Summary of colitis mouse models in IBD research

by Yue Shan | Published: March 19th, 2019

 

 

Key TakeawaysKey Takeaways

  • Inflammatory bowel diseases (IBD) result from a combination of genetic susceptibility, immune system dysfunction, environmental factors, and changes in gut microbiota.
  • Various animal models, particularly colitis mouse models, are utilized to study IBD mechanisms and develop therapeutic strategies.
  • Controlling the microbiome is crucial for consistent experimental outcomes. Recommended practices include sourcing mice from consistent vendors, cohousing, or using mixed bedding.

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 Models

In the table below, we summarize commonly used colitis mouse models and provide key features and tips for utilization of each model in IBD studies:

 

ModelDSS inducedTNBS inducedIl10 knockoutMdr1a knockoutAdoptive T-cell transfer
MechanismDSS (dextran sulfate sodium) disrupts the epithelial barrier, exposes lamina propria to luminal contents and causes vascular and mucosal injury; this triggers activation of inflammatory pathwaysTNBS (trinitrobenzene sulfonic acid) serves as a hapten and renders high molecular weight proteins immunogenic; this elicits significant cell-mediated acute Th1 inflammationDeficiency 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 inflammationDeletion of the multidrug resistance pump Mdr1a leads to a defect in epithelial barrier function, causing increased antigen presentation and T-cell hyper-reactivityThe 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
TimelineAcute: colitis lasts 4-7 days after treatment

Chronic: 2-4 months		Acute: colitis lasts 5-7 days after treatmentSpontaneous chronic colitis occurs at 2-3 months of age, but this varies depending on genetic background and microbiome effectsSpontaneous chronic colitis occurs around 3 months of age, but this varies depending on the microbiome effectsLasts 5-10 weeks after injection
ReadoutsEpithelial injury, inflammation, diarrhea, weight lossEpithelial injury, inflammation, diarrhea, weight lossInflammation, injuryInflammation, severe thickening of the mucosaInflammation, injury, diarrhea, weight loss
Effect of genetic background and microbiomeC3H > C57BL/6 > BALB/c;

Male > female;

Enteric bacteria suppress the acute colitis, as germ-free or antibiotic-treated mice develop lethal colitis with intestinal bleeding		BALB/c, C3H/HeJ >> C57BL/6BALB/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 colitisRecipient strains must be syngeneic to donor strain; susceptibility affected by the microbiota and the presence of segmented filamentous bacteria (SFB) in the recipients
StrengthWidely used; technically simple; time saving; mice spontaneously recover after termination of DSS treatmentConsistent localized damage to the distal colon, time- and cost-savingDefined mechanism of inflammationOnset of colitis independent of the presence of Helicobacter; widely used in pharmaceutical researchMinimized effects of donor microbiome; defined mechanism of inflammation and T cell subsets
Translational relevanceNo evidence on the relevance to human diseaseColitis is dependent on NOD2, a cytoplasmic sensor for bacterial peptidoglycan motif that is linked to polymorphism in Crohn's diseasePolymorphisms in the IL-10 receptor are associated with ulcerative colitis presenting in early childhoodMDR1 polymorphisms are associated with human ulcerative colitis; the model predicted the therapeutic failure of anti-IL17 therapies for Crohn's diseaseNo evidence on the relevance to human disease
Recommend to studyInnate immune system; mucosal and epithelial injury and healingInnate immune system; interaction between innate and adaptive immune systemsGut microbiome; loss of immune tolerance; chronic diseaseGut microbiome; therapeutic development for IBDSpecific T cell subsets; role of immune regulation, Treg and integrins
Reference1,23,456,78

Colitis Animal Model Selection Tips

Whereas 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.
 
 
References:
  1. Wirtz, S.; Popp, V.; Kindermann, M.; Gerlach, K.; Weigmann, B.; Fichtner-Feigl, S.; Neurath, M. F. Chemically Induced Mouse Models of Acute and Chronic Intestinal Inflammation. Nat. Protoc. 2017, 12 (7), 1295-1309. PMID: 28569761.
  2. Hernandez-Chirlaque, C.; Aranda, C. J.; Ocon, B.; Capitan-Canadas, F.; Ortega-Gonzalez, M.; Carrero, J. J.; Suarez, M. D.; Zarzuelo, A.; Sanchez de Medina, F.; Martinez-Augustin, O. Germ-Free and Antibiotic-Treated Mice Are Highly Susceptible to Epithelial Injury in DSS Colitis. J. Crohns. Colitis 2016, 10 (11), 1324-1335. PMID: 27117829.
  3. Siegmund, B.; Zeitz, M. Innate and Adaptive Immunity in Inflammatory Bowel Disease. World J. Gastroenterol. 2011, 17 (27), 3178-3183. PMID: 21912465.
  4. Antoniou, E.; Margonis, G. A.; Angelou, A.; Pikouli, A.; Argiri, P.; Karavokyros, I.; Papalois, A.; Pikoulis, E. The TNBS-Induced Colitis Animal Model: An Overview. Ann. Med. Surg. 2016, 11, 9-15. PMID: 27656280.
  5. Mizoguchi, A. Animal Models of Inflammatory Bowel Disease. Prog. Mol. Biol. Transl. Sci. 2012, 105, 263-320. PMID: 22137435.
  6. Wilk, J. N.; Bilsborough, J.; Viney, J. L. The Mdr1a-/- Mouse Model of Spontaneous Colitis: A Relevant and Appropriate Animal Model to Study Inflammatory Bowel Disease. Immunol. Res. 2005, 31 (2), 151-159. PMID: 15778512.
  7. Maxwell, J. R.; Zhang, Y.; Brown, W. A.; Smith, C. L.; Byrne, F. R.; Fiorino, M.; Stevens, E.; Bigler, J.; Davis, J. A.; Rottman, J. B.; et al. Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation. Immunity 2015, 43 (4), 739-750. PMID: 26431947.
  8. Rieder, F.; Kessler, S.; Sans, M.; Fiocchi, C. Animal Models of Intestinal Fibrosis: New Tools for the Understanding of Pathogenesis and Therapy of Human Disease. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 303 (7), G786-801. PMID: 22878121.
  9.  Miyoshi, J.; Leone, V.; Nobutani, K.; Musch, M. W.; Martinez-Guryn, K.; Wang, Y.; Miyoshi, S.; Bobe, A. M.; Eren, A. M.; Chang, E. B. Minimizing Confounders and Increasing Data Quality in Murine Models for Studies of the Gut Microbiome. PeerJ 2018, 6, e5166. PMID: 30013837.

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