Inulin‐Butyrate Nanogel for Modulation of Gut Microbiome, Intestinal Barrier, and Regulatory T‐Cells in Colitis

ABSTRACT Inflammatory bowel diseases (IBD) arise from a vicious cycle of intestinal barrier dysfunction, gut microbiome dysbiosis, and dysregulated immune responses. Current therapies predominantly suppress immunity but fail to address root causes or break this cycle. While inulin, a prebiotic, restores microbial diversity and enables colon‐targeted drug delivery, they lack specificity for inflamed tissue. On the other hand, even though butyrate, a microbial metabolite, is a potent enhancer of intestinal barrier integrity and anti‐inflammatory Treg cell differentiation, their clinical applications are limited by rapid systemic absorption, impractical dosing, and unpleasant odor. To address these limitations, we have developed an inulin‐butyrate conjugate‐based nanogel (IBN) which is capable of targeted modulation of gut microbiome, intestinal barrier, and immune systems in colitis. In dextran sodium sulfate (DSS)‐induced colitis mice, IBN specifically accumulates in the inflamed colon and released high amounts of butyrate via gut microbial enzymes (inulinase/esterase). The inulin shell improved the gut microbiome, while the released butyrate enhances intestinal barrier functions and promotes Treg differentiation, yielding robust therapeutic activity. Taken together, IBN addresses the multifactorial nature of IBD, offering a biocompatible, transformative strategy to disrupt the disease cycle and restore gut homeostasis.