The Role of Toll-Like Receptor 4 in Mediating Gut-Brain Axis Inflammation and Pathologies Seen in Parkinson’s Disease Kung Min Kim
The gut-brain axis is suggested as the important contributor to the neurodegenerative diseases such as Parkinson’s disease (PD). It has been proposed that perturbation of intestinal environment activates enteric glial cells, whose inflammatory response propagates the pathophysiology from periphery to central nervous system (CNS) via the vagus nerve (Sampson et al. 2016, 1475). However, despite neuroinflammation being the common hallmark of neurodegenerative diseases, there is much to learn about the precise mechanism in which the inflammatory cascade is triggered. Perez-Pardo et al. studied the colon biopsy samples of PD patients to examine the molecular profiles and abnormalities. Compared to healthy controls, PD patients were found to have dysfunctional and inflamed intestinal wall. More importantly, it was noted that molecular markers pertaining to the immune activation of Toll-like receptor 4 (TLR4) by bacterial endotoxin were elevated. These findings prompted the authors to hypothesize that a leaky gut resulting from dysbiosis allows the invasion of gram-negative bacteria into the mucosa. Consequently, the pattern recognition receptor TLR4 is activated and proinflammatory cascade is initiated. To test, TLR4 knock-out (KO) mice and wildtype (WT) were treated with daily dose of rotenone to induce PD-like symptoms. Whereas the WT mice exhibited the similar pathophysiology and molecular profiles as the human PD patients, TLR4-KO mice were partially protected from the pathogenesis. They showed less epithelial disruption, low level of inflammation, superior motor functions, and healthier neurons. This translational study is highly relevant to the future direction of developing early diagnostic tools and treatment options for PD and other neurodegenerative conditions associated with TLR4 and the gut-brain axis.
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