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.
