Kayli Hall

Introduction. In Parkinson’s disease (PD) degeneration of dopaminergic neurons in the substantia nigra causes bradykinesia, resting tremor and rigidity.¹ Many patients experience gastrointestinal dysfunction including constipation, dysphagia and delayed gastric emptying up to a decade prior to developing motor symptoms.² PD patient’s gut microbiomes have more abundant LPS-producing Gram-negative phyla than healthy controls.³ Given these findings and the current uncertainty regarding the pathogenic mechanism in Parkinson’s, a study hypothesized that LPS activation of the TLR4 inflammatory cascade causes PD neurodegeneration.⁴ Methods. In part I, six healthy controls and six PD patients fasted overnight and then sigmoid colon biopsies were collected, sections were stained with immunohistochemistry for ZO-1 and TLR4 and a microarray of tissue homogenate measured mRNA expression of fifty genes.⁴ Participants drank a sugar slurry, urine samples were obtained twenty-four hours later and gas chromatography measured excreted sugars.⁴ In part II, seven week old wild-type and TLR4 knock-out mice were given either rotenone suspended in chloroform or chloroform only by oral gavage once daily for twenty-eight days.⁴ Every seven days mice were placed on an accelerating rod and time to fall was recorded.⁴ Intragastric injections of Evans blue dye were administered thirty minutes prior to euthanasia, after which intestinal transit and colon length were measured.⁴ Colon samples were stained with immunofluorescence for ZO-1 and TLR4 and brain samples were stained for tyrosine hydroxylase.⁴ Results. Compared to healthy controls, PD patients had fewer ZO-1 tight junction proteins and more sucralose excretion, indicating a leaky colon.⁴ PD patients had more TLR4 positive cells in the colonic lamina propria and increased expression of fifteen inflammatory mRNAs, including TLR4.⁴ Rotenone-treated TLR4 knock-out mice were partially protected from the delayed intestinal transit, loss of tight junction proteins, decline in motor function and reduction of dopaminergic neurons induced in wild-type mice.⁴ Conclusions. The leaky gut observed in PD patients and the rotenone mouse model are consistent with previous findings and suggest a pathway by which microbial LPS could induce systemic inflammation.⁴ TLR4 activation in PD patients and the neuroprotective effects of TLR4 knock-out in mice suggest a link between the TLR4 inflammatory cascade and neurodegeneration in PD.⁴ Although more research still needs to be done, this study suggests that targeting the TLR4 signaling pathway may be a promising therapeutic approach in the treatment of Parkinson’s disease.⁴

1. Travagli RA, Browning KN, Camilleri M. Parkinson disease and the gut: new insights into pathogenesis and clinical relevance. Nat Rev Gastroenterol Hepatol. Nov 2020;17(11):673-685. doi:10.1038/s41575-020-0339-z
2. Zheng W, He R, Yan Z, et al. Regulation of immune-driven pathogenesis in Parkinson’s disease by gut microbiota. Brain Behav Immun. Jul 2020;87:890-897. doi:10.1016/j.bbi.2020.01.009
3. Lubomski M, Tan AH, Lim SY, Holmes AJ, Davis RL, Sue CM. Parkinson’s disease and the gastrointestinal microbiome. J Neurol. Sep 2020;267(9):2507-2523. doi:10.1007/s00415-019-09320-1
4. Perez-Pardo P, Dodiya HB, Engen PA, et al. Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice. Gut. May 2019;68(5):829-843. doi:10.1136/gutjnl-2018-316844