Altered Gut Microbiome in Parkinson’s Disease and the Influence of Lipopolysaccharide in a Human α-Synuclein Over-Expressing Mouse Model

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.

Gut–Brain Axis: Role of Gut Microbiota on Neurological Disorders and How Probiotics/Prebiotics Beneficially Modulate Microbial and Immune Pathways to Improve Brain Functions

“…Elderly patients had no definitive AD, but had decrease in the abundance of anti-inflammatory E. rectale and B. fragilis and increase in abundance of inflammatory taxon Escherichia / Shigella with higher level of IL-1β, CXCL2, NLRP3, and Aβ peptide as compared to healthy controls and subjects with cognitive impairment but had no Aβ pathology [ 95 ]. The changes of gut microbiota and associated immune responses were also showed in Table 1 [ 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 ]. It has also been reported that proinflammatory gut bacteria-mediated dysbiosis may induce neuroinflammation and cerebral Aβ accumulation in in AD patients, especially Salmonella , Bacillus , Mycobacterium , E. coli , and Staphylococcus [ 118 ].…”

“…A recent study showed that the relative abundance of mucin-degrading Verrucomicrobiae and LPS producing Gammaproteobacteria were found to be higher in both PD patients and a human α-synuclein over expressing mice model of PD (Thy-αSyn), as compared healthy and wild-type controls. LPS administration increased the early motor manifestation in Thy-αSyn mice at 10 weeks [ 97 ]. The neuroprotective effect of gut microbiota on MPTP-induced mice model of PD was demonstrated by Reference [ 100 ].…”

Diet, Microbiota and Brain Health: Unraveling the Network Intersecting Metabolism and Neurodegeneration

“…Both environmentally [ 244 ] and genetically [ 245 ] induced animal models display altered GM. Depletion of microbiota induced by GF condition or chronic broad-spectrum antibiotics was protective against dopaminergic loss and motor dysfunction in PD mice [ 246 , 247 ].…”

Gut Microbiota Approach—A New Strategy to Treat Parkinson’s Disease

“…LPS administration leads to the increasing of intestinal permeability, motor impairment, nigral a-syn aggregation, dopaminergic neuronal loss and reduction in striatal dopamine. So LPSproducing bacteria increasing can change the gut environment and trigger the pathogenesis of PD by a-syn aggregation (Gorecki et al, 2019). LPS or inflammatory endotoxin modulate a-syn amyloidogenesis by the formation of intermediate nucleating species.…”

“…Enterobacteriaceae Gammaproteobacteria LPS Rise the serum LPS population, induce systemic inflammation, promotes a-synuclein deposition, increase LPS-a-syn fibril formation (Guo et al, 2013;Lin et al, 2019;Gorecki et al, 2019;Bhattacharyya et al, 2019)…”