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

What was studied?

This original research investigated the altered gut microbiome in Parkinson’s disease, examining how microbial imbalances relate to inflammation, intestinal permeability, and α-synuclein–linked neurodegeneration. The study combined human stool microbiome profiling with experiments in a human α-synuclein overexpressing mouse model (Thy1-αSyn). It also tested whether exposure to bacterial lipopolysaccharide (LPS), a pro-inflammatory endotoxin produced by Gammaproteobacteria, influences intestinal barrier integrity and motor symptoms. By integrating human, cellular, and animal data, the work explored how dysbiosis-driven LPS might trigger or exacerbate Parkinsonian pathology.

Who was studied?

Two populations were examined. The human cohort included 14 patients with idiopathic Parkinson’s disease and seven healthy controls who provided rectal swab samples for 16S rRNA microbiome sequencing. Patients were stratified into mild and severe subgroups based on clinical scores. In parallel, the Thy1-αSyn transgenic mouse model—known to accumulate human α-synuclein progressively—was used alongside wild-type littermates to assess baseline microbiome composition and the effects of oral LPS exposure. Complementary in vitro experiments used IEC-6 intestinal epithelial cells to evaluate tight-junction responses to LPS.

Most important findings

PD patients showed distinct dysbiosis characterized by reduced bacterial diversity in severe cases and higher relative abundance of Verrucomicrobiae and Gammaproteobacteria compared to controls. These shifts matched pro-inflammatory patterns reported in other cohorts. Notably, Gammaproteobacteria abundance increased more than 600-fold in mild PD, while Verrucomicrobiae expanded significantly in severe PD. In mice, the Thy1-αSyn genotype alone did not produce this pro-inflammatory signature; Gammaproteobacteria remained negligible, and Verrucomicrobiae were significantly lower than in wild-type animals. LPS exposure disrupted epithelial tight-junction proteins ZO-1 and E-cadherin in IEC-6 cells, indicating increased permeability. In Thy1-αSyn mice, chronic low-dose oral LPS induced early motor abnormalities—including increased hindlimb clasp reflex—suggesting heightened vulnerability to inflammatory triggers. Taken together, these findings support a mechanistic link between dysbiosis, increased luminal LPS, intestinal leakiness and propagation of α-synuclein pathology.

Key implications

The study strengthens evidence that dysbiosis—particularly expansion of LPS-producing Gammaproteobacteria and mucin-degrading Verrucomicrobiae—may promote gut-driven inflammation and barrier dysfunction in Parkinson’s disease. Elevated LPS exposure may facilitate α-synuclein aggregation and neuroinflammatory cascades, acting as an environmental accelerator of disease progression. These findings highlight the gut microbiome as a promising target for early detection and therapeutic intervention, including strategies that enhance epithelial integrity or modulate inflammatory taxa.

Citation

Gorecki AM, Preskey L, Bakeberg MC, Kenna JE, Gildenhuys C, MacDougall G, et al. Altered gut microbiome in Parkinson’s disease and the influence of lipopolysaccharide in a human α-synuclein over-expressing mouse model. Front Neurosci. 2019;13:839. doi:10.3389/fnins.2019.00839