Reverse translation approach generates a signature of penetrating fibrosis in Crohn's disease that is associated with anti-TNF response.

Autor:	Xiong S; Department of Gastroenterology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, China., Whitehurst CE; Department of Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, USA., Li L; Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, USA., Heo GS; Washington University in St Louis, St Louis, Missouri, USA., Lai CW; Washington University in St Louis, St Louis, Missouri, USA., Jain U; Washington University in St Louis, St Louis, Missouri, USA., Muegge BD; Washington University in St Louis, St Louis, Missouri, USA., Espenschied ST; Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA., Musich RJ; Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA., Chen M; Department of Gastroenterology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, China., Liu Y; Washington University in St Louis, St Louis, Missouri, USA., Liu TC; Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, Missouri, USA., Stappenbeck TS; Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA stappet@ccf.org.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2022 Jul; Vol. 71 (7), pp. 1289-1301. Date of Electronic Publication: 2021 Jul 14.
DOI:	10.1136/gutjnl-2020-323405
Abstrakt:	Objective: Fibrosis 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. Design: We 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. Results: Mesenteric 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. Conclusion: We 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. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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