Purified Diets Lacking Fermentable Fiber Reduce Microbial Diversity, Alter Epithelial Transcriptome, and Exacerbate Colitis

<b>Background/Objectives</b>: Dietary fibers play key roles in shaping gut microbiome and intestinal homeostasis. While purified diets offer experimental precision and reproducibility in rodent models, they omit the complex mixture of fermentable and non-fermentable fibers found in grain-based chow diets. We hypothesized that excluding fermentable fiber impairs intestinal homeostasis by reducing microbial metabolites and altering the colonic epithelial transcriptome, thereby increasing susceptibility to inflammation. <b>Methods</b>: Wildtype male C57BL/6 mice were maintained on either a standard grain-based chow diet or a purified low-fat diet (LFD) containing 5% non-fermentable cellulose for ten weeks. Fecal microbiomes, short-chain fatty acid (SCFA) profiles, and colonic epithelial transcriptomes were analyzed. A separate group was challenged with dextran sodium sulfate (DSS) following a five-week dietary intervention to compare colitis severity between the two diet groups. <b>Results</b>: Relative to mice fed the grain-based chow, those consuming the purified LFD (containing only non-fermentable cellulose) showed decreased gut microbial diversity and significantly lower SCFA levels. These changes were accompanied by marked differences in colonic epithelial cell transcriptomes. In LFD-fed mice, the top upregulated gene networks included ribosomal pathways and MHC complex protein binding, suggesting increased growth and gut inflammation. The most downregulated pathways included mineral absorption, actin and tubulin binding, and membrane organelle assembly, indicating major alterations in cellular structure and transport. LFD-fed mice also exhibited increased colonic expression of S100a9, a gut inflammation biomarker, and more severe disease symptoms when challenged with DSS compared to chow-fed mice. <b>Conclusions</b>: Fermentable fibers are one of the factors contributing to intestinal homeostasis and mitigating the severity of ulcerative colitis.