The Bidirectional Gut-Microbiota-Brain Axis in Parkinson’s disease: integrating mechanistic biomarkers of disease severity and progression

ABSTRACT In this UO1 application, the Medical College of Georgia and Rush Gastroenterology & Neurology Research Centers propose prospective cross-sectional and longitudinal studies to test the overarching hypothesis that disruptions in the Gut-Microbiota-Brain-Axis (GMBA) contribute to PD pathogenesis / pathophysiology. We posit that a comprehensive model, incorporating validated clinical measures and PD relevant pathophysiological markers of GMBA disruption, will predict disease severity and progression. Aim 1 will evaluate the relationship between GMBA disruption and PD severity (cross sectional), Aim 2 will evaluate the relationship between the GMBA and PD progression over 36 months (longitudinal), and Aim 3 is focused on prodromal PD. The GMBA is multifaceted, and, as such, the global statistical test (GST) approach to examine multiple variables simultaneously will be used to evaluate the different elements of the GMBA including the gut microbiota, intestinal barrier, inflammation, resilience, biological aging, and alpha-synuclein pathology. To accomplish these Aims, this project will leverage an existing Rush sample repository (sample Repository Cohort), a newly recruited group of subjects (New Cohort), and the resources of the NIDDK Consortium (Consortium Cohort). Outcomes from this project will reveal the relationship between the GMBA and PD severity and progression which will shed light on disease mechanism and is expected to define new therapeutic approaches for PD. Our Aim 3 offers the Consortium an infrastructure to approach the same GMBA modeling for the group’s study of the very earliest phases of defined disease. For all Aims, this project, in combination with the NIDDK Consortium evaluating the GMBA in PD, will facilitate the sharing of metadata and samples which is expected to vertically shift the field.