Role of enteric glia and microbiota-gut-brain axis in parkinson disease pathogenesis

The microbiota-gut-brain axis or simple gut-brain axis (GBA) is a complex and interactive bidirectional communication network linking the gut to the brain. Alterations in the composition of the gut microbiome have been linked to GBA dysfunction, central nervous system (CNS) inflammation, and dopaminergic degeneration, as those occurring in Parkinson's disease (PD). Besides inflammation, the activation of brain microglia is known to play a central role in the damage of dopaminergic neurons. Inflammation is attributed to the toxic effect of aggregated alpha-synuclein, in the brain of PD patients. It has been suggested that the alpha-synuclein misfolding might begin in the gut and spread "prion-like", via the vagus nerve into the lower brainstem and ultimately to the midbrain, known as the Braak hypothesis. In this review, we discuss how the microbiota-gut-brain axis and environmental influences interact with the immune system to promote a pro-inflammatory state that is involved in the initiation and progression of misfolded alpha-synuclein proteins and the beginning of the early non-motor symptoms of PD. Furthermore, we describe a speculative bidirectional model that explains how the enteric glia is involved in the initiation and spreading of inflammation, epithelial barrier disruption, and alpha-synuclein misfolding, finally reaching the central nervous system and contributing to neuroinflammatory processes involved with the initial non-motor symptoms of PD.