Inulin aggravates colitis through gut microbiota modulation and MyD88/IL-18 signaling.

Different types of dietary fibers exert distinct effects on gut microbiota and overall health, playing a complex role in disease-specific contexts. Here, we found that while supplementation with dietary soluble fiber inulin does not induce inflammation under steady-state conditions, it exacerbates intestinal inflammation in a DSS-induced colitis mouse model in a gut microbiota-dependent manner. Mechanistically, we found that inulin consumption increases the overall bacterial load with expansion of pro-colitis pathobiont, elevates levels of pro-inflammatory component flagellin, and reduces microbial diversity. These microbiota changes drove colitis aggravation via GR-1⁺ cell-mediated inflammation. Using NLRC4/TLR5- and MyD88-deficient mice, we identified microbiota-derived pro-inflammatory signals-particularly flagellin-as key mediators of this effect. Moreover, the exacerbation of colitis was abolished in IL-18 knockout mice, indicating a critical role for inflammasome signaling in mediating this response. Notably, maternal consumption of an inulin-enriched diet during lactation altered the offspring's gut microbiota and increased their susceptibility to DSS-induced colitis. Collectively, our findings suggest that inulin intake exacerbates DSS induced colitis through microbiota-mediated inflammation and MyD88/IL-18 signaling, with the effects persist in the offspring. These results underscore the importance of considering fiber type in disease-specific dietary interventions, supporting the idea that a more balanced intake of natural dietary fibers that foster a diverse and resilient gut microbiota may offer greater benefits for intestinal health.