Strain-specific responses to dextran sulfate sodium-induced ulcerative colitis in BALB/c and C57BL/6 mice: Comparative analysis of local versus extra-intestinal manifestations.

Objective and design: Dextran sulfate sodium (DSS)-induced colitis in rodents is considered a well-established experimental model for the induction of ulcerative colitis (UC) and its extra-intestinal manifestations (EIMs). The influence of strain on EIMs of UC remains poorly understood. The present study elucidated the strain-specific responses to different concentrations of DSS and its effects on the local (colon), systemic (DNA damage in peripheral blood), and extra-intestinal (liver, pancreas, brain) manifestations.

Methods: BALB/c and C57BL/6 mice, two commonly used rodent strains, were assigned to control and DSS (0.5%, 1%, 2%, and 3% w/v) treatment groups. DSS was provided in drinking water for 7 days over three cycles, with a 7-day inter-cycle remission. No other treatments or interventions were provided.

Results: BALB/c exhibited gradual weight loss even at the lower doses of DSS, while C57BL/6 showed an early and sustained weight loss, particularly at the higher doses, contributing to greater severity and mortality. C57BL/6 exhibited significant systemic and colonic damage, with elevated inflammatory markers (nitrite, TNF-α, IL-1β, LPS) and reduced IL-10 in all the target organs. In contrast, MPO activity and goblet cell loss were more significant in BALB/c. C57BL/6 exhibited significant increase in the intestinal permeability as well as expression of TLR4 in colon and brain as compared to BALB/c mice. Overall, C57BL/6 mice showed significant increase in UC associated brain damage at higher concentrations of DSS, whereas BALB/c exhibited significant liver and pancreatic damage in a dose-dependent manner to DSS exposure. The expression of apoptotic cells and NF-κB/ICAM-1 increased dose-dependently in both the strains, with distinct patterns of expressions at the target organs.

Conclusion: Strain-specific differences in inflammation, cell adhesion, apoptosis, and systemic DNA damage may be responsible for the differential severity, susceptibility, and the extent of colonic and extra-colonic damage observed in BALB/c and C57BL/6 mice. These findings underscore the importance of selecting an appropriate experimental model for UC and can offer translational relevance in predicting organ susceptibility and managing the intestinal and extraintestinal complications.