title: 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.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01155492.
authors.affiliation: Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois, United States of America. christopher_b_forsyth@rush.edu
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Forsyth
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Shannon
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kordower
authors.forename: Robin M
authors.initials: RM
authors.lastname: Voigt
authors.forename: Maliha
authors.initials: M
authors.lastname: Shaikh
authors.forename: Jean A
authors.initials: JA
authors.lastname: Jaglin
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.forename: Hemraj B
authors.initials: HB
authors.lastname: Dodiya
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000378:metabolism / Q000382:microbiology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D010539:Permeability; D013395:Sucrose / Q000031:analogs & derivatives / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; D002352:Carrier Proteins; D004731:Endotoxins; D008562:Membrane Glycoproteins; D013395:Sucrose; D014443:Tyrosine; D051844:alpha-Synuclein; D000099231:Lipopolysaccharide-Binding Protein; C002744:3-nitrotyrosine; C044101:endotoxin, Escherichia coli; C026285:trichlorosucrose