The potential role of gut-derived inflammation in multiple system atrophy

Phillip A. Engen, Hemraj B. Dodiya, Ankur Naqib, Christopher B. Forsyth, Stefan J. Green, Robin M. Voigt, Jeffrey H. Kordower, Ece A. Mutlu, Kathleen M. Shannon, Ali Keshavarzian

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)331-346
Number of pages16
JournalJournal of Parkinson's Disease
Volume7
Issue number2
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • Colonic mucosa and feces
  • Lipopolysaccharide
  • Microbiota
  • Multiple system atrophy
  • Tolllike-receptor-4
  • Zonula Occludens-1

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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