|Year : 2018 | Volume
| Issue : 2 | Page : 80-83
Animal models for preclinical drug research on ulcerative colitis: A review
Kritarth Naman M Singh, Paresh G Koli
Department of Pharmacology and Therapeutics, Seth GSMC and KEM Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||10-Dec-2018|
Kritarth Naman M Singh
Department of Pharmacology and Therapeutics, Seth GSMC and KEM Hospital, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Inflammatory bowel disease (IBD) represents a chronic, relapsing, remitting, and inflammatory condition categorized into two forms – ulcerative colitis (UC) and Crohn's disease. According to epidemiological data, the trend of IBD has been increasing in the world, including in India. The current management of UC does not aim at curing the patient from the illness but mainly at attenuating the symptoms and improving the daily life of the patient. Drugs such as sulfasalazine and corticosteroids are used to reduce inflammation, but they are associated with multiple side effects and the efficacy is also limited. Hence, there is an unmet need in exploring new drugs to manage UC in a more efficient and less harmful way. There are various animal models which have been used worldwide by researchers to assess new lead compounds before they can be tested in humans. Various types of models comprise of chemical models, bacterial models, immunity transfer models, and genetic models. In this review article, we try to give an overview of these animal models which can be used in drug research.
Keywords: Corticosteroids, drug research, India, inflammatory bowel disease, ulcerative colitis
|How to cite this article:|
M Singh KN, Koli PG. Animal models for preclinical drug research on ulcerative colitis: A review. J Sci Soc 2018;45:80-3
| Introduction|| |
Inflammatory bowel disease (IBD) represents a chronic, relapsing, remitting, and inflammatory condition that affects an individual throughout life., It is categorized into two forms – ulcerative colitis (UC) and Crohn's disease (CD). In UC, inflammation is continuous and confined to the colon and the rectum. The ulcers are superficial, and involve only the mucosal layer of intestinal wall. On the other hand, in CD, the inflammation is discontinuous and can affect any part of the gastrointestinal tract (from the mouth to the anus). The lesions in CD are “patchy” and involve all the layers of the intestinal wall. IBD is the result of the interactions of exogenous (composition of normal intestinal flora) and endogenous host factors (intestinal epithelial cell barrier function/innate and adaptive immune function) including environmental factors (smoking and enteropathogens) that ultimately lead to a chronic state of deregulated mucosal immune function.
According to epidemiological data, the trend of IBD has been increasing in the world. In India, UC is more prevalent as compared to CD. A review on UC epidemiology has reported that India has the highest incidence and prevalence of UC in Asia. Although no study has investigated the overall incidence of UC in India, a study by Sood et al. has reported the incidence of UC to be 6.0/100,000 in the state of Punjab.
UC is a debilitating condition associated with many complications. It is an important known risk factor for the development of colon cancer. The current management of UC does not aim at curing the patient from the illness but mainly at attenuating the symptoms and improving the daily life of the patient suffering with it. The current treatment regimen includes the use of anti-inflammatory agents such as sulfasalazine and corticosteroids. These drugs are used to reduce inflammation, but they are associated with multiple side effects. Thus, patients of UC tend to have a reduced quality of life from continuing disease activity and significant complications with a risk of developing colon cancer later in life. These facts show that there is a need for developing newer drugs, which can only be done only after planning preclinical and then clinical research.
There are various animal models which have been used worldwide by various researchers to assess new lead compounds before they can be tested in humans. In this review article, we try to give an overview of the important animal models which can be used, highlighting the various advantages and disadvantages of each.
Ulcerative colitis and preclinical research
Animal models of UC have been used in preclinical research for over five decades. The development of animal models started when laboratory animals who were fed extracts from certain species of seaweed displayed similar symptoms to human IBD. Subsequent refinement and development led to a variety of chemically induced animal models.
Studies using various animal models led to the in-depth understanding of the features of human IBD pathogenesis, some of which are:
- Various causes of induced or genetically-based inflammation lead to different pathways of immunopathogenesis
- The normal gut microbiota plays an important role in intestinal inflammation
- Intestinal inflammation results due to lack of oral tolerance as well as disturbance of the epithelial barrier; and
- IBD is mediated by abnormal T helper cell response and defective innate immunity.
Many chemicals, bacteria, immunity transfer, and genetic models have been used in research to induce UC in animals [Table 1].
|Table 1: Animal models used in preclinical research on ulcerative colitis|
Click here to view
These animal models have been described in brief below:
Dextran sulfate sodium ,,
Dextran sulfate sodium (DSS) is a polyanionic derivative of dextran with a chemical formula of (C6H7 Na3O14S3)n. There are various applications of the compound which include lipoproteins precipitation, probe hybridization to membrane-immobilized DNA, and the release of DNA from DNA-histone complexes. It has been used on a wide scale in research to induce intestinal colitis and colorectal cancer in mice and rats.
DSS is most commonly administered in the drinking water for peroral treatment of the animals with the compound. The concentration of the compound which is often used is 3%. An inflammatory response is initiated by DSS in wild-type animals which starts distally after about 5 days and is limited to the colonic mucosa. It is still not well understood how DSS starts the inflammation in the colon. However, a recent study investigating DSS both in vitro and in vivo revealed that DSS has a direct effect on the inner mucus layer, leading to bacterial penetration of this layer before any inflammatory signs could be seen. Thus, it can be concluded that a loss of the inner colon mucus layer is the initial episode leading to bacterial penetration and ultimately, the development of an inflammatory response.
DSS-induced colitis has also been utilized for investigating the effects of the gut microbiota on the development of colitis. This is exemplified by studies demonstrating that the NOD2 abnormalities give rise to mice that develop changes in susceptibility to DSS colitis and the latter is associated with (or perhaps caused by) changes in the gut microbiome.
DSS-induced colitis is a commonly used experimental model for many reasons which are:
- The simplicity of administration process which is usually done in the drinking water
- Ease of dosage control which helps in determining colitis severity
- Duration control is possible to study the process of inflammation or recovery process
- Multiple chemical compounds, gene or cell therapy, and microbial interventions have been found to be effective therapeutically in DSS-induced colitis.
2, 4, 6–trinitrobenzene sulfonic acid ,
Trinitrobenzene sulfonic acid (TNBS) is an oxidizing Nitroaryl compound which is administered intrarectally in animals to induce IBD. It causes induction of colonic damage which leads to necrotic regions associated with inflammatory areas. High myeloperoxidase activity causes damage mainly characterized by neutrophilic infiltration into the colonic tissue. An increase in the mucosal permeability is a result of the damage to the colonic epithelium and interstitium. TNBS may cause a decrease in the mucosal hydrophobicity by interacting with the phospholipids present on the surface of the colonic mucosa. This decreased hydrophobicity is believed to contribute to TNBS-induced inflammation of the colon. TNBS causes necrosis and deep tissue damage which mimics the transmural involvement of CD; hence, it may be preferred to be a better experimental model of CD rather than UC.
TNBS-induced colitis models have helped to be an important source for generating vital information about the cytokines involved in the human IBD. It has also helped in shaping the therapy regimens of the human disease.
Oxazolone colitis ,
Intrarectal administration of the hapten compound oxazolone along with ethanol in animals causes acute colitis. Oxazolone leads to acute superficial mucosal inflammation in the distal part of colon. There is colonic infiltration by lymphocytes and neutrophils along with associated edema in lamina propria. There is type helper 2 (Th2) cell-mediated immune response with an elevation in the production of interleukins. This animal model is distinguished from TNBS-induced colitis by the presence of Th2-mediated response instead of Th1 found in the TNBS model.
Acetic acid-induced colitis ,
Administration of diluted acetic acid through the rectal route is another method to induce colitis in rodents. The treatment with acetic acid causes colonic mucosal damage which leads to a condition similar to UC. MacPherson and Pfeiffer were the first ones to demonstrate this model where they administered 10%–50% acetic acid intrarectally to the rat for 10 s, followed by flushing the lumen three times with saline. Acetic acid caused diffuse colitis in a dose-dependent manner in these rodents, with histopathological features including ulceration of the distal colon and crypt abnormalities. The latest practice utilizing 4% acetic acid for 15–30 s. The low cost of the chemical as well as the ease of administration are few advantages of acetic acid-induced colitis model. The epithelial injury induced by acetic acid is not immunological in the first 24 h. Thus, drugs which target the immune responses should be evaluated after 24 h of induction.
Salmonella-induced colitis ,
Salmonella typhimurium and Salmonella Dublin are Gram-negative bacteria that can cause foodborne intestinal diseases. Direct administration of S. typhimurium to mice orally causes a systemic infection that may resemble the picture of intestinal inflammation after pretreatment with oral antibiotics. The pretreatment helps to disturb the normal bacterial microflora causing high growth of S. typhimurium within 1 day. The intestinal inflammation caused by such colonization has histopathological characteristics which are similar to the human UC in terms of epithelial crypt damage and infiltration of neutrophils. The induction of colitis causes the systemic infection within 5–7 days of infection. Salmonella has also been shown to act as an effective vector for the introduction of some gene components into the colonic mucosa to elicit immune response for vaccines against colitis.
Adherent-invasive Escherichia coli,
Adherent-invasive Escherichia coli (AIEC) could adhere to the epithelial cells of both small and large intestine with equal affinity. However, AIEC infection cannot induce colitis on its own. During the entire course of AIEC infection, colonic inflammation is induced in animal models using the infection along with low-dose DSS administration to cause mild epithelial damage. Disruption of the intestinal microflora, including the probiotic biofilm, is caused by certain antibiotics which lead to the development of an ideal environment for the opportunistic AIEC to adhere to and invade IECs and macrophages. The changes induced by this model closely resemble the human UC.
Adoptive transfer models of colitis 
The adoptive transfer model includes the process of transferring T-cells or immune tissue from one mouse into an adoptive host leading to the development of colitis. The various donors and hosts which have been used include:
- CD4+ T-cells transferred into severe combined immunodeficiency (SCID) mice
- hsp60-specific CD8+ T-lymphocytes into T-cell receptor –/– or SCID mice
- CD4+ CD25-T-cells into SCID mice.
The adoptive models are well-characterized models of chronic colitis induced by disturbing the T-cell homeostasis. These models are particularly useful in understanding how different T-cell populations might contribute to the pathogenesis of IBD as they rely on the transfer of T cells.
Genetic models of colitis 
The advancement in the genetic technologies has resulted in the development of multiple genes whose variants may be related to elevated predisposition to IBD. Tools such as genome-wide association study have recognized susceptibility genes. The various murine models containing relevant genetic variants, or those incorporating these newly identified variants, have been used to further explore the genetic contribution to colitis. Some of the genetic models of colitis are mentioned in [Table 2].
| Conclusion|| |
There are various ways in which potential drugs for UC can be studied in animals before they are tested in humans. It is difficult to pinpoint which animal model is the best, as various factors such as availability of chemicals or bacterial isolates as well as the financial backup with the research institute decide the choice of models as well. Genetic animal breeds are being developed more commonly from the last few years and with increasing financial aids to research organizations, it is possible that, in the near future, genetic models of colitis will become an important way of studying potential drugs and targets for UC.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]