The Gut and Parkinson's Disease-A Bidirectional Pathway

Abstract

Humans evolved a symbiotic relationship with their gut microbiome, a complex microbial community composed of bacteria, archaea, protists, and viruses, including bacteriophages. The enteric nervous system (ENS) is a gateway for the bidirectional communication between the brain and the gut, mostly through the vagus nerve (VN). Environmental exposure plays a pivotal role in both the composition and functionality of the gut microbiome and may contribute to susceptibility to neurodegenerative disorders, such as Parkinson's disease (PD). The neuropathological hallmark of PD is the widespread appearance of alpha-synuclein aggregates in both the central and peripheral nervous systems, including the ENS. Many studies suggest that gut toxins can induce the formation of α-syn aggregates in the ENS, which may then be transmitted in a prion-like manner to the CNS through the VN. PD is strongly associated with aging and its negative effects on homeostatic mechanisms protecting from inflammation, oxidative stress, and protein malfunction. In this mini-review, we revisit some landmark discoveries in the field of Parkinson's research and focus on the gut-brain axis. In the process, we highlight evidence showing gut-associated dysbiosis and related microbial-derived components as important players and risk factors for PD. Therefore, the gut microbiome emerges as a potential target for protective measures aiming to prevent PD onset.

Keywords: Parkinson's disease; enteric nervous system; microbiome; neurotoxicants; probiotics.

Figure 1

The gut epithelium is a multifunctional interface. The bidirectional interplay between the brain and the gut is mediated by neural, such as the vagus nerve (VN-gateway), and humoral pathways, such as the lymphatic tissue and the bloodstream (Non-VN gateways). A monolayer of epithelial cells separates the intestinal lumen and the complex gut microbiome from the underlying lymphoid and enteric nervous tissues. The structure of alpha-synuclein amyloid fibrils (PDB 2N0A) is based on atomic-resolution molecular data from NGL Viewer (19). Members of the gut microbiome and their extracellular compounds may trigger responses in the VN through enteroendocrine cells, which are contacted by vagus nerve terminals through specialized structures called neuropods (NP) (20). Microbial antigens can cross the gut epithelium through microfold cells, playing a central role in localized inflammatory responses [adapted from Bohórquez et al. (21)]. Toll-like receptors are microbe-sensing proteins, present in intestinal epithelial cells, mediating recognition of commensal bacteria from the harmful/inflammatory ones. ENS, enteric nervous system; M, microfold cells; NP, neuropods; PP, Peyer's patches; TLR4, Toll-like receptor 4; VN, vagus nerve.