Published online Apr 21, 2022. doi: 10.3748/wjg.v28.i15.1536
Peer-review started: November 25, 2021
First decision: January 11, 2022
Revised: January 18, 2022
Accepted: March 6, 2022
Article in press: March 6, 2022
Published online: April 21, 2022
Crohn's disease (CD) is a chronic nonspecific intestinal inflammatory disease. The aetiology and pathogenesis of CD are still unclear. Anal fistula is the main complication of CD and is a difficult problem to solve at present. In recent years, there has been an increasing number of potential treatments for patients with inflammatory bowel diseases. However, these new treatments have not been fully developed into routine and safe technical procedures.
The main limitation in developing new therapies for CD with anal fistula is connected with the deficiency of preclinical safety and credible experimental data records. Therefore, an ideal animal model is needed to establish models of persistent anal fistula and an inflamed rectal mucosa.
The aim of this study was to improve the induction method of colitis and establish a reliable and reproducible perianal fistulizing CD animal model to evaluate new treatment strategies.
Twenty male New Zealand rabbits underwent rectal enema with different doses of 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce proctitis. Group A was treated with an improved equal interval small dose increasing method. The dosage of group B was constant. Seven days later, the rabbits underwent surgical creation of a transsphincteric fistula. Then, three rabbits were randomly selected each group every 7 d to remove the seton from the fistula. The rabbits were examined by endoscopy every 7 d, and biopsy forceps were used to obtain tissue samples from the obvious colon lesions for histological analysis. The disease activity index (DAI), colonoscopy and histological scores were recorded. Perianal endoscopic ultrasonography (EUS) was used to evaluate the healing of fistulas.
Except for the DAI score, the colonoscopy and histological scores in group A were significantly higher than those in the other groups (P < 0.05). In the ideal model rabbit group, on the 7th day after the removal of the seton, all animals had persistent lumens on EUS imaging, showing continuous full-thickness high signals. Acute and chronic inflammation, epithelialization, fibrosis, and peripheral proctitis of consecutive rectum are the histological features of fistula.
A preclinical model of perianal fistulizing CD in rabbits was established by using an improved method of CD colitis induction. The model can simulate the human environment, and intestinal and fistula lesions can be evaluated by EUS, endoscopic and histological examinations to assess new therapeutic strategies.
The establishment of a model of fistula associated with colitis allows the evaluation of different therapeutic approaches. However, fistula formation in animal models does not fully reflect the condition in humans. We hope that the simple, reliable and repeatable fistula animal model established by this improved colitis induction method can be used to evaluate new treatment strategies. The criteria for the difference between the two experimental conditions (constant-dose or increased-dose TNBS) introduced in the study still need to be verified by larger animal experiments, and the molecular mechanism involved should be investigated. The optimal animal model should include genetically mediated development of CD with anal fistula. However, an ideal model for preclinical research is difficult to establish due to the long experimental period required.