DSS-Induced Colitis: Mechanisms and Research Insights

Dextran sulfate sodium (DSS)-induced colitis is a widely used experimental model for studying inflammatory bowel disease (IBD). By administering DSS in drinking water, researchers can induce acute or chronic inflammation that mimics key features of human ulcerative colitis. This model helps investigate disease mechanisms and evaluate potential therapeutic interventions.

Understanding DSS-induced colitis provides insights into intestinal barrier dysfunction, immune responses, and microbiome alterations relevant to IBD pathology. Researchers continue to refine this model to explore new biomarkers and treatment strategies.

Mechanisms Of Epithelial Damage

The epithelial barrier in the colon serves as the first line of defense against luminal antigens, toxins, and microbial components. DSS disrupts this barrier by damaging epithelial cells, increasing permeability, and exposing the underlying lamina propria to harmful substances. The sulfated polysaccharide structure of DSS interacts with the negatively charged mucosal surface, destabilizing the protective mucus layer and compromising tight junction integrity. This allows luminal contents to penetrate deeper into intestinal tissue.

Tight junction proteins such as occludin, claudins, and zonula occludens-1 (ZO-1) are dysregulated following DSS exposure, weakening barrier function. Studies have shown a significant reduction in ZO-1 and occludin expression, correlating with increased paracellular permeability. This disruption permits bacterial products like lipopolysaccharides (LPS) to translocate, exacerbating epithelial injury. The loss of barrier integrity also triggers epithelial apoptosis, as seen in histological analyses where DSS exposure increases TUNEL-positive staining in colonic crypts.

Mucus layer depletion further contributes to epithelial damage. The colonic mucus, primarily composed of mucin glycoproteins like MUC2, prevents direct bacterial contact with epithelial cells. DSS reduces MUC2 production and accelerates mucus degradation, resulting in a thinner protective layer. This depletion increases epithelial vulnerability and promotes bacterial adhesion, worsening tissue injury.

Epithelial regeneration is impaired due to disrupted stem cell function within colonic crypts. Lgr5+ intestinal stem cells, responsible for replenishing the epithelial lining, exhibit reduced proliferation following DSS exposure. This is accompanied by crypt architectural distortion and decreased expression of proliferative markers such as Ki-67. The inability to efficiently repair epithelial damage prolongs barrier dysfunction, sustaining inflammation and tissue destruction.

Cytokine And Chemokine Regulation

Epithelial damage in DSS-induced colitis triggers a cascade of cytokine and chemokine responses that shape the inflammatory landscape. Damaged epithelial cells release alarmins such as IL-33 and HMGB1, which recruit immune mediators and stimulate pro-inflammatory cytokines. Among the most upregulated cytokines are tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), all of which promote immune cell activation and further epithelial damage.

Chemokines direct immune cell migration to inflamed mucosa. Elevated levels of CCL2, CCL5, and CXCL1 correlate with increased infiltration of monocytes, neutrophils, and T cells. CCL2 (monocyte chemoattractant protein-1) facilitates monocyte recruitment, leading to macrophage-driven inflammation. CXCL1 attracts neutrophils, contributing to crypt abscesses and epithelial erosion. The interplay between chemokines and their receptors sustains tissue injury by perpetuating leukocyte infiltration and increasing oxidative stress.

Anti-inflammatory cytokines attempt to counterbalance immune activation, but their effect is often insufficient to control disease progression. IL-10 and transforming growth factor-beta (TGF-β) modulate inflammation by suppressing pro-inflammatory signaling. Studies show IL-10-deficient mice develop more severe colitis, highlighting its protective role in maintaining mucosal homeostasis. Similarly, TGF-β signaling is impaired, as seen by reduced phosphorylation of SMAD proteins, weakening its ability to suppress inflammation. The imbalance between pro- and anti-inflammatory mediators sustains tissue damage.

Gut Microbiome Interactions

DSS exposure alters the gut microbiome, contributing to disease progression. Dysbiosis, characterized by a reduction in beneficial commensals and an expansion of pathogenic species, is a hallmark of this model. Studies using 16S rRNA sequencing consistently report a decline in Firmicutes and an increase in Proteobacteria. The depletion of short-chain fatty acid (SCFA)-producing bacteria such as Lactobacillus and Faecalibacterium reduces butyrate levels, compromising epithelial energy metabolism and weakening mucosal defenses. Butyrate supports intestinal homeostasis by enhancing mucus production and promoting epithelial renewal. Its depletion exacerbates gut barrier dysfunction, increasing exposure to luminal antigens.

As microbial diversity declines, opportunistic pathogens proliferate, aggravating colonic injury. Escherichia coli and Klebsiella species, both members of Enterobacteriaceae, thrive in the inflamed gut due to altered nutrient availability. These bacteria use nitrate and other inflammation-derived metabolites as alternative electron acceptors, outcompeting obligate anaerobes. Their overgrowth contributes to oxidative stress and epithelial injury. Shotgun metagenomic analyses confirm an enrichment of genes associated with oxidative stress resistance and nitrate respiration in DSS-treated mice.

Metabolomic studies highlight functional consequences of these microbial shifts. DSS-induced colitis is associated with reduced microbial-derived tryptophan metabolites, which serve as ligands for the aryl hydrocarbon receptor (AhR). AhR activation reinforces intestinal barrier integrity by promoting epithelial differentiation and mucus stability. The depletion of these metabolites weakens protective mechanisms, increasing mucosal susceptibility to damage. Additionally, bile acid metabolism is altered, with a decrease in secondary bile acids such as lithocholic acid and deoxycholic acid, which help regulate inflammation. Their reduction heightens susceptibility to colitis.

Adipose Tissue Involvement

Visceral fat plays an active role in DSS-induced colitis through metabolic and endocrine signaling. Mesenteric adipose tissue, surrounding the intestines, undergoes significant changes in response to inflammation. DSS-treated mice exhibit hypertrophy of mesenteric fat depots, resembling the “creeping fat” observed in human IBD. This expansion is accompanied by increased lipolysis, leading to the release of free fatty acids that exacerbate inflammation through oxidative stress and lipid peroxidation.

Adipokines secreted by mesenteric fat influence colonic pathology. Leptin, primarily associated with energy balance, is elevated in DSS-induced colitis and disrupts epithelial permeability by modulating tight junction proteins. Adiponectin, which generally exerts anti-inflammatory effects, displays a paradoxical role. While systemic adiponectin levels are often reduced in obesity-related inflammation, DSS exposure increases local adiponectin expression in mesenteric fat, potentially as a compensatory mechanism. However, this upregulation does not appear to mitigate disease severity, suggesting adiponectin resistance in inflamed tissues.

Clinical Signs In Research Models

DSS-induced colitis models exhibit clinical manifestations that resemble human ulcerative colitis, making them valuable for studying disease progression and therapeutic interventions. Weight loss begins within the first few days of DSS administration and worsens as inflammation progresses. Reduced food intake and dehydration contribute to systemic stress. Researchers monitor these parameters alongside stool consistency and fecal occult blood, as diarrhea and rectal bleeding indicate colonic injury. Disease severity correlates with DSS concentration and exposure duration, allowing controlled induction of acute or chronic colitis.

Histopathological analysis provides deeper insights into disease severity. Colonic tissue from DSS-treated animals exhibits crypt loss, epithelial ulceration, and inflammatory cell infiltration. Shortened colon length, a widely used macroscopic indicator of inflammation, reflects the extent of tissue remodeling and fibrosis, particularly in chronic colitis models. Investigators employ disease activity indices integrating weight loss, stool consistency, and rectal bleeding to quantify severity, ensuring reproducibility across studies. These clinical signs, combined with histological evaluation, facilitate the assessment of therapeutic efficacy.

Potential Biomarkers

Identifying biomarkers for DSS-induced colitis improves disease monitoring and therapeutic evaluation. Biomarkers can be molecular, histological, or functional, each providing insights into disease progression. Circulating C-reactive protein (CRP) and serum amyloid A (SAA) are elevated in DSS-treated animals, reflecting systemic inflammation. Fecal calprotectin, a neutrophil-derived protein, serves as a non-invasive indicator of intestinal inflammation and correlates with disease severity. These markers enable longitudinal studies to track disease dynamics.

Metabolomic profiling expands the biomarker landscape by identifying metabolic shifts associated with colitis. Reduced short-chain fatty acids, particularly butyrate and propionate, emphasize the role of microbial metabolism in disease pathology. Alterations in plasma amino acid profiles, such as decreased tryptophan and increased kynurenine levels, highlight immune-metabolic crosstalk. These metabolic biomarkers enhance understanding of DSS-induced colitis and offer potential therapeutic targets. By integrating molecular and functional biomarkers, researchers can refine disease assessment and improve translational relevance.