01803nas a2200217   4500000000100000008004100001260001500042100001900057700002400076700001700100700002100117700001800138700002100156700002400177245012100201856003800322300001100360490000700371520119300378022001401571       2024                            d  c2024-09-131 aEmily J. Jones1 aBenjamin M. Skinner1 aAimee Parker1 aLydia R. Baldwin1 aJohn Greenman1 aSimon R. Carding1 aSimon G. P. Funnell00aAn in vitro multi-organ microphysiological system (MPS) to investigate the gut-to-brain translocation of neurotoxins  uhttps://doi.org/10.1063/5.0200459  a0541050 v183 aThe death of dopamine-producing neurons in the substantia nigra in the base of the brain is a defining pathological feature in the development of Parkinson's disease (PD). PD is, however, a multi-systemic disease, also affecting the peripheral nervous system and gastrointestinal tract (GIT) that interact via the gut–brain axis (GBA). Our dual-flow GIT–brain microphysiological system (MPS) was modified to investigate the gut-to-brain translocation of the neurotoxin trigger of PD, 1-methyl-4-phenylpyridinium (MPP+), and its impact on key GIT and brain cells that contribute to the GBA. The modular GIT–brain MPS in combination with quantitative and morphometric image analysis methods reproduces cell specific neurotoxin-induced dopaminergic cytotoxicity and mitochondria-toxicity with the drug having no detrimental impact on the viability or integrity of cellular membranes of GIT-derived colonic epithelial cells. Our findings demonstrate the utility and capability of the GIT-brain MPS for measuring neuronal responses and its suitability for identifying compounds or molecules produced in the GIT that can exacerbate or protect against neuronal inflammation and cell death.  a1932-1058