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.

Introduction

The use of patient-centric monitoring modalities for assessing therapies, such as vedolizumab (VDZ), are of growing interest to optimize disease outcomes in patients with Crohn’s disease (CD). Transmural healing is an emerging outcome assessed by intestinal ultrasonography (IUS), which allows frequent evaluation of CD.^1,2 Real-world evidence on the effectiveness of current treatments for induction and maintenance of a transmural response to inform treatment decisions is limited.

Aims & Methods

The SUNRISE study aims to describe patients with CD treated with VDZ achieving a composite outcome of complete remission, and transmural response, utilizing IUS. SUNRISE is an ongoing observational, prospective study (NCT05192863) being conducted across 10 sites in Canada, Israel and Italy. Adults with moderately to severely active CD, with a bowel wall thickness of > 3 mm based on IUS, and who newly initiated intravenous VDZ are eligible. Complete remission (defined as a composite endpoint of clinically corticosteroid-free [Harvey–Bradshaw Index score of < 5 points and no concomitant corticosteroids], biochemical [C-reactive protein and faecal calprotectin normalization] and transmural remission [assessed by IUS]) and transmural response after VDZ treatment are reported after induction with VDZ (Weeks 10/14) and every 6 months until Month 18 or early discontinuation. In addition, health-related quality of life (as measured by the Short Inflammatory Bowel Disease Questionnaire), healthcare resource utilization and patient satisfaction with IUS are reported.

Results

This interim analysis included 70 patients; median (interquartile range [IQR]) age was 50.0 (39.0–67.0) years, time since CD diagnosis was 4.0 (0.9–17.2) years and treatment duration (n = 69) was 5.0 (3.2–6.1) months. At Month 6 after VDZ initiation, the proportion of patients achieving complete remission, and transmural remission and response were 3/11 (27.3%), 9/28 (32.1%) and 12/28 (42.9%) patients, respectively; data at Weeks 10/14 are shown in the Table. Median (IQR) Short Inflammatory Bowel Disease Questionnaire total score was 4.3 (3.7–5.6) at baseline, 4.5 (3.4–5.3) at Week 10, 4.7 (3.9–5.6) at Week 14 and 5.0 (4.4–6.1) at Month 6. At Month 6, 10/21 patients (47.6%) ranked IUS as their preferred test over colonoscopy, magnetic resonance elastography and computed tomography enterography. Of 40 patients with available data at Month 6, 6 (15.0%) discontinued treatment, 5 (12.5%) switched to subcutaneous VDZ and 1 (2.5%) skipped ≥ 1 dose of VDZ. During the observation period, 2/70 patients (2.9%) had a CD-related hospitalization, and 1/70 patient (1.4%) each had a CD-related emergency room visit or CD-related surgery (fistula removal).

Table​

Conclusion

The SUNRISE study provides real-world evidence for the use of VDZ to achieve transmural healing in patients with CD and supports patient preference for IUS over other monitoring modalities. Additional follow-up data are required to confirm these findings.
This abstract was previously presented at the European Crohn’s and Colitis Organisation (ECCO) 2025 congress. This study and medical writing support was funded by Takeda Pharmaceuticals International AG, Zurich, Switzerland.

References

1. Ilvemark J.F.K.F. et al. J Crohns Colitis 2022;16:554–80.
2. Turner D. et al. Gastroenterol 2021;160:1570–83.

Disclosure

D.C. has received speaker’s fees and/or research support from AbbVie, Janssen, Takeda and Taro, and consultancy fees from AbbVie, Takeda and Taro.
G.F. has received personal fees from AbbVie, Abivax, AlfaSigma, Celltrion, Ferring, Galapagos, Janssen, Lilly, Pfizer, Sandoz, STADA and Takeda.
P.B. is an employee and stockholder of Takeda Pharmaceuticals International AG, Zurich, Switzerland.
F.C. is an employee of the contract research organization IQVIA Solutions Italy s.r.l., hired by Takeda Pharmaceuticals International AG for the following activities: project and site management, data management, quality control and statistical analysis.
M.M. is an employee and stockholder of Takeda Pharma AG, Zurich, Switzerland.
K.L.N. has received advisory board fees from AbbVie, Bristol Myers Squibb, Celltrion, Ferring, Janssen and Pfizer, and speaker’s fees and research support from AbbVie, Janssen and Pfizer.
U.K. has received advisory and speaker’s fees from AbbVie, Bristol Myers Squibb, Celltrion, Janssen, Medtronic, Pfizer and Takeda, and research support from Janssen, Medtronic and Pfizer.