Mayo Clinic Consortium for Gut Brain Communication in Parkinson's Disease

PROJECT SUMMARY Gastrointestinal (GI) symptoms, especially constipation, affect >50% of persons with PD (PwPD). However, these concepts are exclusively based on tertiary care studies that used incomplete definitions of constipation. Our population study found that constipation preceded the motor symptoms of PD by up to 20 or more years. Our proposal is predicated on the integrated, multi-hit hypothesis that environmental exposures, especially in genetically vulnerable persons, are perpetuated by an inflammatory gut microbiome and epigenetic changes, resulting in accumulation of misfolded α synuclein in the gut and its transfer to the central nervous system, followed by enteric and central neurodegeneration, GI and anorectal dysfunctions, and GI symptoms in PD. This proposal will assimilate the bigger-picture cellular networks that drive disease processes, enteric neuropathology, brain-gut dysfunctions, and the clinical phenotype in PwPD-C and without constipation (PwPD- noC). We have assembled a multi-disciplinary team from the Departments of Gastroenterology, Neurology, Physiology, and Radiology and the Center for Individualized Medicine at Mayo Clinic, Dr. Gary Miller (Columbia University), and Dr. Rodger Liddle (Duke University) to compare brain-gut dysfunctions (Aim 1), omics-based disease signatures (Aim 2), and the exposome (Aim 3) in 60 PwPD-C, 60 PwPD-noC, and 30 healthy controls. When integrated with the clinical phenotype, this information will identify biomarkers and pathways that predispose to constipation in PwPD. Aim 1 will compare neurological and GI clinical features, in vivo GI functions (GI transit and anorectal functions), enteric neuropathology (α-synuclein deposition in EEC and neurons and neuronal loss) and neuroimaging abnormalities (18FFDG-PET and MRI) in PwPD-C, PwPD-noC, and healthy controls. Aim 2 will discover changes in gut microbial composition and dynamics associated with PD-C by assessing the fecal metagenome (Aim 2a) and the colonic mucosal transcriptome (Aim 2b) and epigenome (Aim 2c). Aim 3 will identify signatures associated with PD-C in and across the peripheral blood exposome and metabolome. We will identify exogenous chemical exposures (e.g., pollutants and pesticides) representing the exposome and endogenous small molecule metabolites representing biological pathways or the metabolome using cutting-edge high-resolution mass spectroscopy platforms and environmental questionnaires. Integrated with the epigenome and transcriptome, Aim 3 will likely enrich our understanding of the risk factors for PD.