The Role of the Gut Microbiota in the Pathogenesis of Parkinson's Disease

Abstract

It is well-recognized that the gut microbiota (GM) is crucial for gut function, metabolism, and energy cycles. The GM also has effects on neurological outcomes via many mechanisms, such as metabolite production and the gut-brain axis. Emerging evidence has gradually indicated that GM dysbiosis plays a role in several neurological diseases, such as Parkinson's disease (PD), Alzheimer's disease, depression, and multiple sclerosis. Several studies have observed that PD patients generally suffer from gastrointestinal disorders and GM dysbiosis prior to displaying motor symptoms, but the specific link between the GM and PD is not clearly understood. In this review, we aim to summarize what is known regarding the correlation between the GM and PD pathologies, including direct, and indirect evidence.

Keywords: enteric nervous system; fecal transplant; gut microbiota; gut-brain axis; microbiota-targeted therapies; parkinson's disease.

Copyright © 2019 Yang, Zhao, Ali Shah, Wu, Lai, Zhang, Li, Guan, Zhao, Li, Gao, Zhou and Yang.

Figures

Figure 1

The main components of the gut-brain axis. The gut-brain axis consists of bidirectional communication between the ENS and CNS. The CNS and hypothalamic-pituitary-adrenal (HPA) axis (shown as a dashed line) can be affected by environmental factors, including emotion, and stress. The HPA concludes with cortisol release and is regulated by a complex interaction between the amygdala (AMG), hippocampus (HIPP), and hypothalamus (HYP), which comprise the limbic system. HYP secretion of corticotropin-releasing factor (CRF) stimulates adrenocorticotropic hormone (ACTH) secretion from the pituitary gland, which in turn leads to cortisol release from the adrenal gland. In parallel, the CNS communicates with intestinal targets through both afferent and efferent autonomic pathways (SNA). Diverse factors from different parts of the GI tract, including the GM, enteric neurons, and enteric glial cells (EGG), interact with 5-hydroxytryptamine (5-HT), short-chain fatty acids (SCFAs), and neurotransmitters (GABA) to affect the CNS, resulting in bidirectional communication.

Figure 2

Components of tight junctions. Tight junctions (TJs) of epithelial intestinal cells form selective barriers that regulate paracellular permeability. The main proteins that compose TJs include zonula occludens-1 (ZO-1), claudins, and occludin.

Figure 3

Schematic representation of α-synuclein accumulation and aggravation from the ENS to the brain. Environmental factors like microorganisms (including the GM) and unknown pathogens may initiate a pathological process in the enteric nerve cell plexus, leading to mucosal inflammation, and oxidative stress and further α-synuclein accumulation. The vagal nerve may act as a path for the spread of α-synuclein pathology from the ENS to the brain through the brainstem, midbrain, basal forebrain, and finally, the cortical areas.

Figure 4

Potential mechanism of probiotic treatment in PD. The GM impacts PD via three primary modalities (neuronal mechanism, endocrine mechanism, and immunological mechanism). [1] The GM can both produce and stimulate certain neurotransmitters via/or not via secretory ECs. ECs can also produce certain neuroactive factors, such as PYY, Trp, and His. These two types of components cross into the BBB and impact the CNS. Some gut hormones stimulated by neuroactive components, like ghrelin and IPA, can have dual effects on the CNS. The GM can directly trigger electrical signals in the ENS through the vagus nerve to the DMV. Finally, the GM may release glucose through SCFAs and FFA to propagate signals through the ENS. [2] The GM can directly and indirectly affect a battery of endocrine signaling components. SCFAs, as the main microbial metabolites, are major signaling molecules that may activate several pathways, as shown in the figure. HPA axis stimulation and the release of endocrine components are also triggered by the GM. Those endocrine components, including cortisol, and ferulic acid, have multiple roles in several pathways in PD. [3] Specific GM members could suppress both chronic and pathological inflammation. Microbe-associated molecular patterns on the surface of GM members directly activate receptors on immune cells like DCs and upregulate/suppress inflammatory cytokines. Finally, the GM influences the production of mucin through the gut. AC, acetylcholine; BBB, blood–brain barrier; CNS, central nervous system; CRMP2, collapsin response mediator protein family; DA, dopamine; DHA, docosahexaenoic acid; DMV, dorsal motor nucleus of the vagus; EC, enterochromaffin cell; ENS, enteric nervous system; EPA, eicosapentaenoic acid; FFAR, free fatty acid receptors; GABA, gamma aminobutyric acid; GM, gut microbiota; His, histamine; HPA axis, hypothalamic–pituitary–adrenal axis; IFNγ, interferon gamma; IL-10, interleukin 10; IL-12, interleukin 12; IPA, indole-3-propionic acid; PYY, peptide YY; ROS, reactive oxygen species; SCFAs, short-chain fatty acids; TNFα, tumor necrosis factor alpha; Trp, tryptophan; 5HT, serotonin.