Oral Nanomicelle‐Mediated Sequential Butyrate Production in the Intestine for Ulcerative Colitis and Immunosuppression Treatment

Butyrate (BA) is essential for intestinal health, but its intestinal therapeutic applications are hindered by its malodorous nature, premature gastric absorption, and rapid intestinal metabolism. To address these challenges, an inodorous macromolecule β-glucan-BA (GLU-BA) is synthesized via one-step esterification, allowing for BA production in the intestine with burst yet gradual dynamics. After oral administration, GLU-BA self-assembles into nanomicelles, preventing premature gastric absorption. Upon reaching the intestine, endogenous esterases rapidly hydrolyze its ester bonds, triggering a burst BA release while exposing GLU, with the GLU subsequently metabolized by gut microbiota to gradually generate BA. Such sequential production enabled by a single oral administration of GLU-BA ensures significant intestinal BA availability as early as 0.5 h post administration, lasting for at least 12 h. This leads to co-achievement of prompt intervention and sustained therapeutic efficacy, as demonstrated in mouse models of ulcerative colitis and immunosuppression. Additionally, GLU-BA restores gut microbiota dysbiosis, during which BA-producing bacteria are enriched, reinforcing BA intestinal replenishment. With excellent biocompatibility (negligible toxicity after 366 days of daily oral administration), scalable synthesis (∼54 g per one-pot reaction), and broad-spectrum bioactivities of BA, GLU-BA demonstrates to be a promising candidate for clinical applications in treating diseases associated with intestinal disorders.