Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease

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

Gut Microbiota Dysfunction as Reliable Non-invasive Early Diagnostic Biomarkers in the Pathophysiology of Parkinson's Disease: A Critical Review

“…56 Also a-synuclein deposition and the associated neurodegeneration in the enteric nervous system, characterized by increased intestinal permeability, oxidative stress and local inflammation, accounts for the constipation in PD patients. [57][58][59] These pathophysiological symptoms could be observed in the initial stages of PD, years before the important motor symptoms appear, giving support to the hypothesis that PD pathogenesis might have primary connections with the gut.…”

“…PD patients have been detected with more frequent and higher levels of intestinal a-synuclein compared to the same age matched healthy controls. 58,61,62,[86][87][88] This has significance as the over-expression of a-synuclein causes a-synuclein aggregation in the intestine and brain of mice and humans. 76,89,90 Studies have reported detection of phosphorylated a-synuclein in 61.6% of PD samples and lewy bodies/lewy neutrites in 72.4-100.0% of PD samples compared to the detection of 0.0-33.0% of a-synuclein in healthy population, [91][92][93][94][95] suggesting that intestinal synucleinopathy is a relatively sensitive and reliable indicator of PD pathology.…”

“…72 The penetration of E. coli into the intestinal mucosa seems to be expressed more frequently in PD patients as compared to controls, and correlate with increased intestinal permeability and oxidative stress and increased enteric a-synuclein levels. 58 Newly diagnosed PD patients have been detected with increased intestinal permeability and this seems to be present since the earliest clinical stages of the disease. 58 …”

Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila

“…Although the relationship between intestinal homeostasis and mammalian lifespan is less well understood, several age-related changes in the intestinal epithelium of rodents have been reported (9), including intestinal barrier dysfunction (31). The importance of the gut epithelium in human health is demonstrated by the growing number of disorders that have been linked to defects in intestinal barrier function, including intestinal or extraintestinal inflammatory disorders (32,33), multiple sclerosis (34), chronic heart failure (35), cancer (36,37), and Parkinson's disease (38). In terms of mortality in humans, intestinal barrier dysfunction is reportedly common in critically ill patients and linked to development of the multiple organ dysfunction syndrome (39)(40)(41).…”

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…Ellis et al investigated whether HIV-associated sensor neuropathy (SN) in HIV-infected individuals with good CD4 ϩ recovery on virologically suppressive ART could be associated with monocyte activation and found an association between SN and sCD14 levels in the patients' cerebrospinal fluid (118). Furthermore, Forsyth et al described a link between endotoxin exposure markers and early Parkinson's disease (119).…”