Abstract
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
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder of aging, and is projected to affect nearly 10 million citizens of the world’s most populous countries by 2030 [1,2]
The objectives of this study were to: i) assess intestinal permeability in subjects with newly diagnosed, untreated PD and compare the results to controls without a history of neurological disease or PD; ii) determine whether increased intestinal permeability (‘‘leaky gut’’) in PD subjects correlated with markers of bacterial translocation and endotoxin exposure either locally or systemically, and iii) determine whether gut leakiness is associated with mucosal oxidative stress and intestinal neuronal a-synuclein aggregates
We found that increased intestinal permeability and E. coli staining significantly correlated with a-synuclein staining in PD subjects but not in controls
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder of aging, and is projected to affect nearly 10 million citizens of the world’s most populous countries by 2030 [1,2]. There is no optimal treatment for PD and this is at least partly because the majority of patients with PD will be diagnosed and receive treatment after the onset of neurological symptoms when substantial neuronal dysfunction and neuronal loss has already occurred. A more successful approach could be to diagnose and start treatment before neuronal degeneration results in the emergence of clinical signs of PD. It is believed that these a-synuclein aggregates are the first steps resulting in neuronal loss that is responsible for neurological symptoms and signs of PD [5]. A better understanding of how a-synuclein aggregates form will be a key for advancing our understanding of the pathogenesis of PD that could lead to early diagnosis and treatment with potentially much better outcome
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