The Gut-Brain Axis in Homeostasis and Neurodegenerative Disease

In this talk, Dr. Hafler will discuss the gut brain connection, and how it is involved in Parkinson’s Disease. We performed single-cell RNAseq analysis of CSF and blood from 111 individuals, comparing healthy subjects with prodromal PD and manifest PD to patients with the CNS autoimmune disease, multiple sclerosis (MS) and surprisingly identified a pleocytosis in the CSF of patients with prodromal PD. Single-cell RNA sequencing revealed increases in CSF-specific microglia-like macrophages with enhanced JAK-STAT and TNFα signaling signatures with a lack of global T cell activation in CSF as compared to MS. CSF macrophages exhibited similar transcriptional profiles to dural macrophages from human α-synuclein-expressing PD model mice. Finally, shared memory T cell clones were found in humans between gut and CSF T cells consistent with our observation that T cells are primed in the periphery by the gut microbiome and traffic from the white adipose and gastrointestinal tissues to the brain. In total, these findings uncover a myeloid-mediated TNFα inflammatory process in the CNS of patients with prodromal PD suggesting a novel pathological mechanism in disease with immunological linkage between the gut and the CNS driving a myeloid mediated disease etiology triggered by gut T cells.