Gut microbiota promote the propagation of pathologic α-syn from gut to brain in a gut-originated mouse model of Parkinson’s disease

Abstract

The pathology of Parkinson's disease (PD) can originate in gut and gut microbiota is considered as important pathway in gut-brain axis of PD. However, no studies have delineated the interaction of gut microbiota with gut-originated PD. We established a gut-originated PD murine model and subsequently characterized changes in gut microbiota over an eight-month period. Progressive motor dysfunction, decreased dopaminergic neurons and spreading of α-syn pathology was observed at several time points during the 8-month disease progression, along with changes in the composition of the gut microbiota. Increases in Dubosiella at genus level occurred from 4 months, and was highly consistent with the time point of disease progression. Metabolic function prediction of gut microbiota suggested metabolic disorders of branched-chain-amino acids (BCAA), which resulted in accumulation of BCAA in peripheral blood. Removal of gut microbiota by antibiotic treatment reversed the progression of PD, as well as decreased the levels of Dubosiella and BCAA. Remarkably, Dubosiella newyorkensis disrupted the BCAA metabolism and mediated the accumulation of BCAA in mouse colon organoids. Consistent with the results observed in the animal model, abnormally elevated serum BCAA were also detected in the PD patients enrolled in this study. Furthermore, excessive BCAA caused lysosome dysfunction in microglia, suggesting that accumulated BCAA mediated by the gut microbiota may be an important mechanism in preventing the degradation of α-syn. These results show that microbiota-dependent BCAA function to inhibit α-syn degradation, thus enhancing PD progression, and provides compelling evidence for microbiota intervention therapy for PD. Our dynamic tracking of gut microbiota pioneers a new field of study in understanding the role of the gut-brain axis in development of PD, and provides compelling evidence for microbiota intervention therapy for PD.