The Enteric Nervous System in Parkinson's Disease: At the Crossroads of Inflammation, Metabolism and α-Synuclein Pathology

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder traditionally defined by motor symptoms such as tremor, bradykinesia, and rigidity, characterized by α-synuclein aggregation and loss of dopaminergic neurons in the substantia nigra region of the brain. However, non-motor symptoms like gastrointestinal dysfunction, depression, and sleep disturbances often appear years earlier, suggesting that PD may originate outside the central nervous system. Increasing evidence points to the gut, specifically the enteric nervous system (ENS), as a potential starting site, supporting the “body-first” hypothesis of PD. The ENS is a complex nervous system in the gastrointestinal tract that communicates with the brain and regulates digestion. Disruptions in gut homeostasis, including inflammation, may contribute to PD development. Enteric glial cells, key regulators of immune responses and neuronal support in the gut, are thought to play an important role, though their exact involvement remains unclear. This thesis aimed to investigate the role of the ENS in early PD pathology, focusing on enteric glial cells. A human embryonic stem cell-derived ENS model containing both neurons and glial cells was established to study inflammation, metabolism, and α-synuclein pathology. Chapter 2 reviews clinical evidence showing that gastrointestinal symptoms and microbiota changes often precede PD diagnosis. It discusses how gut microbes may influence disease processes through immune modulation, metabolite production, and promotion of α-synuclein aggregation, as well as potential microbiota-targeted therapies. Chapter 3 examines acute inflammation in the ENS model. Exposure to pro-inflammatory cytokines triggered strong inflammatory responses and metabolic changes in enteric glial cells, including altered glycolysis, TCA cycle and glutathione metabolism. Short-chain fatty acids (SCFAs), microbial metabolites, reduced inflammation and reversed these metabolic changes, suggesting a protective role. 13C tracer studies also revealed glia-specific metabolic states, illuminating intrinsic metabolic alterations. Chapter 4 explores chronic-like inflammation. Long-term cytokine exposure induced sustained inflammation, significant metabolic alterations in glial cells resembling PD patient profiles, and increased α-synuclein aggregation in neurons. These findings support the idea that chronic gut inflammation may initiate PD-related pathology. Chapter 5 investigates bacterial amyloids, specifically the curli protein subunit CsgA. Preliminary findings show that while CsgA alone had no pro-inflammatory effect, it enhanced inflammation and α-synuclein accumulation when combined with cytokines. Higher concentrations also promoted aggregation independently, suggesting microbial amyloids may contribute to disease initiation. Overall, this work supports the hypothesis that PD may begin in the ENS. It highlights the roles of inflammation, glial cell metabolism, and microbial factors in early disease processes. The developed ENS model provides a valuable tool for studying PD mechanisms and may help identify new therapeutic strategies targeting the gut-brain axis.