A naturalized gut microbiome interacts with dietary fibers to protect against colonic inflammation.

"Feralized" mice, housed in farmyard-type environments, show a matured immunophenotype, altered intestinal barrier, and a shifted gut microbiome compared to conventionally housed laboratory mice. Since dietary fibers support gut health in part by microbial fermentation into immunomodulatory short-chain fatty acids, we hypothesized that feralization influences the intestinal barrier by enhancing the fiber-degrading properties of the microbiome. We explored whether susceptibility to low-grade dextran sulfate sodium-induced colitis differed between feralized and clean laboratory mice fed diets high or low in fermentable fibers. Feralized mice were protected against colitis, displaying low disease scores and biomarkers of inflammation in feces, plasma, and liver; and altered colonic mucosal gene expression, compared to clean mice. This protection was strongest with a fiber-rich diet, which, in contrast, worsened colitis in clean mice. Transfer of fecal microbiota from feralized mice to clean recipients conferred colitis protection. Fecal metagenome-assembled genomes revealed that the fiber-rich diet enriched the microbiome with predicted genes encoding fiber-degrading enzymes, while the low-fiber diet promoted mucin-degrading enzyme genes. However, the dominant microbial species contributing to these functions differed between feralized and laboratory mice. Differential abundance of bacterial taxa in feralized and laboratory mice further identified potential microbial modulators of colitis that merit targeted investigation in future studies. Overall, these findings suggest that fibers affect intestinal inflammation in a microbiota-dependent manner, underscoring the complex interplay between diet and microbiota in disease development.