Exosome-like nanoparticles from Mulberry bark prevent DSS-induced colitis via the AhR/COPS8

Bark protects the tree against environmental insults. Here, we analysed whether this defensive strategy could be utilised to broadly enhance protection against colitis. As a proof-of-concept, we show that exosome-like nanoparticles (MBELNs) derived from edible mulberry bark confer protection against colitis in a mouse model by promoting heat shock protein family A (Hsp70) member 8 (HSPA8)-mediated activation of the AhR signalling pathway. Activation of this pathway in intestinal epithelial cells leads to the induction of COP9 Constitutive Photomorphogenic Homolog Subunit 8 (COPS8). Utilizing a gut epithelium-specific knockout of COPS8, we demonstrate that COPS8 acts downstream of the AhR pathway and is required for the protective effect of MBELNs by inducing an array of anti-microbial peptides. Our results indicate that MBELNs represent an undescribed mode of inter-kingdom communication in the mammalian intestine through an AhR-COPS8 mediated anti-inflammatory pathway. These data suggest that inflammatory pathways in a microbiota enriched intestinal environment are regulated by COPS8, and that edible plant derived ELNs may hold the potential as new agents for the prevention and treatment of gut-related inflammatory disease.-