Host-targeted apple pectic oligosaccharides repair intestinal barrier in colitis via HSP90β/miRNA/CORO2A axis

While functional oligosaccharides alleviate inflammatory bowel disease (IBD), their mechanisms conventionally attributed to gut microbiota modulation. The direct, host-targeted regulatory pathways of apple pectic oligosaccharides (APOS) remain elusive.

This study aimed to elucidate the host-directed parallel mechanism by which APOS restores intestinal epithelial barrier integrity and immune homeostasis during colitis.

We integrated multi-omics analysis, biophysical binding validation, and a dextran sulfate sodium (DSS)-induced rat colitis model. Mechanistic dependency was validated via in vivo miRNA rescue and in vitro (IEC18 and human Caco-2) models using dual-luciferase assays and bidirectional genetic manipulation.

APOS (200 mg/kg) significantly ameliorated colitis severity. Mechanistically, APOS directly bound to the N-terminal pocket of membrane HSP90β on intestinal epithelial cells. This interaction inhibited the release of miR-148a-5p and miR-216a-3p, thereby de-repressing their shared downstream target, the cytoskeletal regulator CORO2A. CORO2A restoration re-anchored junctional networks (ZO-1, AJAP1 and GJA1) and suppressed Th1/Th17-driven cytokine storms. Crucially, exogenous miRNA supplementation in vivo completely abolished APOS-mediated barrier protection despite maintaining a restored microbiome, confirming the indispensable role of this host-directed pathway.

Operating synergistically with microbial modulation, APOS functions as a highly potent (Human Equivalent Dose 11.35 mg/kg), host-directed therapeutic. By engaging the HSP90β/miRNA/CORO2A axis to rebuild the physical defense line, this study conceptualizes a novel framework for precision nutritional intervention in IBD.