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.
Currently, small extracellular vesicles (sEV) as a nanoscale drug delivery system, are undergoing biotechnological scaling and clinical validation. Nonetheless, preclinical pharmacokinetic studies revealed that sEV are predominantly uptaken by macrophages. Although this “sEV‐macrophage” propensity represents a disadvantage in terms of sEV targeting and their bioavailability as nanocarriers, it also represents a strategic advantage for those therapies that involve macrophages. Such is the case of tumor‐associated macrophages (TAMs), which can reprogram/repolarize their predominantly immunosuppressive and tumor‐supportive phenotype toward an immunostimulatory and anti‐tumor phenotype using sEV as nanocarriers of TAMs reprogramming molecules. In this design, sEV represents an advantageous delivery system, providing precision to the therapy by simultaneously matching their tropism to the therapeutic cell target. Here, we review the current knowledge of the role of TAMs in the tumoral microenvironment and the effect generated by the reprogramming of these phagocytic cells fate using sEV. Finally, we discuss how these vesicles can be engineered by different bioengineering techniques to improve their therapeutic cargo loading and preferential uptake by TAMs.
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