Parkinson’s disease (PD) is the second most prevalent neurodgenerative disease, and poses high costs to affected inidviduals, their families, and society at large. There is no cure, available therapies are symptomatic and often have serious side effects. PD is a complex disease whose etiology is poorly understood, a situation that is at least in part due to its multifactorial nature. Yet, models, in particular mammalian models, aimed at investigating this aspect of the disease are lacking. In this propsal, we hypothesize that the pathogenesis of PD is triggered by a combinatorial effect of (1) reduced gut barrier function driven by microbial mucus foraging as a consequence of microbiome imbalance, (2) exposure of the enteric nervous system to bacterial amyloidogenic peptides that initiate alpha-synuclein (aSyn) aggregation and prion-like propagation from the PNS to the CNS, and (3) abnormal aSyn levels. To test our hypothesis, we will use transgenic mice overexpressing human aSyn and expose them to diet-, bacterial peptide, and, in some cases, targeted microbiome replacement induced challenges. Control groups will test the effect of these challenges individually or in pairwise combination, as well as in wildtype littermate controls. Outcome measures will include behaviour, histopathology (PNS, CNS, intestine), and intestinal microbiome profiling. We expect this multivariate study to provide new insights into the initiation and progression of PD-like disease in mice, and to possibly open up new venues to explore for PD therapeutic or prevention measures.