Accute and repeated DSS exposure induce distinct immune responses with differential relevance to human Ulcerative Colitis

Dextran sulfate sodium (DSS)-induced colitis is a widely used model to study ulcerative colitis (UC). However, the extent to which acute versus repeated DSS exposure mimics human disease remains unclear. Using histopathology, flow cytometry, single-cell RNA sequencing (scRNA-seq) and 16S rRNA profiling we compared disease outcomes, immune infiltrate, transcriptional programs and changes in the microbiome in mice subjected to a single (acute) versus two (repeated) DSS cycles. We found that repeated cycles of DSS-induced colitis in mice result in more severe intestinal inflammation compared to a single exposure, with increased PMN and T cell infiltration, mucosal remodeling, and microbiota normalization. Single-cell transcriptomics revealed that acute vs repeated DSS exposure drives differential programs in immune cell subtypes distinctly overlapping with human UC. Overall, our findings suggest that repeated DSS exposure may more accurately models human disease, highlighting its utility for translational IBD research.