TY - JOUR
T1 - The potential role of gut-derived inflammation in multiple system atrophy
AU - Engen, Phillip A.
AU - Dodiya, Hemraj B.
AU - Naqib, Ankur
AU - Forsyth, Christopher B.
AU - Green, Stefan J.
AU - Voigt, Robin M.
AU - Kordower, Jeffrey H.
AU - Mutlu, Ece A.
AU - Shannon, Kathleen M.
AU - Keshavarzian, Ali
N1 - Publisher Copyright:
© 2017-IOS Press and the authors. All rights reserved.
PY - 2017
Y1 - 2017
N2 - Background: Recent evidence suggests that Parkinson's disease (PD) is associated with intestinal microbiota dysbiosis, abnormal intestinal permeability, and intestinal inflammation. Objective: Our study aimed to determine if these gut abnormalities are present in another synucleinopathy, multiple system atrophy (MSA). Methods: In six MSA and 11 healthy control subjects, we performed immunohistochemistry studies of colonic sigmoid mucosa to evaluate the intestinal barrier marker Zonula Occludens-1 and the endotoxin-related inflammation marker Toll-likereceptor-4 expression. We also assessed colonic sigmoid mucosal and fecal microbiota compositions using high-throughput 16S ribosomal RNA gene amplicon sequencing. Results: MSA subjects showed disrupted tight junction protein Zonula Occludens-1 structure in sigmoid mucosa tissue suggesting intestinal barrier dysfunction. The lipopolysaccharide specific inflammatory receptor Toll-like-receptor-4 was significantly higher in the colonic sigmoid mucosa in MSA relative to healthy controls. Microbiota analysis suggested high relative abundance of gram-negative, putative pro-inflammatory bacteria in various family and genus level taxa, from the phylum Bacteroidetes and Proteobacteria, in MSA feces and mucosa. At the taxonomic level of genus, putative antiinflammatory butyrate-producing bacteria were less abundant in MSA feces. Predictive functional analysis indicated that the relative abundance of a number of genes involved in metabolism were lower inMSAfeces, whereas the relative abundance of genes involved in lipopolysaccharide biosynthesis were higher in bothMSAfeces and mucosa compared to healthy controls. Conclusions: This proof-of-concept study provides preliminary evidence that like PD, MSA subjects display evidence of disrupted intestinal barrier integrity, increased marker of endotoxin-related intestinal inflammation, and pro-inflammatory colonic microbiota.
AB - Background: Recent evidence suggests that Parkinson's disease (PD) is associated with intestinal microbiota dysbiosis, abnormal intestinal permeability, and intestinal inflammation. Objective: Our study aimed to determine if these gut abnormalities are present in another synucleinopathy, multiple system atrophy (MSA). Methods: In six MSA and 11 healthy control subjects, we performed immunohistochemistry studies of colonic sigmoid mucosa to evaluate the intestinal barrier marker Zonula Occludens-1 and the endotoxin-related inflammation marker Toll-likereceptor-4 expression. We also assessed colonic sigmoid mucosal and fecal microbiota compositions using high-throughput 16S ribosomal RNA gene amplicon sequencing. Results: MSA subjects showed disrupted tight junction protein Zonula Occludens-1 structure in sigmoid mucosa tissue suggesting intestinal barrier dysfunction. The lipopolysaccharide specific inflammatory receptor Toll-like-receptor-4 was significantly higher in the colonic sigmoid mucosa in MSA relative to healthy controls. Microbiota analysis suggested high relative abundance of gram-negative, putative pro-inflammatory bacteria in various family and genus level taxa, from the phylum Bacteroidetes and Proteobacteria, in MSA feces and mucosa. At the taxonomic level of genus, putative antiinflammatory butyrate-producing bacteria were less abundant in MSA feces. Predictive functional analysis indicated that the relative abundance of a number of genes involved in metabolism were lower inMSAfeces, whereas the relative abundance of genes involved in lipopolysaccharide biosynthesis were higher in bothMSAfeces and mucosa compared to healthy controls. Conclusions: This proof-of-concept study provides preliminary evidence that like PD, MSA subjects display evidence of disrupted intestinal barrier integrity, increased marker of endotoxin-related intestinal inflammation, and pro-inflammatory colonic microbiota.
KW - Colonic mucosa and feces
KW - Lipopolysaccharide
KW - Microbiota
KW - Multiple system atrophy
KW - Tolllike-receptor-4
KW - Zonula Occludens-1
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UR - http://www.scopus.com/inward/citedby.url?scp=85019188937&partnerID=8YFLogxK
U2 - 10.3233/JPD-160991
DO - 10.3233/JPD-160991
M3 - Article
C2 - 28234259
AN - SCOPUS:85019188937
SN - 1877-7171
VL - 7
SP - 331
EP - 346
JO - Journal of Parkinson's Disease
JF - Journal of Parkinson's Disease
IS - 2
ER -