Impaired Fermentation in the Absence of Gut Microbiota Promotes Inulin-Induced Intestinal Inflammation

Background and aims: Inflammatory bowel diseases (IBD) are characterized by altered gut microbiota composition and impaired dietary fiber fermentation, which can complicate symptom management. Although inulin is a well-established prebiotic fiber, it can exacerbate gut inflammation under certain conditions. We hypothesized that impaired microbial fermentation leaves intact inulin in the gut to activate epithelial immune receptors and promote inflammation, whereas effective fermentation reduces this pro-inflammatory signaling. Methods: We used germ-free (GF) and conventional (CONV) interleukin-10 knockout (Il10⁻/⁻) and wild-type (WT) C57BL/6J mice to assess the role of microbial fermentation and host genetic susceptibility in IBD. GF Il10⁻/⁻ mice were colonized with fecal microbiota from ulcerative colitis (UC) patients or healthy individuals with fiber intolerance (FI). Mice were fed inulin or structurally distinct, physicochemically matched fiber analogs. Colonic inflammatory and barrier-related gene expression and protein levels were assessed by qPCR and ELISA. Results: In GF Il10⁻/⁻ mice, inulin, but not cellulose, induced weight loss, diarrhea, and rectal prolapse. Increased colonic toll-like receptor expression (TLR2, TLR4) as well as elevated serum amyloid A (SAA) and lipocalin-2 levels indicated immune activation by unfermented inulin in GF mice. Colonization with dysbiotic microbiota attenuated these effects. β-fructan fibers including fructooligosaccharides and chicory-derived inulin elicited marked inflammatory responses, whereas agave-derived inulin did not, highlighting the influence of fiber composition in inflammation associated with IBD. Conclusions: Effective microbial fermentation is essential for host tolerance to fermentable fibers. These findings underscore the need of personalized nutrition when recommending fiber supplementation in immune-compromised individuals or those with gut dysbiosis.