Bilirubin Nanomedicine Rescues Intestinal Barrier Destruction and Restores Mucosal Immunity in Colitis

Inflammatory bowel disease (IBD) manifests as intestinalbarrierdestruction, mucosal immunity dysregulation, and disrupted gut microbiomehomeostasis. Conventional anti-inflammatory medications for IBD therapypartially alleviate symptoms but are unable to restore normal barrierand immune function. Here, we report a nanomedicine comprising bilirubin(BR)-attached low-molecular-weight, water-soluble chitosan nanoparticles(LMWC-BRNPs), that promotes restoration of the intestinal barrier,mucosal immunity, and the gut microbiome, thereby exerting robusttherapeutic efficacy. In a mouse model of dextran sulfate sodium salt(DSS)-induced colitis, orally administered LMWC-BRNPs were retainedin the GI tract much longer than other nonmucoadhesive BRNPs owingto the mucoadhesiveness of LMWC via electrostatic interaction. Treatmentwith LMWC-BRNPs led to considerable recovery of the damaged intestinalbarrier compared with the current IBD medication, 5-aminosalicylicacid (5-ASA). Orally administered LMWC-BRNPs were taken up by pro-inflammatorymacrophages and inhibited their activity. They also concurrently increasedthe population of regulatory T cells, thereby leading to the recoveryof dysregulated mucosal immunity. An analysis of the gut microbiomerevealed that LMWC-BRNPs treatment significantly attenuated the increase Turicibacter, an inflammation-related microorganism, resultingin protection of gut microbiome homeostasis. Taken together, our findingsindicate that LMWC-BRNPs restored normal functions of the intestineand have high potential for use as a nanomedicine for IBD therapy.