Extracellular vesicles from pasteurized Akkermansia muciniphila ameliorate inflammatory bowel disease through suppression of STING-driven inflammatory signaling.

INTRODUCTION: Akkermansia muciniphila (A. muciniphila) has shown considerable potential in maintaining intestinal barrier homeostasis and regulating host inflammatory responses, both of which are commonly disrupted in inflammatory bowel disease (IBD). However, the therapeutic application of live A. muciniphila in IBD remains controversial. Interestingly, A. muciniphila-derived extracellular vesicles (AEVs) have been reported to improve intestinal barrier function, immune status, and gut microbiota composition, and may exert superior efficacy in IBD. In parallel, pasteurized A. muciniphila has been shown to retain, or even enhance, beneficial bioactivity compared with the live bacterium in certain disease settings. Here, we investigated whether extracellular vesicles derived from pasteurized A. muciniphila (PAEVs) preserve or further enhance the anti-inflammatory and barrier-protective effects of the parental bacterium. METHODS: A dextran sulfate sodium (DSS)-induced mouse model of colitis was used to evaluate the therapeutic effects of PAEVs and AEVs. Disease severity, body weight loss, colonic histopathology, inflammatory cytokine expression, intestinal barrier integrity, inflammatory signaling pathways, and gut microbiota composition were assessed. RESULTS: PAEVs markedly attenuated DSS-induced colitis, as evidenced by reduced weight loss, improved colonic histology, decreased levels of TNF-α, IL-6, and IFN-γ, and enhanced tight junction proteins. By contrast, AEVs improved only limited parameters, including Occludin expression and TNF-α levels. Mechanistically, PAEV-mediated protection may be associated with suppression of the STING/IκB/NF-κB signaling axis and remodeling of the gut microbiota. DISCUSSION: These findings indicate that PAEVs effectively alleviate experimental IBD by enhancing tight junction proteins, suppressing some inflammatory cytokines, and modulating gut microbiota composition. Compared with AEVs, PAEVs exhibit broader protective effects, suggesting that extracellular vesicles derived from pasteurized A. muciniphila may represent a promising postbiotic strategy for IBD intervention. Importantly, this study offers the first systematic comparison of extracellular vesicles derived from live and pasteurized A. muciniphila, highlighting PAEVs as a distinct and potentially more effective postbiotic vesicle formulation for IBD intervention.