Bacteriocin-transport-inspired oral peptide-probiotic delivery ameliorates IBD complications via autophagy and gut homeostasis.

Abstract

Intestinal fibrosis (IF), a severe complication of inflammatory bowel disease (IBD), remains a critical unmet clinical need. Although the LL37 peptide and probiotics demonstrate therapeutic potential against IF, their clinical translation is hampered by enzymatic hydrolysis and rapid clearance. Here, inspired by the strategy of bacteriocin transport by bacteria (BTB), we developed an orally administered biotherapeutic platform [BTB-alginate (Alg)] featuring an "all-in-one" architecture that enables spatiotemporal coordination of LL37 and probiotics. The BTB-Alg effectively restored intestinal homeostasis through inflammation resolution, immune modulation, and gut microbiota reconstitution. Notably, integrated multiomics analysis and molecular dynamics simulations revealed that LL37 exerts antifibrotic effects by inducing adenosine 5'-monophosphate-activated protein kinase/mammalian target of rapamycin-mediated autophagy, a mechanism validated in clinical specimens. BTB-Alg exhibited potent therapeutic efficacy in three murine models of acute colitis, IBD-associated IF, and <i>Clostridioides difficile</i>-complicated colitis, highlighting its potential as an IBD treatment paradigm. This study offers a clinically translatable strategy for broad gastrointestinal applications.