Abstract
The interaction between the gut microbiota and alpha-synuclein (αSyn) aggregation in Parkinson’s disease (PD) is receiving increasing attention. The objective of this study was to investigate gut microbiota, and effects of an inflammatory lipopolysaccharide (LPS) trigger in a human αSyn over-expressing mouse model of PD (Thy1-αSyn). Stool samples from patients with confirmed PD and Thy1-αSyn mice were analyzed using 16S ribosomal RNA sequencing. Compared to healthy controls, the relative abundance of mucin-degrading Verrucomicrobiae and LPS-producing Gammaproteobacteria were greater in PD patients. In mice, the abundance of Gammaproteobacteria was negligible in both Thy1-αSyn and wild-type (WT) animals, while Verrucomicrobiae were reduced in Thy1-αSyn mice. The effect of LPS on intestinal barrier function was investigated in vitro using intestinal epithelial (IEC-6) cells, and in vivo via administration of LPS in drinking water to Thy1-αSyn mice. Acute exposure to LPS in vitro resulted in a reduction and altered distribution of the tight junction markers ZO-1 and e-Cadherin around the cell membrane in IEC-6 cells, as shown by immunohistochemistry. LPS administration in Thy1-αSyn mice resulted in the emergence of early motor manifestations at 10 weeks, compared to untreated mice who were still asymptomatic at this age. This study reaffirms that an altered microbiome exists in patients with PD, and supports the notion of a proinflammatory gut microbiome environment as a trigger for PD pathogenesis.
Highlights
Parkinson’s disease (PD) has traditionally been characterized by motor impairment but is considered a multisystemic disorder displaying a plethora of non-motor symptoms (Chaudhuri et al, 2006; Emamzadeh and Surguchov, 2018; Greenland et al, 2019)
Clostridia and Bacteroidia were more abundant in healthy controls than mild and severe PD groups, but these differences did not reach statistical significance
Our data demonstrated a significant increase in Gammaproteobacteria coupled with a non-significant reduction in Clostridia and Bacteroidia in people with PD
Summary
Parkinson’s disease (PD) has traditionally been characterized by motor impairment but is considered a multisystemic disorder displaying a plethora of non-motor symptoms (Chaudhuri et al, 2006; Emamzadeh and Surguchov, 2018; Greenland et al, 2019). A key feature of the disease is the formation of insoluble alpha-synuclein (αSyn) aggregates within neurons (Goedert et al, 2013), contributing to the loss of dopaminergic neurons in the basal ganglia. This Lewy body pathology occurs more widely throughout the central and peripheral nervous systems, including the enteric nervous system (Beach et al, 2010). Bacterial treatments in vitro and fecal microbial transplants in vivo support the role of the gut microbiome in αSyn aggregation, gastrointestinal inflammation and motor symptom development (Sampson et al, 2016; Choi et al, 2018; Sun et al, 2018)
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