Outer membrane vesicles from Akkermansia muciniphila antagonize chronic stress-induced colorectal cancer progression by downregulating Fetuin-A

Introduction Chronic stress is known to exacerbate the malignant progression of colorectal cancer (CRC), a leading cause of cancer-related mortality worldwide. While outer membrane vesicles (OMVs) derived from Akkermansia muciniphila ( A. muciniphila ) exhibit anti-tumor potential, their underlying mechanisms in the context of stress remain unclear. This study investigated whether A. muciniphila OMVs could mitigate chronic stress-induced CRC progression by regulating the pro-tumorigenic protein Fetuin-A. Methods and results In vitro , the β -adrenergic agonist isoproterenol (ISO), used to simulate chronic stress, significantly promoted CRC cell proliferation, migration, and invasion while inhibiting cellular uptake of OMVs. Notably, A. muciniphila OMVs effectively rescued the ISO-driven malignant progression in CRC cells by counteracting the upregulation of Fetuin-A. In vivo , using a CRC mouse model combined with chronic unpredictable mild stress, we found that OMV administration markedly suppressed tumor growth. This therapeutic effect was associated with a significant downregulation of Fetuin-A expression in tumor tissues. Conclusion Collectively, our findings demonstrate that A. muciniphila OMVs inhibit chronic stress-driven CRC progression by downregulating Fetuin-A. This study uncovers a novel regulatory mechanism within the “stress–Fetuin-A–CRC” axis and highlights A. muciniphila OMVs as a promising therapeutic strategy for managing stress-associated CRC.