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  • Novel mouse model for studying transmural intestinal fibrosis and creeping fat formation in stricturing Crohn’s disease

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Novel mouse model for studying transmural intestinal fibrosis and creeping fat formation in stricturing Crohn’s disease
  1. Xiaofen Lv1,
  2. Yunqing Zeng1,
  3. Wenlong Ma1,
  4. Yuan Zheng1,
  5. Tengkai Wang1,
  6. Mingru Liu1,
  7. Di Zhang1,2,
  8. Lixiang Li1,3,4,
  9. Xiuli Zuo1,
  10. Yanqing Li1,
  11. Jiaoyang Lu1,5
  1. 1 Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China
  2. 2 Department of Medical Oncology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China
  3. 3 Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China
  4. 4 Shandong Provincial Clinical Research Center for Digestive Disease, Jinan, Shandong, People's Republic of China
  5. 5 Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People's Republic of China
  1. Correspondence to Dr Jiaoyang Lu, Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China; lujiaoyang{at}sdu.edu.cn

https://doi.org/10.1136/gutjnl-2024-333590

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    Stricturing Crohn’s disease (CD) is characterised by transmural intestinal fibrosis accompanied with creeping fat (CrF) formation.1 Such pathological features were successfully recapitulated in a mouse model for the first time by Xiong et al 2 who performed repeated endoscopy-guided forceps biopsies on mouse colon. This method, although effective, requires specific training to use small animal endoscopes and accessories, which are not readily available in many labs. Here, we developed a simpler, reliable and repeatable method to generate mouse transmural fibrosis and CrF using a high-frequency electrocautery device and an (often secondhand) endoscopic submucosal dissection knife, both of which are readily available in tertiary endoscopy centres. We then characterised the model via histological staining and transcriptome sequencing and explored the intersection of differentially expressed genes (DEGs) between mouse CrF and publicly accessible human CrF datasets.3 Additionally, we investigated the impact of dexamethasone (DEX) on mouse colon fibrosis and CrF formation.

    Histopathological analyses demonstrated that increased inflammatory cell infiltration and abnormal extracellular matrix (ECM) deposition were common features of CrF in CD patients (figure 1A–F).4 5 Our model was generated by inserting a Dual knife (Olympus, Tokyo) into mouse distal colon (4 cm from the anus) and applying controlled electrical cautery (cutting mode, voltage set to 5 V) to the mucosa (figure 1G–H). After four cycles of cautery injuries, we observed enlargement of the mesenteric fat and evidence of fat wrapping around the injured area of the colon (figure 1I). Repeated colonic cautery induced transmural and penetrating fibrosis into the wrapping fat with smaller and more numerous adipocytes, including increased inflammatory cell infiltration (figure 1J–L), similar to what is observed in CD patients. We further identified DEGs between the model CrF and the control group mesenteric adipose tissue through transcriptome sequencing. The volcano plot revealed 2443 DEGs (1308 upregulated …

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    Footnotes

    • Contributors JL conceived the method. XL, LL and JL designed the experiments. JL supervised the study. XL, YZ, YZ and WM performed the experiments. TW, ML and DZ were involved in interpretation. XL wrote the manuscript. YZ, WM, TW and JL revised the manuscript. XZ and YL contributed to the revision of the manuscript. All the authors read and approved the final manuscript. JL is the guarantor.

    • Funding This study was funded by the Natural Science Foundation of Shandong Province (ZR2020QH184) and the National Natural Science Foundation of China (82100535, 82370524).

    • Competing interests None declared.

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