Introduction:

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis (UC), presents a significant challenge in the field of gastroenterology. Understanding the complex pathogenesis of IBD and developing effective treatments relies heavily on well-established experimental models. Dextran Sulfate Sodium (DSS)-induced colitis has emerged as a valuable tool in the study of UC, offering insights into disease mechanisms and therapeutic interventions.

This comprehensive review embarks on a journey through the world of DSS-induced colitis, beginning with its historical context and its relevance as an experimental model for IBD. We delve into the mechanisms of DSS-induced colitis, exploring how this agent disrupts intestinal homeostasis, triggers inflammation, and recapitulates key features of UC. Furthermore, we examine the pathophysiological changes that occur in this model, including epithelial barrier dysfunction, immune cell infiltration, and cytokine dysregulation.

The review also highlights the therapeutic approaches and insights gained from DSS-induced colitis studies. By understanding the nuances of this model, researchers have developed and tested potential treatments for IBD, uncovering promising avenues for clinical intervention. DSS-induced colitis serves as a bridge between basic research and clinical translation, offering a unique perspective on IBD pathogenesis and therapy.(adopted from the book In Vivo Models of Inflammation ^[1])

DSS-Induced Colitis: A Model of Choice:

DSS-induced colitis was first introduced as a research tool in the early 1980s and has since become a widely accepted model for studying UC. The model involves the oral administration of DSS, a negatively charged, high-molecular-weight polysaccharide, to mice or rats. DSS disrupts the colonic epithelial barrier, leading to mucosal damage, immune cell infiltration, and inflammation, closely mirroring key aspects of UC pathology.

Mechanisms of DSS-Induced Colitis:

DSS-induced colitis is a multifaceted model characterized by several interconnected mechanisms:

1. Epithelial Barrier Dysfunction: DSS disrupts the integrity of the colonic epithelial barrier, leading to increased permeability and bacterial translocation. This breach triggers innate immune responses and sets the stage for inflammation.

2. Immune Cell Activation: In response to epithelial damage, innate immune cells, such as macrophages and neutrophils, are recruited to the colonic mucosa. These cells release proinflammatory cytokines and reactive oxygen species, contributing to tissue damage.

3. Inflammatory Responses: DSS-induced colitis results in an exaggerated immune response, characterized by the activation of T cells and the production of proinflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). This cytokine storm amplifies inflammation and exacerbates tissue damage.

4. Microbiota Dysbiosis: DSS administration alters the composition of the gut microbiota, favoring the expansion of pathogenic bacteria. This dysbiosis further contributes to inflammation and immune activation.

Pathophysiological Changes in DSS-Induced Colitis:

DSS-induced colitis recapitulates several key features of UC, making it a valuable model for studying the disease:

1. Mucosal Damage: DSS disrupts the colonic mucosal architecture, leading to ulcerations, crypt distortion, and epithelial cell loss, closely resembling UC-associated mucosal damage.

2. Immune Cell Infiltration: Immune cell infiltration into the colonic mucosa is a hallmark of both UC and DSS-induced colitis. Macrophages, neutrophils, and T cells accumulate in the inflamed tissue.

3. Cytokine Dysregulation: DSS-induced colitis mirrors the cytokine dysregulation seen in UC, with elevated levels of proinflammatory cytokines like TNF-α, IL-1β, and IL-6.

4. Altered Barrier Function: Impaired epithelial barrier function is a common feature in both DSS-induced colitis and UC, leading to increased permeability and bacterial translocation.

5. Weight Loss and Diarrhea: DSS-treated animals typically exhibit symptoms such as weight loss and diarrhea, which parallel the clinical manifestations of UC.

Therapeutic Insights from DSS-Induced Colitis:

DSS-induced colitis studies have provided valuable insights into potential therapeutic approaches for IBD:

1. Anti-Inflammatory Agents: Compounds with anti-inflammatory properties, including mesalamine derivatives and corticosteroids, have demonstrated efficacy in ameliorating DSS-induced colitis, highlighting their potential utility in UC treatment.

2. Immunomodulatory Agents: Immunomodulators such as thiopurines and calcineurin inhibitors have been tested in this model, offering insights into their immunosuppressive effects and potential benefits in IBD therapy.

3. Biologic Therapies: Biologic agents targeting specific immune pathways, including anti-TNF-α antibodies and anti-IL-12/23 antibodies, have shown promise in DSS-induced colitis studies, mirroring their clinical applications in UC treatment.

4. Dietary Interventions: Dietary modifications, such as the use of prebiotics, probiotics, and dietary fiber, have been explored in DSS-induced colitis models, suggesting potential strategies to modulate gut microbiota and mitigate inflammation.

5. Stem Cell Therapy: Stem cell-based approaches have shown therapeutic potential in DSS-induced colitis, offering hope for regenerative therapies in IBD.

Future Directions and Challenges:

While DSS-induced colitis has greatly contributed to our understanding of UC and IBD, several challenges and opportunities lie ahead:

1. Complexity of Human Disease: Despite its similarities to UC, DSS-induced colitis represents an acute, chemical-induced model that does not fully capture the complexity of human IBD, including its chronic nature and multifactorial etiology.

2. Translational Relevance: Translating findings from DSS-induced colitis to clinical practice requires careful consideration of differences between murine models and human disease, necessitating further validation of therapeutic strategies.

3. Personalized Medicine: The heterogeneity of IBD necessitates personalized treatment approaches. DSS-induced colitis studies may aid in identifying biomarkers and therapies tailored to specific patient profiles.

4. Microbiota-Host Interactions: Advancements in microbiome research have underscored the critical role of the gut microbiota in IBD. Incorporating microbiome analysis into DSS-induced colitis studies may yield insights into microbial dysbiosis and therapeutic interventions.

5. Novel Therapies: The growing understanding of immunology and molecular mechanisms opens doors to innovative therapies. Researchers can continue to explore the potential of emerging treatment modalities, such as targeted immunomodulators, gene therapies, and cell-based approaches, using the DSS-induced colitis model.

Conclusion:

Dextran Sulfate Sodium (DSS)-induced colitis stands as a cornerstone in the realm of experimental models for studying inflammatory bowel disease (IBD), specifically ulcerative colitis (UC). Its ability to recapitulate key features of UC pathology, combined with its tractability, has made it an indispensable tool in advancing our understanding of IBD pathogenesis and therapeutic interventions.

This review has provided a comprehensive exploration of DSS-induced colitis, encompassing its mechanisms, pathophysiological changes, and relevance in IBD research. By bridging the gap between basic research and clinical application, this model continues to shape our understanding of IBD and offers hope for the development of novel therapies tailored to the complexities of human disease. While challenges and nuances persist, DSS-induced colitis remains an invaluable asset in the quest to alleviate the burden of IBD for patients worldwide.