Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease
By C. Forsyth, K. Shannon, J. Kordower, Robin M. Voigt, M. Shaikh, Jean A. Jaglin, J. Estes, H. Dodiya, Ali Keshavarzian. PLoS ONE, 2011
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Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging. The pathological hallmark of PD is neuronal inclusions termed Lewy bodies whose main component is alpha-synuclein protein. The finding of these Lewy bodies in the intestinal enteric nerves led to the hypothesis that the intestine might be an early site of PD disease in response to an environmental toxin or pathogen. One potential mechanism for environmental toxin(s) and proinflammatory luminal products to gain access to mucosal neuronal tissue and promote oxidative stress is compromised intestinal barrier integrity. However, the role of intestinal permeability in PD has never been tested. We hypothesized that PD subjects might exhibit increased intestinal permeability to proinflammatory bacterial products in the intestine. To test our hypothesis we evaluated intestinal permeability in subjects newly diagnosed with PD and compared their values to healthy subjects. In addition, we obtained intestinal biopsies from both groups and used immunohistochemistry to assess bacterial translocation, nitrotyrosine (oxidative stress), and alpha-synuclein. We also evaluated serum markers of endotoxin exposure including LPS binding protein (LBP). Our data show that our PD subjects exhibit significantly greater intestinal permeability (gut leakiness) than controls. In addition, this intestinal hyperpermeability significantly correlated with increased intestinal mucosa staining for E. coli bacteria, nitrotyrosine, and alpha-synuclein as well as serum LBP levels in PD subjects. These data represent not only the first demonstration of abnormal intestinal permeability in PD subjects but also the first correlation of increased intestinal permeability in PD with intestinal alpha–synuclein (the hallmark of PD), as well as staining for gram negative bacteria and tissue oxidative stress. Our study may thus shed new light on PD pathogenesis as well as provide a new method for earlier diagnosis of PD and suggests potential therapeutic targets in PD subjects. Trial Registration Clinicaltrials.gov NCT01155492
Subfields: Neurology, Speech and Hearing
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Citations in the corpus
- Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. (2016, background): “coli (a bacterial species assigned to the family Enterobacteriaceae) and concluded that a compromised intestinal barrier might help to expose the ENS to noxa in PD [17].”
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- Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. (2017, background): “…immune epithelial cells M A N U S C R I P T A C C E P TE D MANUSCRIPT 17 and immune system cells, but also neurons and glial cells in PD patients (Forsyth et al., 2011). and promote compositions higher to PD found in colleagues patients whereas controls. of GMB by our data may induce the…”
- The Central Nervous System and the Gut Microbiome (2016, background): “coli compared to healthy controls (Forsyth et al., 2011), further demonstrating the presence of an altered gut microbial community in individuals diagnosed with neurodegenerative diseases.”
- The Impact of Diet and Lifestyle on Gut Microbiota and Human Health (2014, background): “coli and greater endotoxin (LPS) exposure, and these changes correlate with the enteric neuronal damage [143], leading to suggestions that a pathogen may be responsible for PD [144] and a breakdown in mucosal barrier function may play a central role.”
- Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease. (2019, background): “636 Neuron 103, 627–641, August 21, 2019 shown that this is associated with increased intestinal permeability and translocation of bacteria and their products, resulting in oxidative stress (Forsyth et al., 2011).”
- Colonic bacterial composition in Parkinson's disease (2015, background): “We have shown that: (1) Patients with early stage/newly diagnosed PD have intestinal hyperpermeability; and (2) disruption of intestinal barrier integrity in PD patients is associated with a-Syn aggregation in the sigmoid mucosa, oxidative injury, and penetration of bacteria into the sigmoid mucosa ”