Exploring the Differential Host Responses to DSS and UC-Derived Microbiota in a Mouse Model of Colitis

Ulcerative colitis (UC) is a chronic inflammatory condition of the colon, characterized by recurring mucosal inflammation. Current evidence suggests that dysbiosis may drive the disease, but mechanistic links remain incompletely understood. To further investigate the host-microbiome interactions, three UC-induction methods were used on a pseudo germ-free mouse model: (1) DSS, (2) fecal microbiota transplantation (FMT) from a UC patient, and (3) combination of both DSS and FMT simultaneously. Disease severity (DAI), immune cell profiles (flow cytometry), colon transcriptomics (RNA sequencing), and microbiota composition (16S rRNA sequencing) were assessed. Our study revealed distinct effects of DSS and FMT on experimental colitis. DSS had a more pronounced impact on disease severity, while FMT exerted a stronger influence on several immune populations and downregulation of genes associated with tight junctions and mucins. Microbiome analysis demonstrated distinct compositional profiles across all experimental groups. The combined FMT and DSS model exhibited features of both induction methods, resulting in exacerbated clinical scores, barrier dysfunction, and inflammatory responses. Our study provides valuable insight into host–microbiome interactions in UC and introduces a dual-hit approach that may more accurately recapitulate its multifactorial pathogenesis than DSS alone.