P0008 A multi-omics approach across multiple chronic inflammatory diseases identifies a distinct type-1-interferon endotype of Inflammatory Bowel Disease
Authors: Mishra N , Tran F , Kimmig F , Aden K , Credidio G , Wolff C , Ruge T , Blase J I , Bernardes J P , Ellinghaus D , Zeuner R , Frey N , Lieb W , Franke A , Schreiber S , Rosenstiel P 
Published: January 2025

Background

IBD shares many clinical and immunological features with other chronic inflammatory diseases (CIDs) like rheumatoid arthritis (RA) and psoriasis (Pso). Extraintestinal manifestations, particularly in the joints and skin, often overlap with these CIDs. We hypothesize that a systems medicine approach involving omics-driven phenotyping of multiple CIDs can yield a novel, therapy-relevant molecular taxonomy of disease. In this study, we aim to identify IBD-specific molecular signatures and those shared with other CIDs, as well as novel endotypes of IBD.

Methods

We recruited a cross-sectional cohort of 650 patients with CIDs (CD, UC, RA, Pso, psoriatic arthritis [PsA], and systemic lupus erythematosus [SLE]) along with 202 healthy controls (HC) at the University Hospital Kiel. Active or inactive disease was defined by clinical activity scores (i.e., CD: CDAI &lt;150; UC: partial Mayo ≤2). Blood samples were collected and subjected to RNA sequencing and methylation profiling. Detailed clinical phenotypes and 5 years-follow-up data were obtained by chart review. We conducted differential gene expression and methylation analyses comparing each CID with HCs to identify shared molecular signatures. Core (activity-independent) signatures were defined by the overlap of differential expression in both active vs. HC and inactive disease vs. HC. Biclustering methods (UnPaSt) were used to uncover distinct patient endotypes based on expression profiles.

Results

IBD shared the most differential signatures with RA, indicating common pathways in their pathogenesis. Core signatures upregulated across all CIDs correlated with DNA methylation changes, reflecting the molecular mechanism of chronicity, and were enriched in pathways related to cytokine signaling, neutrophil chemotaxis, and humoral immune response. While methylation signatures in enhancer regions were shared among most CIDs, disease-specific methylation was mainly located in CpG islands. One disease-overarching subgroup of 71 patients with active disease, identified by biclustering, exhibited upregulation of interleukin-27 and type-1 interferon signaling, including 16 out of 121 active IBD patients with a skewed sex ratio toward females and higher rates of therapy escalations within 5 years (Log-rank test: p=0.0089).

Conclusion

Our study highlights shared and disease-specific immune dysregulation pathways contributing to the pathogenesis of IBD and other CIDs. We show the clear presence of core signatures of disease regardless of disease activity, which could represent insights into actionable targets for causative treatments and better disease control of CIDs. With our approach, we identified a distinct molecular endotype of IBD with worse prognosis, warranting further validation studies.

References

This project has received funding from the DFG Cluster of Excellence 2167 "Precision medicine in chronic inflammation", the BMBF (e:Med Network iTREAT 01ZX2202A), the European Union/Horizon2020 (SYSCID, No 733100) and the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 831434 (3TR) and No 853995 (ImmUniverse).The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. The content provided in this publication reflects the author's views only. Neither the Innovative Medicines Initiative (IMI JU) nor the European Commission are responsible for any use that may be made of the information it contains.