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

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Inflammatory bowel disease
Original research
Reverse translation approach generates a signature of penetrating fibrosis in Crohn’s disease that is associated with anti-TNF response
  1. Shanshan Xiong1,
  2. Charles E Whitehurst2,
  3. Li Li3,
  4. Gyu Seong Heo4,
  5. Chin-Wen Lai4,
  6. Umang Jain4,
  7. Brian D Muegge4,
  8. Scott T Espenschied5,
  9. Ryan J Musich5,
  10. Minhu Chen1,
  11. Yongjian Liu4,
  12. Ta-Chiang Liu6,
  13. Thaddeus S Stappenbeck5
  1. 1 Department of Gastroenterology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, China
  2. 2 Department of Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, USA
  3. 3 Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, USA
  4. 4 Washington University in St Louis, St Louis, Missouri, USA
  5. 5 Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
  6. 6 Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, Missouri, USA
  1. Correspondence to Dr Thaddeus S Stappenbeck, Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA; stappet{at}ccf.org

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.

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

Data availability statement

Data are available in a public, open access repository. Agilent microarray data generated from the human CD and mouse specimens are deposited at ArrayExpress with the accession numbers E-MTAB-8570 and E-MTAB-8566, respectively. https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8570/https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8566/.

https://doi.org/10.1136/gutjnl-2020-323405

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    Data availability statement

    Data are available in a public, open access repository. Agilent microarray data generated from the human CD and mouse specimens are deposited at ArrayExpress with the accession numbers E-MTAB-8570 and E-MTAB-8566, respectively. https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8570/https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8566/.

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    Footnotes

    • Twitter @not applicable

    • Contributors SX, CEW, MC, YL, T-CL, TS planned the experiments. SX, LL, GSH, C-WL, UJ, STE, RJM, BM performed the experiments and analysis. SX, CWL, T-CL, YL, TS wrote the draft of the manuscript. All authors contributed to the edits of the manuscript.

    • Funding This work was funded by Boehringer Ingelheim. T-CL was funded by 1R01DK125296 and 1R01DK124274. TS was additionally funded by 1R01DK122790 and 1R01AT009741. T-CL and TS were also funded by Helmsley Charitable Foundation.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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