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Background: The notion that the gut microbiota plays a role in neurodevelopment, behavior and outcome of neurodegenerative disorders is recently taking place. A number of studies have consistently reported a greater abundance of Akkermansia muciniphila in Parkinson’s disease (PD) fecal samples. Nevertheless, a functional link between A. muciniphila and sporadic PD remained unexplored. Here, we investigated whether A.muciniphila conditioned medium could initiate the misfolding process of α-synuclein (αSyn) in enteroendocrine cells (EECs), which are part of the gut epithelium and possess many neuron-like properties. Results: We found that A. muciniphila conditioned medium is directly modulated by mucin, induces intracellular calcium (Ca2+) release, and causes increased mitochondrial Ca2+ uptake in EECs, which in turn leads to production of reactive oxygen species (ROS) and αSyn aggregation. Indeed, oral administration of A. muciniphila cultivated in the absence of mucin to aged mice also led to αSyn aggregation in cholecystokinin (CCK)-positive enteroendocrine cells. Noteworthy, buffering mitochondrial Ca2+ reverted all the damaging effects observed. Conclusion: Thereby, these molecular insights provided here offer evidence that bacterial proteins are capable of inducing αSyn aggregation in enteroendocrine cells.