Gut-brain axis and environmental factors in Parkinson's disease: bidirectional link between disease onset and progression

Abstract

Parkinson's disease has long been considered a disorder that primarily affects the brain, as it is defined by the dopaminergic neurodegeneration in the substantia nigra and the brain accumulation of Lewy bodies containing α-synuclein protein. In recent decades, however, accumulating research has revealed that Parkinson's disease also involves the gut and uncovered an intimate and important bidirectional link between the brain and the gut, called the "gut-brain axis." Numerous clinical studies demonstrate that gut dysfunction frequently precedes motor symptoms in Parkinson's disease patients, with findings including impaired intestinal permeability, heightened inflammation, and distinct gut microbiome profiles and metabolites. Furthermore, α-synuclein deposition has been consistently observed in the gut of Parkinson's disease patients, suggesting a potential role in disease initiation. Importantly, individuals with vagotomy have a reduced Parkinson's disease risk. From these observations, researchers have hypothesized that α-synuclein accumulation may initiate in the gut and subsequently propagate to the central dopaminergic neurons through the gut-brain axis, leading to Parkinson's disease. This review comprehensively examines the gut's involvement in Parkinson's disease, focusing on the concept of a gut-origin for the disease. We also examine the interplay between altered gut-related factors and the accumulation of pathological α-synuclein in the gut of Parkinson's disease patients. Given the accessibility of the gut to both dietary and pharmacological interventions, targeting gut-localized α-synuclein represents a promising avenue for developing effective Parkinson's disease therapies.

Figure 1

Schematic of gut-related factors contributing to the α-syn pathology. Gut microbiome can trigger enteric inflammation, increased intestinal permeability, and α-syn aggregation. LPS can stimulate TLR4 found on epithelial, immune, and enteric glial cells, leading to a leaky gut, as well as intestinal inflammation. Additionally, LPS promotes the expression of α-syn and may directly affect the homeostatic functioning of α-syn. Curli has been proposed to facilitate the gut α-syn aggregation. Additionally, changes in gut metabolites, including SCFA, may also influence gut α-syn pathology. External factors such as dietary factors and toxins may traverse the gastric epithelial lining, alter the gut microenvironment including the microbiome, intestinal permeability, and inflammation, and result in α-syn pathology. Dietary α-syn is subsequently ingested and may infect the host through mechanisms such as transcellular uptake by enterocytes, antigen sampling by dendritic cells or M cells, or through passive invasion due to leaky gut. Upon entering the human body, MPs/NPs may not only alter the gut microenvironment, but may also bind to α-syn, promoting α-syn aggregation and contributing to α-syn pathology. EECs, which possess direct connections to the lumen and the nervous system, are capable of producing α-syn and may serve as a source for its aggregation. Vicious cycles may develop, as dysbiosis, leaky gut, inflammation, and α-syn aggregation reinforce and sustain one another. Created with Adobe Illustrator (version 2024). α-syn: α-Synuclein; EEC: Enteroendocrine cell; LPS: lipopolysaccharide; MPs/NPs: micro/nano-plastics; TLR4: Toll-like receptors 4.

Figure 2

A schematic representation of α-syn accumulation and spreading from the gut to the brain and possible α-syn targeted therapeutics. Gut-related factors such as dysbiosis, leaky gut, gut inflammation, external factor and host genetic factors may trigger α-syn pathology in the gut. α-syn pathology spreads via the vagal nerve to the brainstem and subsequently to higher brain regions causing Lewy pathology, neuroinflammation, and loss of dopaminergic neurons leading to the motor symptoms of PD. Possible therapeutic strategies include modulating α-syn directly (via targeting a-syn aggregation) or indirectly (via targeting gut microbiome or external factors). Small molecule inhibitors of α-syn aggregation, such as ENT-01, Anle138b, and NPT200-11 may restore abnormal aggregation of αsyn. Minimizing dietary a-syn may reduce the pool of gut luminal α-syn. Lifestyle modifications, including regular exercise and a healthy diet, are known to beneficial impact the microbiome composition. Many microbiome-targeted strategies, including prebiotics, probiotics, postbiotics, symbiotics, antimicrobial agents, fecal microbiome transplantation, or small molecule inhibitor, such as AX-5006 might impact the gut microbiome composition. The use of toxins, such as pesticides and herbicides, or micro-/nano-plastics should be minimized and substituted with safer options. Created with Adobe Illustrator (version 2024). α-syn: α-Synuclein; PD: Parkinson’s disease.