-TNF-α therapy despite negative bronchoalveolar lavage for acid-fast bacillus and mycobacterial culture.
Treatment with rifampin, levofloxacin, and ethambutol for 9 months achieved clinical cure but left permanent sequelae including left-sided weakness, gait ataxia, bilateral hearing impairment, and persistent scarring in brainstem and lungs.
This case illustrates the risk of severe infections with TNF-α inhibitors and emphasizes the importance of thorough screening before initiating biologic therapy in Crohn's disease.

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Abstract

Clinical Case Summary

Tumor necrosis factor-alpha (TNF-α) inhibitors are used to treat Crohn’s disease due to their immunosuppressive effect; however, serious adverse events may occur.
A 40-year-old female followed at a tertiary hospital gastroenterology clinic, was diagnosed with Crohn’s disease in 2017. She started immunosuppressive therapy with adalimumab, which was switched to infliximab in 2022 due to loss of response. Before the switch, screening tests (Interferon-Gamma Release Assays and Purified Protein Derivative) yielded negative results. Three months later, she presented with systemic decline, weight loss, and cough. Neurological signs emerged: left-sided weakness, hyperreflexia, hypoesthesia, dysmetria, disdiadochokinesia, and gait ataxia.
Laboratory tests were nonspecific, showing elevated C-reactive protein without leukocytosis. Chest computed tomography revealed multiple centrilobular micronodules with a diffuse tree-in-bud pattern, predominantly in upper lobes. Brain magnetic resonance imaging showed a 13 mm lobulated, peripherally enhancing brainstem lesion with central necrosis in the right pons and midbrain.
Bronchoalveolar lavage was negative for acid-fast bacillus and mycobacterial culture. Despite no microbiological confirmation, disseminated tuberculosis was diagnosed based on clinical, epidemiological context, and anti-TNF-α therapy.
She was treated with rifampin, levofloxacin, and ethambutol for 9 months due to hepatotoxicity and ototoxicity from first- and second-line drugs. Despite clinical cure, scarring lesions persisted in the brainstem and lungs.
Late sequelae included left-sided weakness and sensory loss, gait ataxia, and bilateral hearing impairment.
This case highlights the risk of severe infections with biologic agents and the importance of thorough screening prior to their use.

References

Torres J, Bonovas S, Doherty G, Kucharzik T, Gisbert JP, Raine T, Adamina M, Armuzzi A, Bachmann O, Bager P, Biancone L, Bokemeyer B, Bossuyt P, Burisch J, Collins P, El-Hussuna A, Ellul P, Frei-Lanter C, Furfaro F, Gingert C, Gionchetti P, Gomollon F, González-Lorenzo M, Gordon H, Hlavaty T, Juillerat P, Katsanos K, Kopylov U, Krustins E, Lytras T, Maaser C, Magro F, Marshall JK, Myrelid P, Pellino G, Rosa I, Sabino J, Savarino E, Spinelli A, Stassen L, Uzzan M, Vavricka S, Verstockt B, Warusavitarne J, Zmora O, Fiorino G. ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment. J Crohns Colitis. 2020 Jan 1;14(1):4-22. doi: 10.1093/ecco-jcc/jjz180. PMID: 31711158.
Onal IK, Kekilli M, Tanoglu A, Erdal H, Ibis M, Arhan M. Tuberculosis and Crohn's Disease Revisited. J Coll Physicians Surg Pak. 2015 Jun;25(6):443-8. PMID: 26100999.

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Clinical Case

Session

CLINICAL CASES (Posters)

Published

2025

More Like This:

ENDO-HISTO FOUNDATIONAL FUSION MODEL: A NOVEL ARTIFICIAL INTELLIGENCE APPROACH FOR PREDICTING HISTOLOGIC REMISSION AND EARLY RESPONSE TO THERAPY IN A PHASE 2 ULCERATIVE COLITIS CLINICAL TRIAL

Valery Naranjo

EXOPHIALA DERMATITIDIS EXACERBATES COLITIS THROUGH THE SYK-CARD9 SIGNALING PATHWAY

Yufang Wang

THE ROLE AND MECHANISM OF RIBONUCLEOTIDE REDUCTASE M2 (RRM2) IN SORAFENIB RESISTANCE OF HEPATOCELLULAR CARCINOMA

Qiang Yu

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

Stefano Fiorucci

JAK INHIBITORS EXHIBIT SUPERIOR CLINICAL EFFICACY COMPARED TO ANTI-IL-23 BIOLOGICS IN REFRACTORY ULCERATIVE COLITIS

Naila Arebi

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

UEG Presentation

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ENDO-HISTO FOUNDATIONAL FUSION MODEL: A NOVEL ARTIFICIAL INTELLIGENCE APPROACH FOR PREDICTING HISTOLOGIC REMISSION AND EARLY RESPONSE TO THERAPY IN A PHASE 2 ULCERATIVE COLITIS CLINICAL TRIAL

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ENDO-HISTO FOUNDATIONAL FUSION MODEL: A NOVEL ARTIFICIAL INTELLIGENCE APPROACH FOR PREDICTING HISTOLOGIC REMISSION AND EARLY RESPONSE TO THERAPY IN A PHASE 2 ULCERATIVE COLITIS CLINICAL TRIAL

Marietta Iacucci 1, Giovanni Santacroce 1, Pablo Meseguer 2, Rocio Del Amor 3, Alejandro Diéguez 3, Bisi Bode Kolawole 4, Ujwala Chaudhari 4, Irene Zammarchi 1, Brian Hayes 5, Rory Crotty 5, Davide Zardo 6, Yasuharu Maeda 1, Ilaria Ditonno 1, Valentina Vadori 4, Louise Burke 5, Klaus Gottlieb 7, Charles Owen 7, William J. Eastman 7, Subrata Ghosh 1, Enrico Grisan 4, Valery Naranjo 3

Affiliations

1 University College Cork, Cork, Ireland

2 Universitat Politècnica de València, Valencia, Spain|||valgrAI – Valencian Graduate School and Research Network of Artificial Intelligence, Valencia, Spain

3 Universitat Politècnica de València, Valencia, Spain

4 London South Bank University, London, United Kingdom

5 Cork University Hospital, Cork, Ireland

6 San Bortolo Hospital, Vicenza, Italy

7 Eli Lilly and Company, Indianapolis, United States

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Abstract

Introduction

Artificial Intelligence (AI)- enabled endoscopy and histology offer accurate, objective, and rapid assessment of disease activity in Ulcerative Colitis (UC). Emerging multi-source AI models integrating diverse datasets may enhance standardised disease evaluation and outcome prediction.

Aims & Methods

This study aimed to develop a novel AI model fusing endoscopic and histological findings to improve the assessment of disease remission and predict early response to therapy in UC clinical trials. A novel multimodal AI fusion algorithm was developed by integrating paired endoscopic videos and histological whole-slide images (WSIs) from the phase 2 clinical trial of Mirikizumab in UC (NCT02589665). The endoscopy branch of the model was trained with 291 white-light videos, using a convolutional neural network to select informative frames and the BioMedCLIP foundational model to extract features. The histology branch utilised the CONCH foundational model and was fine-tuned on 291 WSIs to obtain patch-level features. Features from both modalities were aggregated and fused using multi-head self-attention. The model’s ability to assess histological remission and response to therapy at weeks 12 and 52 was evaluated. Histological remission was defined as Geboes ≤2B.0, while a response to therapy at different time points was based on histological remission or improvement (Geboes <3.1).

Results

The fusion model outperformed single-modality assessments for histological remission, achieving a sensitivity of 89.72% (95% CI: 82.35–94.76), specificity of 89.67% (95% CI: 84.34–93.67), and accuracy of 89.69% (95% CI: 85.61–92.94). It demonstrated remarkable performance in assessing response to therapy at 12 and 52 weeks, with sensitivity of 97.96% (95% CI: 89.15–99.95), specificity of 86.84% (95% CI: 71.91–95.59) and accuracy of 93.10% (95% CI 85.59 – 97.43) for histological remission at week 52. Substantial agreement was observed between the AI fusion model and central readout.

	Histologic remission			Response to therapy
	Endoscopy-only	Histology-only	Endo-Histo fusion	Histologic improvement week 12	Histologic improvement week 52	Histologic remission week 12	Histologic remission week 52
Sensitivity (95% CI)	75.80% (66.46 – 83.47)	85.98% (77.93 – 91.94)	89.72% (82.35 – 94.76)	86.54% (74.21 – 94.41)	93.88% (88.13 – 98.72)	79.59% (65.66 – 89.76)	97.96% (89.15 – 99.95)
Specificity (95% CI)	73.91% (66.94 - 80.10)	88.59% (83.08 – 92.79)	89.67% (84.34 – 93.67)	76.00% (61.83 – 86.94)	81.58% (65.67 – 92.26)	73.58% (59.67 – 84.74)	86.84% (71.91 – 95.59)
PPV (95% CI)	62.79% (53.84 - 71.14)	81.42% (73.01 – 88.11)	83.48% (75.41 – 89.75)	78.95% (66.11 – 88.62)	86.79% (74.66 – 94.52)	73.58% (59.67 – 84.74)	90.57% (79.34 – 96.87)
NPV (95% CI)	83.95% (77.37 – 89.24)	91.57% (86.48 – 95.21)	93.75% (89.09 – 96.84)	84.44% (70.54 – 93.51)	91.18% (76.32 – 98.14)	79.59% (65.66 – 89.76)	97.06% (84.67 – 99.93)
Accuracy (95% CI)	74.57% (69.16 – 79.47)	87.63% (83.29 – 91.18)	89.69% (85.61 – 92.94)	81.37% (72.45 – 88.40)	88.51% (79.88 – 94.35)	76.47% (67.04 – 84.31)	93.10% (85.59 – 97.43)
F1 Score (95% CI)	68.64% (62.31 – 74.51)	83.64% (78.07 – 88.27)	86.49% (81.27 – 90.69)	82.57% (74.13 – 89.17)	90.20% (82.71 – 95.20)	76.47% (67.04 – 84.31)	94.12% (87.64 – 97.81)

Abbreviations: CI, confidence interval; NPV, negative predictive value; PPV, positive predictive value.

Conclusion

This innovative multimodal fusion AI model enhances the assessment of histological remission and accurately predicts response to therapy. By potentially standardising central readouts and enabling automated disease assessment, this novel tool marks a significant advancement towards precision medicine in clinical trials.

Disclosure

Marietta Iacucci received research grants and consultant fees from Olympus, Pentax, Eli Lilly, and Janssen. All other authors declare no competing interests.

Event

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

Artificial intelligence in IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

ENDO-HISTO FOUNDATIONAL FUSION MODEL: A NOVEL ARTIFICIAL INTELLIGENCE APPROACH FOR PREDICTING HISTOLOGIC REMISSION AND EARLY RESPONSE TO THERAPY IN A PHASE 2 ULCERATIVE COLITIS CLINICAL TRIAL

Valery Naranjo

EXOPHIALA DERMATITIDIS EXACERBATES COLITIS THROUGH THE SYK-CARD9 SIGNALING PATHWAY

Yufang Wang

THE ROLE AND MECHANISM OF RIBONUCLEOTIDE REDUCTASE M2 (RRM2) IN SORAFENIB RESISTANCE OF HEPATOCELLULAR CARCINOMA

Qiang Yu

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

Stefano Fiorucci

JAK INHIBITORS EXHIBIT SUPERIOR CLINICAL EFFICACY COMPARED TO ANTI-IL-23 BIOLOGICS IN REFRACTORY ULCERATIVE COLITIS

Naila Arebi

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

UEG Presentation

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

EXOPHIALA DERMATITIDIS EXACERBATES COLITIS THROUGH THE SYK-CARD9 SIGNALING PATHWAY

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EXOPHIALA DERMATITIDIS EXACERBATES COLITIS THROUGH THE SYK-CARD9 SIGNALING PATHWAY

Rui Zhong 1, Meng Sun 1, Jingyi Ju 1, Mengqi Luo 1, Yufang Wang 1

Affiliations

1 West China Hospital of Sichuan University, Chengdu, China

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Abstract

Introduction

As a small but important component of the intestinal microbiota, the fungal community (mycobiota) has received increasing attention for its involvement in the pathogenesis of Crohn's disease (CD)¹. In our previous study, we identified a significantly increased relative abundance of Exophiala dermatitidis (E. dermatitidis) in the gut of patients with CD, particularly those with active disease². Caspase recruitment domain family member 9 (CARD9), a key adaptor molecule in antifungal immune responses³, has also been strongly associated with CD susceptibility⁴. In this study, we aimed to explore the potential role and underlying mechanisms of E. dermatitidis in intestinal inflammation.

Aims & Methods

To evaluate the impact of E. dermatitidis on intestinal inflammation, we generated Card9-knockout (KO) (Card9^-/-) mice and constructed a dextran sulfate sodium (DSS)-induced colitis model colonized by E. dermatitidis. The underlying molecular mechanisms were investigated by a range of biochemical approaches. Flow cytometry was performed to analyze the proportions of myeloid cells, including CX3CR1⁺ macrophages, in the colonic lamina propria (LP).

Results

Compared to mice with DSS-induced colitis alone (WT-DSS group), the DSS-treated mice colonized by E. dermatitidis (WT-DSS + Ed group) showed a significant weight loss, a worsening of disease activity, a shorter length of the large intestine, and more severe intestinal inflammation characterized by increased inflammatory cell infiltration and crypt destruction in the histological examination of colon hematoxylin and eosin (H&E) staining. Card9^-/- mice were used to further investigate whether E. dermatitis-mediated inflammation was dependent on the CARD9 signaling pathway. We observed that CARD9 deficiency protected against E. dermatitidis-exacerbated colitis, as measured by a higher trend of body weight, longer colon lengths, and amelioration of disease activity in the KO-DSS + Ed group. In addition, flow cytometric analysis of the colonic lamina propria revealed a higher percentage proportion of CX3CR1+ macrophages in the WT-DSS + Ed group and a markedly reduced proportion in the KO-DSS + Ed group. Furthermore, we identified the Mincle-Syk-CARD9-nuclear factor kappa-B (NF-κB) signaling pathway as playing an important role in mediating the inflammatory immune responses to E. dermatitidis.

Conclusion

E. dermatitidis exacerbates the DSS-induced colitis in mice through the Mincle-Syk-CARD9-NF-κB pathway with the participation of CX3CR1+ macrophages, providing a novel therapeutic strategy for CD targeting specific intestinal fungi.

References

1. Sokol H, Leducq V, Aschard H, et al. Fungal microbiota dysbiosis in IBD. Gut 2017;66:1039-1048.
2. Zeng L, Feng Z, Zhuo M, et al. Fecal fungal microbiota alterations associated with clinical phenotypes in Crohn's disease in southwest China. PeerJ 2022;10:e14260.
3. Hu A, Hu Z, Zou H, et al. CARD9 in host immunity to fungal, bacterial, viral, and parasitic infections: An update. Frontiers In Microbiology 2022;13:1021837.
4. Franke A, McGovern DPB, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature Genetics 2010;42:1118-1125.

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

More Like This:

ENDO-HISTO FOUNDATIONAL FUSION MODEL: A NOVEL ARTIFICIAL INTELLIGENCE APPROACH FOR PREDICTING HISTOLOGIC REMISSION AND EARLY RESPONSE TO THERAPY IN A PHASE 2 ULCERATIVE COLITIS CLINICAL TRIAL

Valery Naranjo

EXOPHIALA DERMATITIDIS EXACERBATES COLITIS THROUGH THE SYK-CARD9 SIGNALING PATHWAY

Yufang Wang

THE ROLE AND MECHANISM OF RIBONUCLEOTIDE REDUCTASE M2 (RRM2) IN SORAFENIB RESISTANCE OF HEPATOCELLULAR CARCINOMA

Qiang Yu

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

Stefano Fiorucci

JAK INHIBITORS EXHIBIT SUPERIOR CLINICAL EFFICACY COMPARED TO ANTI-IL-23 BIOLOGICS IN REFRACTORY ULCERATIVE COLITIS

Naila Arebi

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

UEG Presentation

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

THE ROLE AND MECHANISM OF RIBONUCLEOTIDE REDUCTASE M2 (RRM2) IN SORAFENIB RESISTANCE OF HEPATOCELLULAR CARCINOMA

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THE ROLE AND MECHANISM OF RIBONUCLEOTIDE REDUCTASE M2 (RRM2) IN SORAFENIB RESISTANCE OF HEPATOCELLULAR CARCINOMA

Qiang Yu 1

Affiliations

1 Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

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Abstract

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer-related deaths globally, with increasing incidence and mortality rates. Most patients are diagnosed at advanced stages, missing the opportunity for radical treatment. Sorafenib, a tyrosine kinase inhibitor, is the first-line treatment for advanced HCC; however, drug resistance typically develops within 6 months. Therefore, elucidating the mechanisms of sorafenib resistance and identifying new therapeutic targets are of significant importance. Our study focuses on the role and mechanism of Ribonucleotide Reductase M2 (RRM2) in sorafenib resistance in HCC.

Aims & Methods

The primary objective of this study is to investigate the role of RRM2 in sorafenib resistance in HCC and explore its underlying mechanisms. We aim to clarify whether RRM2 regulates aerobic glycolysis via the HIF-1α/HK2 pathway, thereby affecting sorafenib sensitivity. Our methods include:

Analyzing RRM2 expression in HCC tissues and its correlation with clinical outcomes, such as disease-free survival (DFS) and overall survival (OS).
Establishing sorafenib-resistant HCC cell lines (LM3-SR and SMMC7721-SR) and manipulating RRM2 expression using lentiviral vectors for knockdown and overexpression.
Conducting in vitro experiments to assess the effects of RRM2 on cell proliferation, apoptosis, glycolysis, and sorafenib sensitivity using assays such as CCK8, flow cytometry, and Seahorse analysis.
Performing in vivo studies using a nude mouse xenograft model to evaluate the impact of RRM2 knockdown on tumor growth and sorafenib efficacy.
Utilizing RNA-seq, Western blot, PCR, and other techniques to investigate the molecular mechanisms, including the potential regulation of HIF-1α and HK2 by RRM2.

Results

Clinical Correlation: RRM2 expression was significantly higher in HCC tissues compared to adjacent normal tissues. Higher RRM2 levels were associated with shorter DFS and OS in HCC patients.
In Vitro Findings: RRM2 knockdown in sorafenib-resistant HCC cells (LM3-SR and SMMC7721-SR) increased sensitivity to sorafenib, as evidenced by reduced cell viability and increased apoptosis. Additionally, RRM2 knockdown decreased glycolysis, as indicated by reduced lactate production and glucose uptake. Conversely, RRM2 overexpression in HCC cells promoted resistance to sorafenib and enhanced glycolysis.
Molecular Mechanisms: RRM2 regulated the expression of glycolytic enzymes, particularly HK2, through the HIF-1α pathway. Knockdown of RRM2 reduced HIF-1α and HK2 expression, while overexpression of HIF-1α or HK2 could reverse the effects of RRM2 knockdown on glycolysis and sorafenib sensitivity.
In Vivo Validation: In a nude mouse xenograft model, RRM2 knockdown enhanced the inhibitory effects of sorafenib on tumor growth, as demonstrated by reduced tumor volume and increased apoptosis.

Conclusion

Our study demonstrates that RRM2 plays a crucial role in sorafenib resistance in HCC by regulating aerobic glycolysis via the HIF-1α/HK2 pathway. Targeting RRM2 or its downstream pathways may represent a promising strategy to overcome sorafenib resistance and improve therapeutic outcomes in HCC patients. Future work will focus on further elucidating the molecular mechanisms and exploring the potential clinical applications of RRM2 as a therapeutic target.

Disclosure

The authors declare that they have no conflict of interest.

Event

UEG Week Berlin 2025

Topics

Hepatobiliary Immunology Mechanisms & Personalised Medicine

Submission format

Abstract

Session

Bench to bedside and beyond frontiers in HCC

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

ENDO-HISTO FOUNDATIONAL FUSION MODEL: A NOVEL ARTIFICIAL INTELLIGENCE APPROACH FOR PREDICTING HISTOLOGIC REMISSION AND EARLY RESPONSE TO THERAPY IN A PHASE 2 ULCERATIVE COLITIS CLINICAL TRIAL

Valery Naranjo

EXOPHIALA DERMATITIDIS EXACERBATES COLITIS THROUGH THE SYK-CARD9 SIGNALING PATHWAY

Yufang Wang

THE ROLE AND MECHANISM OF RIBONUCLEOTIDE REDUCTASE M2 (RRM2) IN SORAFENIB RESISTANCE OF HEPATOCELLULAR CARCINOMA

Qiang Yu

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

Stefano Fiorucci

JAK INHIBITORS EXHIBIT SUPERIOR CLINICAL EFFICACY COMPARED TO ANTI-IL-23 BIOLOGICS IN REFRACTORY ULCERATIVE COLITIS

Naila Arebi

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

UEG Presentation

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

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

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

Cristina Di Giorgio 1, Carmen Massa 1, Michele Biagioli 1, Ginevra Lachi 1, Eleonora Giannelli 1, Silvia Marchianò 1, Ginevra Urbani 1, Benedetta Sensini 1, Francesca Paniconi 1, Maria Rosaria Sette 1, Elva Morretta 2, Maria Chiara Monti 2, Angela Zampella 2, Stefano Fiorucci 1

Affiliations

1 University of Perugia, Perugia, Italy

2 University of Naples, Federico II, Naples, Italy

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Abstract

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).

Event

UEG Week Berlin 2025

Topics

Hepatobiliary Immunology Mechanisms & Personalised Medicine

Submission format

Abstract

Session

Advances in management of immune-mediated biliary disease

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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ENDO-HISTO FOUNDATIONAL FUSION MODEL: A NOVEL ARTIFICIAL INTELLIGENCE APPROACH FOR PREDICTING HISTOLOGIC REMISSION AND EARLY RESPONSE TO THERAPY IN A PHASE 2 ULCERATIVE COLITIS CLINICAL TRIAL

Valery Naranjo

EXOPHIALA DERMATITIDIS EXACERBATES COLITIS THROUGH THE SYK-CARD9 SIGNALING PATHWAY

Yufang Wang

THE ROLE AND MECHANISM OF RIBONUCLEOTIDE REDUCTASE M2 (RRM2) IN SORAFENIB RESISTANCE OF HEPATOCELLULAR CARCINOMA

Qiang Yu

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

Stefano Fiorucci

JAK INHIBITORS EXHIBIT SUPERIOR CLINICAL EFFICACY COMPARED TO ANTI-IL-23 BIOLOGICS IN REFRACTORY ULCERATIVE COLITIS

Naila Arebi

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

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JAK INHIBITORS EXHIBIT SUPERIOR CLINICAL EFFICACY COMPARED TO ANTI-IL-23 BIOLOGICS IN REFRACTORY ULCERATIVE COLITIS

Magdalini Manti 1, Nikolaos Kamperidis 1, Alexandros Toskas 1, Ravi Misra 1, Jeremy Nightingale 1, Naila Arebi 1

Affiliations

1 St Mark's National Bowel Hospital, London, United Kingdom

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Abstract

Introduction

Biologic therapies play a pivotal role in the management of ulcerative colitis (UC). Anti-TNFα agents are recommended as first-line biologics according to ECCO guidelines; however, JAK inhibitors have recently emerged as a viable alternative (1). Vedolizumab has also demonstrated effectiveness when introduced early in the disease course with a greater 52-week treatment persistence and reduced hospitalisation rates compared to anti-TNFα agents as second-line therapy (2). The AGA guidelines (3) now favour biologics such as anti-IL-23 and JAK inhibitors over Vedolizumab or S1P receptor modulators in patients previously exposed to anti-TNFα agents. Notably, Guselkumab is not yet approved for UC treatment in the UK. The latest ECCO guidelines (1) do not address the role of biologics in third-line or subsequent treatment settings, and there remains a lack of clear clinical guidance.

Aims & Methods

This study aimed to retrospectively evaluate the effectiveness of third-line biologic therapies in adult patients with UC over a 12-month period. Clinical response was assessed using the Simple Clinical Colitis Activity Index (SCCAI), Partial Mayo Score, and Physician Global Assessment, while biochemical and endoscopic responses were measured at 3, 6, and 12 months post-induction. Biochemical markers included faecal calprotectin and CRP levels. Endoscopic response was assessed using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Colectomy rates were also recorded. Patients treated at a UK tertiary care centre were included up to March 2025. Statistical analyses were conducted using SPSS.

Results

A total of 24 patients were included in the analysis, with 13 receiving anti-IL-23 therapy and 11 treated with JAK inhibitors. Within the anti-IL-23 group, 5 patients received Mirikizumab and 8 Ustekinumab; Risankizumab was not used in this cohort. In the JAK group, 3 patients were treated with Upadacitinib, 4 with Filgotinib, and 4 with Tofacitinib. A statistically significant reduction in SCCAI scores at 6 months was observed in the JAK groups compared to anti-IL-23 (7.64 ± 3.61 vs 4.90 ± 1.97, p = 0.047). However, biochemical response, assessed by faecal calprotectin reduction, did not reach statistical significance at either 3 or 6 months (p = 1.000 and p = 0.314, respectively). Endoscopic response, measured by changes in UCEIS at 12 months, also showed no significant difference between groups (p = 0.668). Subgroup analysis within the anti-IL-23 cohort revealed no significant difference in SCCAI reduction between Ustekinumab and Mirikizumab at 3 months. Similarly, while Upadacitinib was associated with the greatest SCCAI reduction among the JAK inhibitors at 3 months, the difference among the three agents was not statistically significant (p = 0.106). Subtotal colectomy was performed in one patient in the Mirikizumab group following completion of induction therapy, and in two additional patients within three months of initiating the same agent (Table 1).

Biologic	Patients (N)	Colectomy(N)	Drug persistence
Mirikizumab	5	3	3/5
Ustekinumab	8	1	5/8
Upadacitinib	3	0	3/3
Filgotinib	4	0	3/4
Tofacitinib	4	0	4/4

Table 1. Patients’ characteristics regarding clinical, biochemical and surgical outcomes within 12 months.

Conclusion

JAK inhibitors showed an improvement in SCCAI at 6 months compared to anti-IL-23 agents. No significant differences were found in biochemical or endoscopic response.

References

1. Raine T, Bonovas S, Burisch J, Kucharzik T, Adamina M, Annese V, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. Journal of Crohn’s and Colitis. 2022 Jan 28;16(1):2–17.
2. Miller C, Kwok H, Harrow P, Vega R, Seward E, Mehta S, et al. Comparative effectiveness of a second-line biologic in patients with ulcerative colitis: vedolizumab followed by an anti-TNF versus anti-TNF followed by vedolizumab. Frontline Gastroenterol. 2022 Sep;13(5):392–401.
3. Singh S, Loftus EV, Limketkai BN, Haydek JP, Agrawal M, Scott FI, et al. AGA Living Clinical Practice Guideline on Pharmacological Management of Moderate-to-Severe Ulcerative Colitis. Gastroenterology. 2024 Dec;167(7):1307–43.

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

IBD (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

ENDO-HISTO FOUNDATIONAL FUSION MODEL: A NOVEL ARTIFICIAL INTELLIGENCE APPROACH FOR PREDICTING HISTOLOGIC REMISSION AND EARLY RESPONSE TO THERAPY IN A PHASE 2 ULCERATIVE COLITIS CLINICAL TRIAL

Valery Naranjo

EXOPHIALA DERMATITIDIS EXACERBATES COLITIS THROUGH THE SYK-CARD9 SIGNALING PATHWAY

Yufang Wang

THE ROLE AND MECHANISM OF RIBONUCLEOTIDE REDUCTASE M2 (RRM2) IN SORAFENIB RESISTANCE OF HEPATOCELLULAR CARCINOMA

Qiang Yu

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

Stefano Fiorucci

JAK INHIBITORS EXHIBIT SUPERIOR CLINICAL EFFICACY COMPARED TO ANTI-IL-23 BIOLOGICS IN REFRACTORY ULCERATIVE COLITIS

Naila Arebi

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

UEG Presentation

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NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

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NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Kaming Ma 1, Parakkal Deepak 2, Matthew Ciorba 3, Siyan Cao 1

Affiliations

1 Washington University in St. Louis, St. Luis, United States

2 Washington University in St. Louis, St. Louis, United States

3 Matthew Ciorba, MD Professor of Medicine, Director of Inflammatory Bowel Disease Center, Waschington University in Saint Louis, Washington DC, United States

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Abstract

Introduction

Very early onset inflammatory bowel disease (VEO-IBD) is often associated with a severe disease course and unique characteristics including an underlying monogenic defect. In this study, we identified new pathogenic mutations in CGNL1 associated with VEO-IBD and other inflammatory GI disease. CGNL1 (Cingulin Like 1) encodes an epithelial junctional protein whose function was previously unknown in the gastrointestinal tract.

Aims & Methods

Whole exome sequencing (WES) was performed on the affected patient with VEO-IBD and all first-degree relatives with IBD and other inflammatory disease. Intestinal epithelial organoids (IEOs) were generated from the affected patient and were characterized by transepithelial electrical resistance (TEER), FITC-dextran permeability assay on epithelial cell monolayer, immunostaining, RNA sequencing, and transmission electron microscopy (TEM). In addition, we generated a new Cgnl1^-/- mouse model, which was characterized using FITC-dextran permeability assay, TEM, dextran-sodium sulfate (DSS)-induced colitis, and infections by Citrobacter rodentium and Clostridioides difficile. Single-cell datasets were analyzed to determine CGNL1 expression in IBD, primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH).

Results

In the affected patient with VEO-IBD who required early total colectomy and pouch formation with coexistent PSC and celiac disease, WES identified two rare, new, pathogenic variants in the CGNL1 gene. Both pathogenic variants were also present in the patient’s younger sister, who has a similar history including early-onset, fulminant ulcerative colitis requiring total colectomy with ileostomy and PSC-AIH overlap syndrome. Furthermore, multiple relatives of the patient suffer from IBD and other inflammatory conditions including celiac disease, eosinophilic esophagitis, and type-1 diabetes. The RNA and protein levels of CGNL1 were significantly diminished in the patient’s intestinal epithelial cells compared to that of healthy individuals and other IBD patients by RNA-seq, immunoblotting, and immunostaining. The patient’s IEOs from pouch body and pre-pouch ileum formed smaller 3D spheroids with altered cell composition and significantly impaired barrier function compared to those from healthy controls and other IBD patients. Immunofluorescence and TEM demonstrated that CGNL1 is required for the assembly of junctional complexes in human IEOs and an epithelial cell line. Similarly to findings from the patient, impaired junctional complexes in intestinal epithelial cells and elevated intestinal permeability were present in Cgnl1^-/- mice at steady state. Cgnl1^-/- mice showed substantial vulnerability to DSS-induced colitis and bacterial infections that directly compromise the epithelial barrier. In addition, 6-month-old Cgnl1^-/- mice exhibited spontaneous inflammation in the colon and terminal ileum due to disrupted intestinal barrier, which was microbiome-dependent. Furthermore, single-cell analysis revealed diminished expression of CGNL1 in the intestinal and hepatic epithelial cells from patients with IBD or PSC/AIH, respectively.

Conclusion

The pathogenic CGNL1 variants contribute to VEO-IBD by disrupting gut barrier integrity, as demonstrated by patient’s cells and novel murine models. This study expands our understanding of epithelial barrier impairment in the pathogenesis of VEO-IBD, and highlights intestinal epithelium as a therapeutic target in some IBD patients.

Event

UEG Week Berlin 2025

Topics

IBD Mechanisms & Personalised Medicine

Submission format

Abstract

Session

New insights into IBD pathology

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

ENDO-HISTO FOUNDATIONAL FUSION MODEL: A NOVEL ARTIFICIAL INTELLIGENCE APPROACH FOR PREDICTING HISTOLOGIC REMISSION AND EARLY RESPONSE TO THERAPY IN A PHASE 2 ULCERATIVE COLITIS CLINICAL TRIAL

Valery Naranjo

EXOPHIALA DERMATITIDIS EXACERBATES COLITIS THROUGH THE SYK-CARD9 SIGNALING PATHWAY

Yufang Wang

THE ROLE AND MECHANISM OF RIBONUCLEOTIDE REDUCTASE M2 (RRM2) IN SORAFENIB RESISTANCE OF HEPATOCELLULAR CARCINOMA

Qiang Yu

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

Stefano Fiorucci

JAK INHIBITORS EXHIBIT SUPERIOR CLINICAL EFFICACY COMPARED TO ANTI-IL-23 BIOLOGICS IN REFRACTORY ULCERATIVE COLITIS

Naila Arebi

NEW PATHOGENIC MUTATIONS IN AN EPITHELIAL JUNCTION GENE CONTRIBUTING TO VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Siyan Cao

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