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

Shanshan Xiong, Charles E. Whitehurst, Li Li, Gyu Seong Heo, Chin Wen Lai, Umang Jain, Brian D. Muegge, Scott T. Espenschied, Ryan J. Musich, Minhu Chen, Yongjian Liu, Ta Chiang Liu, Thaddeus S. Stappenbeck

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1289-1301
Number of pages13
JournalGut
Volume71
Issue number7
DOIs
StatePublished - Jul 1 2022

Keywords

  • Crohn's disease
  • fibrosis
  • imaging
  • inflammatory bowel disease
  • mucosal injury

Fingerprint

Dive into the research topics of 'Reverse translation approach generates a signature of penetrating fibrosis in Crohn's disease that is associated with anti-TNF response'. Together they form a unique fingerprint.

Cite this