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Reverse translation approach generates a signature of penetrating fibrosis in Crohn's disease that is associated with anti-TNF response
- Source :
- Gut. 71(7)
- Publication Year :
- 2020
-
Abstract
- ObjectiveFibrosis is a common feature of Crohn’s disease (CD) which can involve the mesenteric fat. However, the molecular signature of this process remains unclear. Our goal was to define the transcriptional signature of mesenteric fibrosis in CD subjects and to model mesenteric fibrosis in mice to improve our understanding of CD pathogenesis.DesignWe performed histological and transcriptional analysis of fibrosis in CD samples. We modelled a CD-like fibrosis phenotype by performing repeated colonic biopsies in mice and analysed the model by histology, type I collagen-targeted positron emission tomography (PET) and global gene expression. We generated a gene set list of essential features of mesenteric fibrosis and compared it to mucosal biopsy datasets from inflammatory bowel disease patients to identify a refined gene set that correlated with clinical outcomes.ResultsMesenteric fibrosis in CD was interconnected to areas of fibrosis in all layers of the intestine, defined as penetrating fibrosis. We found a transcriptional signature of differentially expressed genes enriched in areas of the mesenteric fat of CD subjects with high levels of fibrosis. Mice subjected to repeated colonic biopsies showed penetrating fibrosis as shown by histology, PET imaging and transcriptional analysis. Finally, we composed a composite 24-gene set list that was linked to inflammatory fibroblasts and correlated with treatment response.ConclusionWe linked histopathological and molecular features of CD penetrating fibrosis to a mouse model of repeated biopsy injuries. This experimental system provides an innovative approach for functional investigations of underlying profibrotic mechanisms and therapeutic concepts in CD.
- Subjects :
- 0301 basic medicine
Pathology
medicine.medical_specialty
Inflammatory bowel disease
Pathogenesis
03 medical and health sciences
Mice
0302 clinical medicine
Crohn Disease
Fibrosis
Biopsy
Gene expression
medicine
Animals
Humans
Mesentery
Crohn's disease
medicine.diagnostic_test
business.industry
Gastroenterology
Histology
medicine.disease
Intestines
030104 developmental biology
030220 oncology & carcinogenesis
Tumor necrosis factor alpha
Tumor Necrosis Factor Inhibitors
business
Subjects
Details
- ISSN :
- 14683288
- Volume :
- 71
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Gut
- Accession number :
- edsair.doi.dedup.....8c122aa36fa69b2f8347c311ba59d063