The Potential Role of Gut-Derived Inflammation in Multiple System Atrophy

Article type: Research Article

Authors: Engen, Phillip A.^{a; 1} | Dodiya, Hemraj B.^{a; g; 1} | Naqib, Ankur^{d; 1} | Forsyth, Christopher B.^{a; f} | Green, Stefan J.^{d; e} | Voigt, Robin M.^a | Kordower, Jeffrey H.^b | Mutlu, Ece A.^a | Shannon, Kathleen M.^{c; *} | Keshavarzian, Ali^{a; g; h; i; *}

Affiliations: [a] Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL, USA | [b] Department of Neurology, Rush University Medical Center, Chicago, IL, USA | [c] Department of Neurology, University of Wisconsin School of Public Health, Madison, WI, USA | [d] DNA Services Facility, Research Resources Center, University of Illinois at Chicago, Chicago, IL, USA | [e] Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, USA | [f] Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA | [g] Department of Pharmacology, Rush University Medical Center, Chicago, IL, USA | [h] Department of Physiology, Rush University Medical Center, Chicago, IL, USA | [i] Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands

Correspondence: [*] Correspondence to: Ali Keshavarzian, M.D., Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, 1725 W Harrison St, Suite 206, Chicago IL 60612, USA. Tel.: +1 312 563 3890; Fax: +1 312 563 3883; E-mail: Ali Keshavarzian@rush.edu and Kathleen M. Shannon, M.D., Department of Neurology, University of Wisconsin School of Public Health, 1685 Highland Avenue Madison, WI 53705- 2281, USA. Tel.: +1 608 263 5448; Fax: +1 608 263 0412; E-mail: shannon@neurology.wisc.edu.

Note: [1] These authors contributed equally to this work.

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-like-receptor-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 “anti-inflammatory” 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 in MSA feces, whereas the relative abundance of genes involved in lipopolysaccharide biosynthesis were higher in both MSA feces 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.

Keywords: Multiple system atrophy, microbiota, colonic mucosa and feces, lipopolysaccharide, Zonula Occludens-1, Tolllike-receptor-4

DOI: 10.3233/JPD-160991

Journal: Journal of Parkinson's Disease, vol. 7, no. 2, pp. 331-346, 2017