Abstract

Inflammatory bowel disease (IBD) manifests as a sustained gastrointestinal condition driven by an ongoing dysregulated immunity, defective mucosal barrier, and microbiota dysbiosis. Parasitic helminths exert immunomodulation chiefly via excretory/secretory proteins (ESP). This study assessed the remedial effects alongside the mechanistic pathways of the ESP derived from Echinococcus multilocularis ( Emu -ESP) within a dextran sulfate sodium (DSS)-provoked colitis paradigm in mice. Our results indicated that Emu -ESP treatment significantly mitigated DSS-induced colitis and notably alleviated gut microbiota dysbiosis associated with colitis. Mechanistically, Emu -ESP preserved the gut barrier by enhancing the expression of mucin and epithelial junction genes in vivo and reduced organoid injury ex vivo with decreased apoptosis and NF-κB signaling. Furthermore, Emu -ESP could promote macrophage polarization toward the M2 phenotype during colitis. In conclusion, the therapeutic effectiveness of Emu -ESP is linked to its regulation of pathways that suppress inflammation, maintain intestinal barrier function, and prevent microbiota dysbiosis, suggesting it as a promising treatment for intestinal inflammatory disorders. Graphical Emu -ESP treatment alleviates intestinal inflammation. Mechanistically, this effect is reflected by the protection of the intestinal barrier function, maintenance of gut microbiota balance, and activation of M2 macrophage polarization. Ex vivo models of intestinal organoid inflammation further support that Emu -ESP alleviates inflammatory responses. Additionally, a reduction in NF-κB activation and apoptosis was observed in Emu -ESP-induced protection of colonic organoids.