Akkermansia muciniphila induces mitochondrial calcium overload and α -synuclein aggregation in an enteroendocrine cell line

The gut microbiota influence neurodevelopment, modulate behavior, and contribute to neurodegenerative disorders. Several studies have consistently reported a greater abundance of Akkermansia muciniphila in Parkinson disease (PD) fecal samples. Therefore, we investigated whether A. muciniphila-conditioned medium (CM) could initiate alpha-synuclein (alpha Syn) misfolding in enteroendocrine cells (EEC) - a component of the gut epithelium featuring neuron-like properties. We found that A. muciniphila CM composition is influenced by the ability of the strain to degrade mucin. Our in vitro experiments showed that the protein-enriched fraction ofmucin-free CM induces RyR-mediated Ca2+ release and increased mitochondrial Ca2+ uptake leading to ROS generation and aSyn aggregation. Oral administration of A. muciniphila cultivated in the absence of mucin to mice led to alpha Syn aggregation in cholecystokinin (CCK)-positive EECs but no motor deficits were observed. Noteworthy, buffering mitochondrial Ca2+ reverted the damaging effects observed. These molecular insights offer evidence that bacterial proteins can induce alpha Syn aggregation in EECs.

Automated summary

This research found a higher abundance of Akkermansia muciniphila in fecal samples of Parkinson's disease patients and showed that the composition of A. muciniphila conditioned medium is influenced by the strain's ability to degrade mucin. Experimental results indicate that bacterial proteins can induce alpha-synuclein aggregation in enteroendocrine cells, but buffering mitochondrial calcium can reverse the damaging effects.