Ulcerative Colitis Animal Model Development Services
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by continuous segments of immune-mediated inflammation and ulceration in the mucosa of the colon. Developing robust animal models of UC is essential for understanding the disease's pathophysiology and for testing potential therapeutic interventions. At Protheragen, we offer comprehensive services for developing and validating animal models of ulcerative colitis.
Overview of Ulcerative Colitis Animal Models
Ulcerative Colitis (UC) is a chronic, relapsing inflammatory disorder of the colon, with clinical manifestations including abdominal pain, rectal bleeding, and persistent diarrhea. Its complex pathogenesis involves a dysregulated immune response, genetic predispositions, and environmental factors, including the gut microbiota. For decades, animal models have served as the cornerstone of UC research, offering a controlled environment to unravel the intricate mechanisms of the disease and to rigorously test novel therapeutic interventions. While no single animal model can perfectly replicate the complexity and heterogeneity of human UC, a well-curated and diverse set of models is crucial for comprehensive drug discovery and development.
Fig.1 Histoarchitectural changes in the colon tissue after exposure to 5% DSS, illustrating induction of acute colitis. (Gancarcikova S., et al., 2020)
Ulcerative colitis (UC) animal models are scientifically designed experimental systems that replicate the pathological features of human ulcerative colitis in laboratory animals. These models are crucial for understanding the disease mechanisms, evaluating new therapeutic strategies, and accelerating drug development. By inducing colonic inflammation through various methods, researchers can study the role of immune responses, genetic susceptibility, and environmental factors in UC pathogenesis. For example, dextran sulfate sodium (DSS)-induced UC models allow researchers to investigate mucosal barrier disruption and inflammatory activation, providing valuable insights into the disease process.
Our Services
At Protheragen, we understand that each research project has unique requirements. Our team of expert biologists and veterinarians works closely with clients to develop customized UC animal models tailored to their specific research questions. Whether it's adjusting the severity of chemically induced colitis or generating genetically modified mice with specific gene knockouts, we ensure that our models meet the highest standards of quality and reproducibility.
Chemical Induction Models
These models are valued for their simplicity and reproducibility. We use well-established agents to reliably induce colitis.
- DSS-Induced Colitis: DSS (Dextran Sulfate Sodium) disrupts the tight junctions of intestinal epithelial cells, damaging the intestinal mucosal barrier and allowing bacteria and antigens from the gut lumen to enter the lamina propria, triggering an immune response and inflammation. From Protheragen's perspective, the DSS-induced colitis model can be utilized to investigate the efficacy of novel anti-inflammatory drugs. For example, by detecting the inhibitory effects of drugs on inflammatory markers (such as TNF-α, IL-6) induced by DSS, as well as their impact on the repair of the intestinal mucosal barrier, the potential therapeutic effects of the drugs can be assessed.
- TNBS-Induced Colitis: TNBS (2,4,6-Trinitrobenzenesulfonic Acid) binds to proteins in the intestinal mucosa to form antigens, activating the immune system and causing an inflammatory response. Protheragen can use the TNBS-induced colitis model to study therapeutic strategies targeting Th1-type immune reactions. For example, developing drugs that can modulate the Th1/Th2 balance, or researching drugs that can inhibit the infiltration of inflammatory cells and the production of cytokines induced by TNBS. Additionally, the impact of drugs on the gut microbiota can be explored, as well as how to alleviate TNBS-induced inflammation by modulating the gut microbiota.
Genetically Modified Models
| Model Types | Immunology Tool; Knockout Mice | Immunology Tool; Knockout Mice |
| Model Name | Rag2-KO Mice | Rag2-KO (Rag2-EGFP) Mice |
| Also Known As | C57BL/6-Rag2em2 | B6;129S-Rag2tm1(loxP-EGFP-PolyA-loxP-Neo- |
| Detailed Description | Partial Exon 3 of the Rag2 gene was deleted to generate Rag2 knockout mice. Deletion of this region will cause a frameshift and result in loss of function of the mouse Rag2 gene. | A loxP-EGFP-PolyA-loxP-Neo-loxP expression cassette was precisely inserted into the start codon site of the Rag2 gene. This Rag2 knockout mouse model is highly suitable for subcutaneous inoculation of liver cancer tissues and tumor cells, allowing for rapid and robust tumor formation and growth. Flow cytometry (FACS) analysis revealed that the peripheral blood of these Rag2 knockout mice contains extremely low levels of T and B lymphocytes, comparable to or even lower than those in Nude mice, and significantly lower than in wild-type mice. Hematoxylin and eosin (HE) staining of tumor tissue sections demonstrated that the tumor sections from Rag2 knockout mice are strikingly similar to those from Nude mice. Given these characteristics, this strain holds great potential to serve as an alternative to Nude and NOD-SCID mice as a tumor-bearing mouse model. |
| NCBI ID | 19374 | 19374 |
| MGI ID | 97849 | 97849 |
| Gene Alias | Rag-2 | Rag-2 |
| Sales Status | Repository live | Embryo cryopreservation |
| Applications & Therapeutic Areas | Immunodeficiency; Tumor-bearing model | Immunodeficiency; Tumor-bearing model |
| Ensembl ID | ENSMUSG00000032864 | ENSMUSG00000032864 |
| Pubmed | Rag2 | Rag2 |
| Human Ortholog | RAG2 | RAG2 |
Other Optional Genetic Models
- MDR1a Knockout (KO) Mice: MDR1a (Multidrug Resistance 1a) knockout mice lack P-glycoprotein, which is unable to effectively efflux drugs and toxins from the gut, leading to the accumulation of these substances in the gut and triggering an immune response and inflammation. This model can simulate the pathological mechanism of intestinal barrier dysfunction in human ulcerative colitis. MDR1a KO mice exhibit inflammation mainly in the colon, characterized by mucosal thickening, abnormal glandular structure, and infiltration of inflammatory cells.
- IL-10 Deficient Mice: IL-10 (Interleukin-10) is an important anti-inflammatory cytokine that can inhibit the production of various pro-inflammatory cytokines, such as TNF-α and IL-6. IL-10 deficient mice are prone to intestinal inflammation due to the lack of IL-10's anti-inflammatory effects, manifesting as chronic colitis and intestinal tissue damage. This model can simulate the pathological mechanism of IL-10 signaling pathway defects in human inflammatory bowel disease (IBD).
Microbial Models
Microbial models allow us to investigate the crucial role of the gut microbiota in UC.
Adherent-Invasive E. coli (AIEC) Infection
AIEC (Adherent-Invasive Escherichia coli) is a pathogenic bacterium associated with Crohn's disease that can adhere to and invade intestinal epithelial cells, triggering an inflammatory response. The AIEC infection model can simulate the pathological mechanisms of gut microbiota dysbiosis and intestinal inflammation in Crohn's disease. After AIEC infection, the tight junctions of intestinal epithelial cells are damaged, leading to intestinal barrier dysfunction, allowing bacteria and antigens to enter the lamina propria, activate the immune system, and produce inflammation. Protheragen can use the AIEC infection model to study therapeutic strategies targeting gut microbiota dysbiosis.
Helminth Infection
Parasitic infections (such as Ascaris, hookworms, etc.) can modulate the host's immune response and alleviate intestinal inflammation. After parasitic infection, the host's immune system produces a Th2-type immune response, secreting cytokines such as IL-4 and IL-5. These cytokines can inhibit Th1-type immune responses and reduce inflammation. Protheragen can use the parasitic infection model to study immune modulation strategies targeting intestinal inflammation. For example, developing drugs that can mimic the immune modulatory effects of parasites, or researching drugs that can modulate the Th1/Th2 balance.
Other Specialized Models
We also offer specialized models that provide unique insights into specific aspects of UC.
T Cell Transfer Model
This model involves transferring CD4+ T cells into immunodeficient mice to induce chronic colitis. It is an excellent tool for investigating T cell-mediated immune responses.
Pseudo Germ-Free (PGF) Models
By using antibiotics to deplete the gut microbiota before inducing colitis with DSS, this model allows us to directly study the role of the microbiota in disease development without the complexities of a naturally diverse microbial community.
Case Study
DSS-Induced Ulcerative Colitis Model
Protheragen has successfully developed a DSS-Induced Ulcerative Colitis Model using C57BL/6 mice. Our modeling process involves providing the mice with free access to a DSS solution for a continuous period of 7 days, followed by a refresh of the solution every three days. After this initial treatment period, the mice are then given normal drinking water for another 7 days, completing one cycle. This cycle is repeated for a total of 35 days to establish the model.
Throughout the modeling period, we observed a cyclical pattern in both body weight and Disease Activity Index (DAI) scores, corresponding to the periods of DSS administration and recovery. By the 35th day of modeling, there was a significant difference in DAI scores between the model group and the control group (p<0.001), indicating that the model has been successfully established and meets our expectations.
Fig 2. Changes in body weight and DAI scores of model mice.
At Protheragen, we recognize that the path from preclinical data to clinical success is fraught with challenges. The lack of a single, predictive animal model for UC necessitates a thoughtful and comprehensive strategy. Our services are designed to overcome these challenges by providing a nuanced, multi-pronged approach that gives a deeper understanding of a drug candidate's mechanism of action (MOA) and its potential efficacy. If you are interested in our services, please feel free to contact us.
References
- Gancarcikova, Sona, et al. "Innovative animal model of DSS-induced ulcerative colitis in pseudo germ-free mice." Cells 9.12 (2020): 2571.
- Bilsborough, Janine, Marie F. Fiorino, and Bradley W. Henkle. "Select animal models of colitis and their value in predicting clinical efficacy of biological therapies in ulcerative colitis." Expert opinion on drug discovery 16.5 (2021): 567-577.
- Low, Daren, Deanna D. Nguyen, and Emiko Mizoguchi. "Animal models of ulcerative colitis and their application in drug research." Drug design, development and therapy (2013): 1341-1357.