The gut microbiome in Parkinson's disease: A culprit or a bystander?

In recent years, large-scale metagenomics projects such as the Human Microbiome Project placed the gut microbiota under the spotlight of research on its role in health and in the pathogenesis several diseases, as it can be a target for novel therapeutical approaches. The emerging concept of a microbiota modulation of the gut-brain axis in the pathogenesis of neurodegenerative disorders has been explored in several studies in animal models, as well as in human subjects. Particularly, research on changes in the composition of gut microbiota as a potential trigger for alpha-synuclein (alpha-syn) pathology in Parkinson's disease (PD) has gained increasing interest. In the present review, we first provide the basis to the understanding of the role of gut microbiota in healthy subjects and the molecular basis of the gut-brain interaction, focusing on metabolic and neuroinflammatory factors that could trigger the alpha-synuclein conformational changes and aggregation. Then, we critically explored preclinical and clinical studies reporting on the changes in gut microbiota in PD, as compared to healthy subjects. Furthermore, we examined the relationship between the gut microbiota and PD clinical features, discussing data consistently reported across studies, as well as the potential sources of inconsistencies. As a further step toward understanding the effects of gut microbiota on PD, we discussed the relationship between dysbiosis and response to dopamine replacement therapy, focusing on Levodopa metabolism. We conclude that further studies are needed to determine whether the gut microbiota changes observed so far in PD patients is the cause or, instead, it is merely a consequence of lifestyle changes associated with the disease. Regardless, studies so far strongly suggest that changes in microbiota appears to be impactful in pathogenesis of neuroinflammation. Thus, dysbiotic microbiota in PD could influence the disease course and response to medication, especially Levodopa. Future research will assess the impact of microbiota-directed therapeutic intervention in PD patients.