Repeated Dextran Sulfate Sodium Exposure Elicits Distinct Immune Responses Reflecting Human Ulcerative Colitis.

Area of Science:

• Immunology
• Gastroenterology
• Microbiome Research

Background:

• Dextran sulfate sodium (DSS)-induced colitis is a common model for ulcerative colitis (UC).
• The utility of acute versus repeated DSS exposure in mimicking human UC remains unclear.
• Understanding these models is crucial for advancing UC research.

Purpose of the Study:

• To compare disease outcomes, immune cell transcriptional programs, and microbiome changes between acute and repeated DSS colitis models.
• To determine which DSS model better represents human UC immune cell states.
• To identify potential therapeutic targets for UC.

Main Methods:

• Histopathology, flow cytometry, single-cell RNA sequencing (scRNA-seq), and 16S rRNA profiling were employed.
• Mice were subjected to single (acute) or two (repeated) cycles of DSS administration.
• Transcriptomic and microbiome data were analyzed and compared to human UC datasets.

Main Results:

• Repeated DSS cycles induced greater colon shortening, mucosal remodeling, and neutrophil infiltration compared to acute DSS.
• scRNA-seq revealed distinct neutrophil and T cell transcriptional programs in repeated DSS, including expanded Treg and exhausted CD8+ T cell subsets.
• Repeated DSS led to microbiome normalization and transcriptomic profiles more closely aligned with active human UC, particularly regarding neutrophils and macrophages.

Conclusions:

• Repeated DSS cycles offer a more relevant experimental model for studying immune cell dynamics in UC.
• This model facilitates the identification of distinct immune cell subtypes relevant to UC pathogenesis and therapeutic strategies.
• The findings highlight the importance of model selection in preclinical UC research.