Variation in Microbiome Composition and Faecal Metabolites Are Associated With Differential Susceptibility to <scp>DSS</scp> ‐Induced Colitis

Variation in microbiome composition is linked to differences in intestinal immune phenotypes and can be leveraged to identify microbiome-driven contributions to phenotypes of interest. Furthermore, such variation has been associated with differing inter-individual susceptibility to the development of inflammatory bowel disease (IBD), a chronic inflammatory disease of the gastrointestinal tract that is driven by dysfunctional immune-microbiome interactions. Here, we identified that differences in microbiome composition in C57BL/6 mice from two commonly used commercial vendors, Charles River (CR) and Jackson (JAX) Laboratories, were associated with variation in the intestinal immune phenotype, with CR mice having greater Th17 levels and faecal IgA. In turn, CR mice demonstrated enhanced susceptibility to the dextran sulfate sodium (DSS)-induced model of colitis compared to JAX mice. Co-housing studies revealed that CR mice could transmit enhanced susceptibility to colitis to JAX mice, implicating differences in microbiome composition as drivers of disease susceptibility. Faecal metabolomics studies using targeted mass spectrometry revealed several metabolites differentially enriched in colitis-susceptible and colitis-resistant mice. Correlation analysis uncovered metabolites that were both negatively and positively associated with colitis severity. Taken together, our study leveraged natural microbiome variation to identify gut microbial metabolites with the potential to predict the severity of IBD. Importantly, we further establish susceptible and non-susceptible murine microbial communities that represent a tractable system in which to further uncover microbiome contributions to IBD in the DSS-colitis model.