Bacteroides Fragilis-Derived Outer Membrane Vesicles Deliver MiR-5119 and Alleviate Colitis by Targeting PD-L1 to Inhibit GSDMD-Mediated Neutrophil Extracellular Trap Formation.

Abstract

Inflammatory bowel disease (IBD) results from a breakdown in the symbiotic relationship between the intestinal commensal microflora and the mucosal immune system. Non-toxigenic Bacteroides fragilis, a common human colon symbiote, has been shown to alleviate colitis. However, the underlying mechanisms of this alleviation remain incompletely understood. Herein, it is demonstrated that promoting the secretion of B. fragilis outer membrane vesicles (Bf^OMVs+) enhances its ability to alleviate dextran sodium sulfate (DSS)-induced colitis, while inhibiting B. fragilis OMV secretion (Bf^OMVs-) reduces this effect. Bf^OMVs+ alleviates colitis by inhibiting neutrophil recruitment and neutrophil extracellular trap (NET) formation. Further, B. fragilis OMVs (Bf-OMVs) are isolated and extracted, then administered them intraperitoneally to DSS-induced colitis mice, observing that Bf-OMVs can target intestinal tissues, the spleen, and bone marrow, and they are internalized by neutrophils to inhibit NET formation, thereby alleviating colitis. The expression profile of miRNAs in Bf-OMVs is assessed, revealing that Bf-OMVs are enriched with mmu-miR-like sRNA, miR-5119, which targets and inhibits PD-L1, leading to the suppression of GSDMD-mediated NET release and promoting the proliferation of intestinal stem cells (ISCs), culminating in the alleviation of colitis. These findings provide new insights into the role of B. fragilis OMVs in the pathogenesis and treatment of IBD.