Mouse models for inflammatory bowel disease (IBD) are of various types and subtypes as the different models have different responses of histology, disease location, therapeutic response, and potential applications.
Chemically Induced Mouse Models
Chemically induced mouse models are the most widely used inflammatory bowel disease study moels. These mouse models are chemically induced by dextran sulfate sodium (DSS), trinitrobenzene sulfonic acid (TNBS), oxazolone, etc. The advantages factors of these models are: relatively cheap and easy to develop.
The subtypes of this model are:
DSS-Induced Colitis Model:
DSS damages epithelial cells when administered and mouse innate immune cells accordingly release cytokines following colon inflammation. The common uses for this model include researching on the role of innate immunity in intestinal inflammation and maintenance of epithelium integrity.
TNBS-Induced Colitis Model:
TNBS is a haptenating agent that causes an immune response upon binding to host proteins. This model replicates clinical Crohn’s disease and the immune response is Th1-mediated, characterized by CD4+ T cells, neutrophils, and macrophages infiltration. TNBS-induced colitis models are good for studying the immunologic aspects of Crohn’s disease and new immunotherapies.
Oxazolone-Induced Colitis Model:
Oxazolone is also a haptenating agent, but induces clinical ulcerative colitis, unlike the TNBS-induced model. The induced immune response is Th2-mediated, which results in diffuse colonic inflammation. This model is generally used for studying delayed-type hypersensitivity reactions in the skin.
Limitations
When researchers use any chemically induced Inflammatory Bowel Disease model there are several variables to take into account like chemical batch, animal supplier, animal strain, gender, dosing level, etc. The same protocols should be always used for ensuring the reproducibility of the research. These models can also be quite severe in their effects of inflammation.
Adoptive T Cell Transfer Mouse Model
The adoptive T cell transfer model induces chronic small bowel and colonic inflammation. This resembles the important core aspects of human inflammatory bowel disease. To generate this model, CD4+CD45RBhi T cells are sorted and isolated from donor BALB/c mice splenocytes. These cell transfers to a syngeneic immunodeficient SCID or RAG2-/- recipient mice generate a colon inflammation model. This inflammation is due to a lack of Treg cells in the naïve T cell population. These models are generally used to study the role of pathogenic T cells in mucosal inflammation.
Limitations
A full overview or understanding of the colitis is not feasible as immunodeficient mice are used to generate this model.
Genetically Engineered Mouse Models
Genetically engineered mouse models spontaneously develop colitis and these models harbor susceptibility genes of human inflammatory bowel disease. The constitutive knockout IL-10-/- mouse is the most well-known genetically engineered IBD model.
IL-10-/- Knockout Mouse
Spontaneous colitis develops in IL-10 Knockout mice as the Treg cells of these animals cannot produce IL-10. Colonic inflammation is seen in these models and disease severity is more in the case of BALB/c mice as compared to C57BL/6 mice. These models can be used for studying different immune anomalies and mechanisms besides studying Treg cells.
Limitations
The long disease development time is a limitation though piroxicam can accelerate the onset of colitis then again, dose, formulation, etc. have to be carefully validated.
Microbiome-Induced Mouse Models
Intestinal bacteria microbiome is implicated in immune-mediated intestinal inflammation as the microbiome is critical for colitis development and has been widely investigated by researchers.
There is scientific evidence that antibiotics do result in attenuated mucosal inflammation in patients and moreover, a fecal microbiota transplant has also been strategized to reverse disease condition by adjusting intestinal flora anomalies and maintaining homeostasis.
Researchers have also found that introducing bacteria (e.g. Helicobacter hepaticus) or microbiota combinations results in accelerated disease onset in the case of mouse IBD models. Therefore, these models provide a great tool for studying the microbial role and antimicrobial therapies related to IBD.
Limitations
Limitations of these models include variable colonization leading to difficulty in the induction of the IBD model and might cause problems in feeding metabolism for the models.
IBD mouse models are truly an essential and invaluable tool for preclinical inflammatory bowel disease research and drug development scenarios. Different models of IBD are used for studying different disease mechanisms and therapeutics. Researchers can therefore focus on optimizing these conditions and coming up with the best-suited model for their research efficacy enhancement in case of inflammatory bowel disease.
