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EXOPHIALA DERMATITIDIS EXACERBATES COLITIS THROUGH THE SYK-CARD9 SIGNALING PATHWAY

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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.

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

1 West China Hospital of Sichuan University, Chengdu, China

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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What can we learn from monogenic IBD

Alexo Muise 1

1 SickKids Research Institute, Toronto, Canada

Event

UEG Week Berlin 2025

Topics

IBD Mechanisms & Personalised Medicine

Session

The art of making clinical research precise: Predicting therapy response in IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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GUT MYCOBIOME SIGNATURES PREDICT NEOADJUVANT IMMUNOCHEMOTHERAPY RESPONSE IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA: A MACHINE LEARNING APPROACH WITH EXPERIMENTAL VALIDATION

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Introduction

Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis despite advances in neoadjuvant immunochemotherapy (NICT). With highly variable treatment responses, identifying reliable predictive biomarkers remains crucial. While gut microbiome influences on immunotherapy efficacy are increasingly recognized, the specific role of the fungal microbiome (mycobiome) in NICT outcomes for ESCC remains unexplored, representing a significant gap in developing personalized treatment strategies.

Aims & Methods

This study aimed to characterize gut mycobiome signatures in ESCC patients and develop fungal biomarker-based predictive models for NICT response. We conducted ITS2 sequencing on 136 fecal samples collected from 68 ESCC patients (pre- and post-NICT) and 19 healthy controls (HC). Patients were stratified as responders (R, n=26) or non-responders (NR, n=42) based on tumor regression grade (TRG) scores. We performed comprehensive analyses of mycobiome diversity, composition, co-occurrence networks, and functional pathways across groups. The Boruta algorithm was employed for feature selection to identify fungal biomarkers, followed by multilayer perceptron (MLP) machine learning with five-fold cross-validation to develop predictive models. Additionally, ESCC xenograft models were established to investigate gut mycobiome-immune interactions through fecal microbiota transplantation (FMT) and targeted fungal manipulation experiments.

Results

ESCC patients demonstrated significant mycobiome dysbiosis compared to healthy controls, characterized by reduced fungal alpha diversity and distinct beta diversity patterns. At baseline, ESCC patients showed enrichment of Rhodotorula minuta, Actinomucor elegans, and several Candida species. Responders exhibited significantly higher baseline fungal diversity than non-responders, with enrichment of Meyerozyma, Candida boidinii, Trichosporon dermatis, and Cryptococcus species, whereas non-responders showed predominance of Saccharomyces, Nakaseomyces, and pathogenic Candida species (C. glabrata, C. parapsilosis, C. albicans). Responders also displayed more complex, stable fungal co-occurrence networks with higher density and clustering coefficients. Post-NICT, both groups showed partial recovery of mycobiome diversity, with significant increases in beneficial fungal taxa. Functional pathway analysis revealed distinct metabolic profiles between responders and non-responders. Using the Boruta algorithm, we identified 23 genus-level and 22 species-level fungal biomarkers that demonstrated high predictive value. The MLP model based on genus-level markers achieved AUCs of 90.2% (training) and 91.9% (test), while the species-level model showed comparable performance. In animal experiments, mice receiving R-FMT exhibited reduced tumor growth and enhanced CD8+ T cell infiltration compared to NR-FMT recipients. Notably, Candida boidinii supplementation synergized with anti-PD-1 therapy, while Saccharomyces depletion enhanced treatment sensitivity.

Conclusion

Our findings establish the gut mycobiome as a powerful predictor of NICT response in ESCC, with machine learning models achieving >90% accuracy using fungal biomarkers. Experimental validation not only confirms mechanistic links between specific fungi and antitumor immunity but also demonstrates that targeted mycobiome modulation can enhance immunotherapy efficacy. This dual approach of prediction and intervention offers a novel framework for precision oncology in ESCC, potentially transforming clinical decision-making and treatment outcomes in this challenging malignancy.

References

1. Li J, Xu J, Zheng Y, et al. Esophageal cancer: Epidemiology, risk factors and screening. Chin J Cancer Res. 2021; 33(5): 535-547.
2. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012; 366(22): 2074-2084.
3. Schroeder W, Ghadimi M, Schloesser H, et al. Long-Term Outcome After Histopathological Complete Response with and Without Nodal Metastases Following Multimodal Treatment of Esophageal Cancer. Ann Surg Oncol. 2022.
4. Rosner S, Liu C, Forde PM, Hu C. Association of Pathologic Complete Response and Long-Term Survival Outcomes Among Patients Treated With Neoadjuvant Chemotherapy or Chemoradiotherapy for NSCLC: A Meta-Analysis. JTO Clin Res Rep. 2022; 3(9): 100384.
5. Coker OO, Nakatsu G, Dai RZ, et al. Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer. Gut. 2019; 68(4): 654-662.
6. Dohlman AB, Klug J, Mesko M, et al. A pan-cancer mycobiome analysis reveals fungal involvement in gastrointestinal and lung tumors. Cell. 2022; 185(20): 3807-3822.
7. Wurster S, Albert ND, Kontoyiannis DP. Candida auris Bloodstream Infection Induces Upregulation of the PD-1/PD-L1 Immune Checkpoint Pathway in an Immunocompetent Mouse Model. Msphere. 2022; 7(2): e81721.

GUT MYCOBIOME SIGNATURES PREDICT NEOADJUVANT IMMUNOCHEMOTHERAPY RESPONSE IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA: A MACHINE LEARNING APPROACH WITH EXPERIMENTAL VALIDATION

le liu 1, Liping Liang 2, Shijie Mai 3

1 Zhujiang Hospital, Southern Medical University, Guangzhou, China

2 Guangzhou First People's Hospital, Guangzhou, China

3 Nanfang Hospital, Southern Medical University, Guangzhou, China

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Gut Microbiota Immunology Mechanisms & Personalised Medicine Oesophagus

Submission format

Abstract

Session

Oncobiome

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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IL-23

Laurent Peyrin-Biroulet 1

1 Inserm NGERE and University of Lorraine, Vandœuvre-lès-Nancy, France

Event

UEG Week Berlin 2025

Topics

IBD Mechanisms & Personalised Medicine

Session

What's new in advanced therapies for IBD in 2025?

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Wound healing in fistula and surgical wounds

Christianne Johanna Buskens 1

1 Academic Medical Center, Amsterdam, Netherlands

Event

UEG Week Berlin 2025

Topics

IBD Primary Care Surgery

Session

Disease primer: From inflammation to restoration - wound healing in IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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REAL-LIFE VS CLINICAL TRIAL ACCESS TO BIOLOGICAL THERAPY: FINDINGS FROM AN ITALIAN-AMERICAN STUDY ON INFLAMMATORY BOWEL DISEASE

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Introduction

Treatment goals in inflammatory bowel disease (IBD) have evolved beyond symptom control to include mucosal healing, prevention of disease-related complications, improvement of health-related quality of life, and reduction of long-term disability, as outlined by the STRIDE II initiative¹. Despite significant progress in the development of advanced therapies (ADTs), up to 50% of IBD patients fail to respond to currently available treatments, underscoring the urgent need for new therapies, which are investigated in randomized clinical trials (RCTs). However, stringent eligibility criteria in RCTs limit the inclusion of real-world IBD patients, potentially compromising the generalizability of trial findings to daily clinical practice.

Aims & Methods

The aim of this study was to evaluate the proportion of real-life IBD patients who would be eligible for ongoing RCTs and to assess the representativeness of this population. Moreover, we aimed to identify the most frequently unmet eligibility criteria leading to patient exclusion and to characterize the clinical profiles that differentiate eligible from ineligible patients.
This prospective, observational, multicenter study was conducted between October 2023 and October 2024 at 2 tertiary IBD referral centers: the Fondazione Policlinico Universitario “A. Gemelli” in Rome, Italy, and the Crohn’s & Colitis Center at the University of Miami, USA. Consecutive patients with IBD indicated for a new ADT were enrolled. Each patient was systematically screened for inclusion and exclusion criteria across all actively recruiting phase 2b and 3 RCTs available at each center at the time of evaluation (6 RCTs in Rome: 4 UC and 2 CD; 5 RCTs in Miami: 3 UC and 2 CD).

Results

A total of 166 IBD patients (69 UC and 97 CD) were enrolled, with 129 patients from the Italian cohort and 37 from the American cohort. Among UC patients, only 16 (23.2%) met the eligibility criteria for at least 1 RCT, whereas 53 (76.8%) were deemed ineligible (p<0.001). In the CD group, just 10 patients (10.3%) were eligible for at least 1 RCT, compared to 87 (89.7%) who were not (p<0.001). The most common reasons for ineligibility among UC patients included: Modified Mayo score not within the required range of 5–9 (50.7%), absence of bowel urgency (63.8%), Mayo Endoscopic Subscore <2 (39.1%), failure to comply with ADT washout requirements (56.5%), insufficient number of prior ADT failures (39.0%), and recent use of topical 5-ASA or steroids within 4 weeks prior to screening (62.3%).
In CD patients, the most frequently unmet criterion was a CDAI between 220 and 450 (92.8%), followed by insufficiently liquid stool frequency (≥4 very soft or liquid stools/day; 75.3%), SES-CD<6 (39.2%), and the presence of CD-related complications such as strictures or fistulas (13.1%).

Conclusion

The majority of real-life IBD patients, particularly those with CD, are ineligible for participation in current RCTs—primarily due to relatively mild disease activity or ongoing need for concomitant therapies that are not permitted by trial protocols. Importantly, many real-world CD patients initiate new ADTs based on radiologic signs of disease activity, the presence of disease complications, or as prophylaxis for post-surgical recurrence, rather than clinical activity scores alone. Similarly, UC patients may require ADTs even in the context of corticosteroid dependence and low-grade disease activity. These findings underscore the need to revisit and broaden eligibility criteria in future RCTs to ensure greater external validity and alignment with the heterogeneity of real-life IBD population.

References

1. Turner D, Ricciuto A, Lewis A, D'Amico F, Dhaliwal J, Griffiths AM, Bettenworth D, Sandborn WJ, Sands BE, Reinisch W, Schölmerich J, Bemelman W, Danese S, Mary JY, Rubin D, Colombel JF, Peyrin-Biroulet L, Dotan I, Abreu MT, Dignass A; International Organization for the Study of IBD. 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 Apr;160(5):1570-1583. doi: 10.1053/j.gastro.2020.12.031. Epub 2021 Feb 19. PMID: 33359090.

REAL-LIFE VS CLINICAL TRIAL ACCESS TO BIOLOGICAL THERAPY: FINDINGS FROM AN ITALIAN-AMERICAN STUDY ON INFLAMMATORY BOWEL DISEASE

Federica Di Vincenzo 1, Stephanie Ioannou 2, Chiara Principessa 3, Ivan Capobianco 1, Antonio Gasbarrini 4, Lucrezia Laterza 4, Maria T. Abreu 5, Franco Scaldaferri 4

1 Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy

2 University of Miami - Jackson Health System, Miami, United States

3 Università Cattolica del Sacro Cuore, Roma, Italy

4 Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy

5 University of Miami Miller School of Medicine, Department of Medicine, Division of Gastroenterology, Miami, FL 33136; F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, United States