Gut dysfunction may be the source of pathological aggregation of alpha-synuclein in the central nervous system through Paraquat exposure in mice

Background: One of the most common types of neurodegenerative diseases (NDDs) is Lewy body disease (LBD), which is characterized by excessive accumulation of alpha-synuclein (alpha-syn) in the neurons and affects around 6 million individuals globally. In recent years, due to the environmental factors that can affect the development of this condition, such as exposure to herbicides and pesticides, so it has become a younger disease. Currently, the vast majority of studies on the neurotoxic effects of paraquat (PQ) focus on the late mechanisms of neuronal-glial network regulation, and little is known about the early origins of this environmental factor leading to LBD. Objective: To observe the effect of PQ exposure on intestinal function and to explore the key components of communicating the gut-brain axis by establishing a mouse model. Methods and results: In this study, C57BL/6J mice were treated by intraperitoneal injection of 15 mg/kg PQ to construct an LBD time-series model, and confirmed by neurobehavioral testing and pathological examination. After PQ exposure, on the one hand, we found that fecal particle counts and moisture content were abnormal. on the other hand, we found that the expression levels of colonic tight junction proteins decreased, the expression levels of inflammatory markers increased, and the diversity and abundance of gut microbiota altered. In addition, pathological aggregation of alpha-syn was consistent in the colon and midbrain, and the metabolism and utilization of short-chain fatty acids (SCFAs) were also markedly altered. This suggests that pathological alpha-syn and SCFAs form the gut may be key components of the communicating gut-brain axis. Conclusion: In this PQ-induced mouse model, gut microbiota disruption, intestinal epithelial barrier damage, and inflammatory responses may be the main causes of gut dysfunction, and pathological alpha-syn and SCFAs in the gut may be key components of the communicating gut-brain axis.