Interplay between the dopamine-gut-motility pathway, Parkinson’s disease and the gut microbiota

Abstract

More than half of patients with Parkinson’s disease suffer from constipation. Current treatments fail to alleviate this constipation. Therefore, there is interest in identifying the cause behind the Parkinson’s disease-associated constipation. Parkinson’s disease may induce constipation through alteration of the dopamine-gut motility pathway, which itself is also not well understood. Parkinson’s disease is also associated with changes in gut microbiota composition. The change in gut microbiota composition may cause and/or be caused by the altered gut motility. Therefore, this research proposal aims to uncover the mechanisms of the dopamine-gut motility pathway, the cause behind Parkinson’s disease-induced constipation, and the causal relationship between Parkinson’s disease and changes to the gut microbiota composition. To investigate the dopamine-gut-motility pathway, the involvement of multiple intracellular and intercellular second messengers will be tested for various cell types. In addition, dopamine’s effect on transcription will also be analysed. To investigate if Parkinson’s disease affects the dopamine-gut motility pathway, the impact of Parkinson’s disease on dopamine-receptor levels, enteric neuron density and dopamine levels in the gut will be analysed. The importance of the gut microbiota for the gut motility changes seen in Parkinson’s disease will be investigated by removing and replacing the gut microbiota. Finally, the causality between changes in gut microbiota composition and Parkinson’s disease will be investigated by analysing the impact of reduced gut motility on gut microbiota composition and the gut microbiota’s impact on Parkinson’s disease development. This research will pave the way for new Parkinson’s disease treatments and diagnosis options.