DOP67 A transcriptional module associated with neutrophil degranulation is highly conserved across species and is a core molecular pathway of treatment resistance in ulcerative colitis

Autor: D Cozzetto, J Lo, N Powell
Rok vydání: 2023
Předmět:
Zdroj: Journal of Crohn's and Colitis. 17:i144-i144
ISSN: 1876-4479
1873-9946
DOI: 10.1093/ecco-jcc/jjac190.0107
Popis: Background Advanced therapeutics are changing the treatment landscape in ulcerative colitis (UC), but drug resistance is still common. New strategies are needed to identify the molecular and cellular drivers of treatment resistance and inform the development of novel molecular diagnostics and therapies. In this study we analysed transcriptional modules conserved across species and different colitis models to look for fundamentally important pathways of disease. Methods We surveyed the colonic transcriptome in preclinical UC models, including the T-cell transfer, Il10-/-, DSS, DNBS, anti-CD40 mAb and TRUC (Tbx21-/- x Rag2-/- UC) models and multiple cohorts of patients with UC. Gene expression and pathway level changes were defined. Conserved gene and pathway level changes were defined and their relationship to treatment response with anti-TNF, ustekinumab and vedolizumab assessed in independent UC cohorts, including key registration trials. Results Principal component analysis showed clear separation between control and experimental colitis samples, which clustered according to the specific model and classification, such as chemically induced (DSS and DNBS), T-cell dependent (T-cell transfer model and Il10-/-, and T-cell independent, innate-mediated models (anti-CD40 mAb and TRUC models). Between 1700 and 8200 genes were differentially expressed (FDR < 0.05) between the experimental models and the corresponding controls; 145 genes had expression levels at least doubled up in all cases. Pathway analysis highlighted significant shared effects (FDR Conclusion This transcriptional atlas provides a new lens to scrutinize fundamental biological pathways of gut inflammation and new opportunities to understand the core molecular features of the resistome. A set of neutrophil degranulation genes was associated with resistance to anti-cytokine therapies in UC.
Databáze: OpenAIRE
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