Intestinal Dysbiosis and Lowered Serum Lipopolysaccharide-Binding Protein in Parkinson’s Disease

Abstract

BackgroundThe intestine is one of the first affected organs in Parkinson’s disease (PD). PD subjects show abnormal staining for Escherichia coli and α-synuclein in the colon.MethodsWe recruited 52 PD patients and 36 healthy cohabitants. We measured serum markers and quantified the numbers of 19 fecal bacterial groups/genera/species by quantitative RT-PCR of 16S or 23S rRNA. Although the six most predominant bacterial groups/genera/species covered on average 71.3% of total intestinal bacteria, our analysis was not comprehensive compared to metagenome analysis or 16S rRNA amplicon sequencing.ResultsIn PD, the number of Lactobacillus was higher, while the sum of analyzed bacteria, Clostridium coccoides group, and Bacteroides fragilis group were lower than controls. Additionally, the sum of putative hydrogen-producing bacteria was lower in PD. A linear regression model to predict disease durations demonstrated that C. coccoides group and Lactobacillus gasseri subgroup had the largest negative and positive coefficients, respectively. As a linear regression model to predict stool frequencies showed that these bacteria were not associated with constipation, changes in these bacteria were unlikely to represent worsening of constipation in the course of progression of PD. In PD, the serum lipopolysaccharide (LPS)-binding protein levels were lower than controls, while the levels of serum diamine oxidase, a marker for intestinal mucosal integrity, remained unchanged in PD.ConclusionsThe permeability to LPS is likely to be increased without compromising the integrity of intestinal mucosa in PD. The increased intestinal permeability in PD may make the patients susceptible to intestinal dysbiosis. Conversely, intestinal dysbiosis may lead to the increased intestinal permeability. One or both of the two mechanisms may be operational in development and progression of PD.

Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease

“…These include depletions in members of family Lachnospiraceae and Ruminococceae in recipient mice, a notable finding as these same genera are significantly reduced in fecal samples directly from PD patients (Keshavarzian et al, 2015). Conversely, the gut microbiomes in human subjects with PD contain an increased abundance of Proteobacteria (Hasegawa et al, 2015; Keshavarzian et al, 2015; Scheperjans et al, 2015; Unger et al, 2016), remarkably similar to our results in mice. Whether these specific microbes play a role in disease processes remains unknown.…”

“…Given recent evidence that PD patients display altered microbiomes (Hasegawa et al, 2015; Keshavarzian et al, 2015; Scheperjans et al, 2015), we sought to determine whether human gut microbes affect disease outcomes when transferred into GF mice. We collected fecal samples from 6 human subjects diagnosed with PD, as well as 6 matched healthy controls (Table S1).…”

“…To augment mouse models, dysbiosis (alterations to the microbial composition) of the human microbiome has been reported in subjects diagnosed with several neurological diseases (Schroeder and Backhed, 2016). For example, fecal and mucosa-associated gut microbes are different between individuals with PD and healthy controls (Hasegawa et al, 2015; Keshavarzian et al, 2015; Scheperjans et al, 2015; Unger et al, 2016). Yet, how dysbiosis arises and whether this feature contributes to PD pathogenesis remains unknown.…”

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

“…76,85,[96][97][98] Several studies have also indicated abnormalities in the tight junctions of intestine without complete damage in the mucosa, but characterized by a decrease in the barrier promoting protein levels and disruptions of tight junction networks, 76,92,93 thus showing a phenotype consistent with low-grade inflammation. 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.…”

α-Synuclein in gut endocrine cells and its implications for Parkinson’s disease

“…Recently, it has been shown that individuals with PD have an altered gut microbial composition (25)(26)(27)(28), raising the possibility that gut microbes affect PD pathogenesis. In a mouse model of PD, gut microbiota promoted α-synuclein aggregation and the development of motor disturbances (29).…”