Inflammatory bowel diseases (IBD) arise from a convergence of underlying genetic susceptibility, immune system dysfunction, environmental factors, and shifts in gut microbiota. Due to the multifactorial feature of these diseases, different animal models have been utilized to investigate the underlying mechanisms and develop potential therapeutic strategies.
Colitis Animal ModelsIn the table below, we summarize commonly used colitis mouse models and provide key features and tips for utilization of each model in IBD studies:
|Model||DSS induced||TNBS induced||Il10 knockout||Mdr1a knockout||Adoptive T-cell transfer|
|Mechanism||DSS (dextran sulfate sodium) disrupts the epithelial barrier, exposes lamina propria to luminal contents and causes vascular and mucosal injury; this triggers activation of inflammatory pathways||TNBS (trinitrobenzene sulfonic acid) serves as a hapten and renders high molecular weight proteins immunogenic; this elicits significant cell-mediated acute Th1 inflammation||Deficiency of interleukin 10 production, a key immunosuppressive cytokine, leads to expansion of Th1 and Th17 cells and defective function of regulatory T cells, resulting in chronic inflammation||Deletion of the multidrug resistance pump Mdr1a leads to a defect in epithelial barrier function, causing increased antigen presentation and T-cell hyper-reactivity||The supplemented donor naïve T cells interact with antigens and develop into colitogenic T cells in the immunodeficient recipient mice (Rag2 KO or SCID), resulting in chronic inflammation|
|Timeline||Acute: colitis lasts 4-7 days after treatment|
Chronic: 2-4 months
|Acute: colitis lasts 5-7 days after treatment||Spontaneous chronic colitis occurs at 2-3 months of age, but this varies depending on genetic background and microbiome effects||Spontaneous chronic colitis occurs around 3 months of age, but this varies depending on the microbiome effects||Lasts 5-10 weeks after injection|
|Readouts||Epithelial injury, inflammation, diarrhea, weight loss||Epithelial injury, inflammation, diarrhea, weight loss||Inflammation, injury||Inflammation, severe thickening of the mucosa||Inflammation, injury, diarrhea, weight loss|
|Effect of genetic background and microbiome||C3H> C57BL/6> BALB/c;
Enteric bacteria suppress the acute colitis, as germ-free or antibiotic-treated mice develop lethal colitis with intestinal bleeding
|BALB/c, C3H/HeJ>> C57BL/6;
Microbiota is required for the onset of colitis, i.e., germ-free mice do not develop colitis
|BALB/c, C3H>> C57BL/6;
Microbiota is required for the onset of colitis, i.e., germ-free mice do not develop colitis;
Incidence varies based on the presence of Helicobacter
|Microbiota is required for the onset of colitis, i.e., germ-free mice do not develop colitis||Recipient strains must be syngeneic to donor strain; susceptibility affected by the microbiota and the presence of segmented filamentous bacteria (SFB) in the recipients|
|Strength||Widely used; technically simple; time saving; mice spontaneously recover after termination of DSS treatment||Consistent localized damage to the distal colon, time- and cost-saving||Defined mechanism of inflammation||Onset of colitis independent of the presence of Helicobacter; widely used in pharmaceutical research||Minimized effects of donor microbiome; defined mechanism of inflammation and T cell subsets|
|Translational relevance||No evidence on the relevance to human disease||Colitis is dependent on NOD2, a cytoplasmic sensor for bacterial peptidoglycan motif that is linked to polymorphism in Crohn's disease||Polymorphisms in the IL-10 receptor are associated with ulcerative colitis presenting in early childhood||MDR1 polymorphisms are associated with human ulcerative colitis; the model predicted the therapeutic failure of anti-IL17 therapies for Crohn's disease||No evidence on the relevance to human disease|
|Recommend to study||Innate immune system; mucosal and epithelial injury and healing||Innate immune system; interaction between innate and adaptive immune systems||Gut microbiome; loss of immune tolerance; chronic disease||Gut microbiome; therapeutic development for IBD||Specific T cell subsets; role of immune regulation, Treg and integrins|
Colitis Animal Model Selection TipsWhereas each of the models may be most suitable for specific studies, several tips are applicable to all models to ensure the success of an experiment:
- Selection of strain background strongly affects the severity of colitis and the outcome of experiments. For example, C57BL/6 mice develop more severe colitis than BALB/c in responding to DSS treatment, whereas Il10 knockouts on the BALB/c background develop colitis earlier and more severely than Il10 knockouts on the C57BL/6 background.
- Microbiome has been reported to play an important role in human IBD and to affect the outcome of animal models. Thus, the variability in the microbiome among different facilities may account for inconsistency among experiments. To minimize the variability, it is important to tightly control the microbiome of mice. Practices such as sourcing from a consistent vendor, cohousing or mixed bedding9 in performance assay are highly recommended.
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