Animal Models: The View of the Pathologist

Ann Driessen and Pamela Baldin, H-ECCO Members

Ann Driessen

Pamela Baldin

The animal model is a useful tool to unravel different pathogenetic mechanisms, to detect biomarkers for monitoring and to test the efficacy and safety of drugs in the preclinical phase. In Inflammatory Bowel Disease (IBD) research, the mouse is the most widely used animal model. Animal models are classified into four categories, namely chemical models, cell transfer models, genetically engineered models, and congenic models. Based on the mechanism of the animal model, different aspects of the pathogenesis of intestinal inflammation in IBD are examined, such as epithelial integrity and wound healing, and innate and adaptive immunity [1].

Animal models are also used to investigate the histopathological features of IBD, but there is no single model showing the entire course of the inflammation. Based on the type of animal model, a different part of the intestine is affected at a different stage of the inflammation. Depending on the dose and the frequency of administration, the chemical model dextran sulphate sodium, for example, causes either a self-limiting colitis or a chronic colitis with an Ulcerative Colitis-like pattern. Other models, such as the congenic animal model, develop a Crohn’s Disease-like ileitis, a segmental and transmural inflammation with granulomas and fistula formation and fibrosis. Fibrosis, a common complication of strictures in Crohn’s Disease, has been the research topic of several animal models, including chemical as well as genetically engineered models. The latter are technically very complex models, which, however, have significantly extended our knowledge on the aetiopathogenesis of IBD  [2].

Histopathology is the gold standard for evaluating intestinal inflammation in animal models. To examine the inflamed mucosa, knowledge of the anatomy of animals is essential as it may differ from human anatomy. In mice, for instance, the caecum is located on the left side [3]. In order to ensure adequate quality of tissue processing, including fixation, the use of histochemical and immunohistochemical stains or molecular techniques and the analysis of tissue samples, a pathologist is required – either a comparative pathologist, i.e. a veterinary pathologist with clinical medical knowledge or a clinical pathologist with some experience in animal pathology. Animal models have been used to evaluate the degree of activity in biopsies of the gut, which is assessed by applying an international nomenclature for non-neoplastic and neoplastic lesions in the gastrointestinal tract of rats and mice and a histological scoring system. Some morphological criteria used to evaluate endoscopic biopsies in humans, such as cryptitis and crypt abscesses, are lacking in rats and mice [4]. The applied histological scoring systems vary as a function of the first hit, such as the luminal side (e.g. chemical) or imbalanced immune disposition (e.g. T-cell transfer), and the localization (small intestine versus colon) in the animal model. Similar to human scoring systems, a standardized approach is used in animals, based on the morphological features architectural disarray, inflammation and epithelial injury. This allows comparison between animal model studies and facilitates the transfer of histopathological findings to those in human IBD [5]. Digital imaging has improved the diagnostic accuracy of scoring of colitis in mice [6].

IBD patients are at risk of developing colon cancer (RR 1.5–2) due to longstanding mucosal inflammation [7]. A similar process, with different stages from normal mucosa to dysplasia and finally invasive cancer, has been investigated in genetically engineered and chemical models. Assessment of the different stages of this carcinogenic process requires a pathologist with knowledge of the grading systems in humans [8]. Reporting of histopathological processing and analysis is frequently of inferior quality because of missing data on histopathological scoring, for example. Therefore guidelines describing the specific requirements for experimental pathology data (MINPEPA), such as tissue sampling and fixation, have been published. These guidelines are based on the recently updated ARRIVE guidelines (Animal Research: Reporting In Vivo Experiments) [9–11]. 

In conclusion, the use of animal models has significantly expanded our knowledge on the aetiopathogenesis of IBD. Research on intestinal inflammation in animal models requires a multidisciplinary approach, in which the pathologist should be involved. Participation of an experienced pathologist in the entire process from tissue sampling, processing and analysis through to reporting according to the MINPEPA guidelines will improve the accuracy and reproducibility of the histopathological data and the quality of the published article [9].


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Posted in ECCO News, Committee News, H-ECCO, Volume 15, Issue 3