Animesh Acharjee, Uday Shivaji, Giovanni Santacroce, Sarah Akiror, Louisa Jeffery, Csilla Varnai, Gary Reynolds, Davide Zardo, Snehali Majumder, Asma Amamou, Georgios V Gkoutos, Marietta Iacucci, Subrata Ghosh
{"title":"Novel Transcriptomic Signatures in Fibrostenotic Crohn's Disease: Dysregulated Pathways, Promising Biomarkers, and Putative Therapeutic Targets.","authors":"Animesh Acharjee, Uday Shivaji, Giovanni Santacroce, Sarah Akiror, Louisa Jeffery, Csilla Varnai, Gary Reynolds, Davide Zardo, Snehali Majumder, Asma Amamou, Georgios V Gkoutos, Marietta Iacucci, Subrata Ghosh","doi":"10.1093/ibd/izaf021","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Fibrosis is a common complication in Crohn's disease (CD), often leading to intestinal strictures. This study aims to explore the transcriptomic signature of fibrostenotic ileal CD for a comprehensive characterization of biological and cellular mechanisms underlying intestinal fibrosis.</p><p><strong>Methods: </strong>Nine CD patients undergoing surgery for fibrotic ileal strictures were prospectively recruited. RNA was extracted from fresh resected samples for bulk transcriptomics. Differentially expressed genes (DEGs) were identified (adj. P value < .05), and machine learning analyses were employed to compare gene expression patterns between strictures and non-strictured margins. Pathway enrichment analysis pinpointed relevant pathways. Furthermore, a random forest model was constructed to evaluate the significance of targeted genes. Relevant genes were subsequently validated through qPCR and further analyzed using a publicly available bulk RNA-seq dataset (GSE192786). Single-cell RNA sequencing (scRNA-seq) analysis was performed using the 10× Chromium Controller platform.</p><p><strong>Results: </strong>Bulk transcriptomics revealed unique transcriptomes with 81 DEGs, 64 significantly up-regulated, and 17 down-regulated in strictures compared to non-strictured margins. Up-regulated genes were mainly associated with inflammation, matrix and tissue remodeling, adipogenesis and cellular stress, while down-regulated genes were linked to epithelial barrier integrity. LY96, AKAP11, SRM, GREM1, EHD2, SERPINE1, HDAC1, and FGF2 showed high specificity for strictures. scRNA-seq linked up-regulated GREM1 exclusively to fibroblasts, while EHD2 and FGF2 showed upregulation in both fibroblasts and endothelial cells. LY96 and SRM were expressed by immune cells, whereas HDAC1, AKAP11, and SERPINE1 showed low expression across all cellular subsets.</p><p><strong>Conclusions: </strong>This study comprehensively characterizes resected CD ileal strictures, elucidating main dysregulated pathways and identifying promising biomarkers and putative therapeutic targets.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.5000,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Inflammatory Bowel Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/ibd/izaf021","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Fibrosis is a common complication in Crohn's disease (CD), often leading to intestinal strictures. This study aims to explore the transcriptomic signature of fibrostenotic ileal CD for a comprehensive characterization of biological and cellular mechanisms underlying intestinal fibrosis.
Methods: Nine CD patients undergoing surgery for fibrotic ileal strictures were prospectively recruited. RNA was extracted from fresh resected samples for bulk transcriptomics. Differentially expressed genes (DEGs) were identified (adj. P value < .05), and machine learning analyses were employed to compare gene expression patterns between strictures and non-strictured margins. Pathway enrichment analysis pinpointed relevant pathways. Furthermore, a random forest model was constructed to evaluate the significance of targeted genes. Relevant genes were subsequently validated through qPCR and further analyzed using a publicly available bulk RNA-seq dataset (GSE192786). Single-cell RNA sequencing (scRNA-seq) analysis was performed using the 10× Chromium Controller platform.
Results: Bulk transcriptomics revealed unique transcriptomes with 81 DEGs, 64 significantly up-regulated, and 17 down-regulated in strictures compared to non-strictured margins. Up-regulated genes were mainly associated with inflammation, matrix and tissue remodeling, adipogenesis and cellular stress, while down-regulated genes were linked to epithelial barrier integrity. LY96, AKAP11, SRM, GREM1, EHD2, SERPINE1, HDAC1, and FGF2 showed high specificity for strictures. scRNA-seq linked up-regulated GREM1 exclusively to fibroblasts, while EHD2 and FGF2 showed upregulation in both fibroblasts and endothelial cells. LY96 and SRM were expressed by immune cells, whereas HDAC1, AKAP11, and SERPINE1 showed low expression across all cellular subsets.
Conclusions: This study comprehensively characterizes resected CD ileal strictures, elucidating main dysregulated pathways and identifying promising biomarkers and putative therapeutic targets.
期刊介绍：
Inflammatory Bowel Diseases® supports the mission of the Crohn''s & Colitis Foundation by bringing the most impactful and cutting edge clinical topics and research findings related to inflammatory bowel diseases to clinicians and researchers working in IBD and related fields. The Journal is committed to publishing on innovative topics that influence the future of clinical care, treatment, and research.
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