A Pilot Microbiota Study in Parkinson’s Disease Patients versus Control Subjects, and Effects of FTY720 and FTY720-Mitoxy Therapies in Parkinsonian and Multiple System Atrophy Mouse Models Original paper

What was studied?

This pilot study systematically examined the differences in gut microbiota composition and gastrointestinal function between patients with Parkinson’s disease (PD) and healthy controls, as well as in mouse models of PD and multiple system atrophy (MSA). The study further evaluated the effects of two therapies—FTY720 (fingolimod), an approved multiple sclerosis drug, and a novel derivative, FTY720-Mitoxy—on the gut microbiota of these mouse models. The primary aim was to identify microbiome alterations associated with PD, uncover potential microbial biomarkers shared between humans and mice, and assess whether these experimental therapies could beneficially modulate the gut microbiota, thereby offering translational insights for future interventions.

Who was studied?

The human component included a small cohort: 9 subjects with neurologist-confirmed PD and 13 healthy, age-matched controls, all recruited from clinics and local PD groups. Strict inclusion and exclusion criteria were applied to minimize confounding factors such as GI diseases, antibiotic use, or other neurodegenerative disorders. The animal studies utilized two well-characterized transgenic mouse models: the A53T alpha-synuclein model representing PD and the CNP-aSyn model for MSA. Both wild-type and transgenic mice were included, with groups receiving either vehicle, FTY720, or FTY720-Mitoxy. Human and mouse fecal samples were analyzed using 16S rRNA gene sequencing to assess microbial composition, and GI function was evaluated with standardized clinical and radiological methods.

Most important findings

In humans, PD patients exhibited a significant increase in the genus Akkermansia and a trend toward increased Bifidobacterium and decreased Prevotella compared to controls. Notably, the Verrucomicrobiaceae family (containing Akkermansia) was detectable only in PD patients. At the family level, Bacteroidaceae and Lachnospiraceae, as well as the genera Prevotella and Bacteroides, were shared between PD patients and PD mouse models, highlighting their potential as cross-species biomarkers.

Constipation was more prevalent among PD patients, as indicated by lower Bristol Stool Form Scale (BSFS) scores and reduced bowel movement frequency. However, overall gut transit times were not significantly different between groups.

In the mouse models, the effects of therapies were distinct. FTY720 had minimal impact on the gut microbiota composition in PD (A53T) mice. In contrast, FTY720-Mitoxy treatment in MSA (CNP-aSyn) mice led to increased abundance of the beneficial Ruminococcus genus and a decrease in the Rikenellaceae family, both of which are associated with anti-inflammatory effects and improved GI health. Additionally, Lachnospiraceae and Ruminococcaceae families—both implicated in short-chain fatty acid production and gut health—were shared among humans and mouse models, further supporting their role as relevant microbiome markers in synucleinopathies.

Key implications

This study reinforces the reproducibility of certain gut microbiome alterations in PD, notably the elevation of Akkermansia and the reduction of Prevotellaceae, suggesting their utility as diagnostic biomarkers. The identification of shared microbial taxa across human patients and mouse models strengthens the translational potential of these animal systems for preclinical microbiome research. Therapeutically, the novel compound FTY720-Mitoxy demonstrated promising microbiome-modulating effects in MSA mouse models, indicating its potential as a neuroprotective and anti-inflammatory agent. Collectively, these results underscore the importance of gut microbiota signatures in PD and MSA and lay the groundwork for future studies targeting microbiome modulation as a therapeutic strategy.

Citation

Vidal-Martinez G, Chin B, Camarillo C, Herrera GV, Yang B, Sarosiek I, Perez RG. A Pilot Microbiota Study in Parkinson’s Disease Patients versus Control Subjects, and Effects of FTY720 and FTY720-Mitoxy Therapies in Parkinsonian and Multiple System Atrophy Mouse Models. J Parkinsons Dis. 2020;10(1):185-192. doi:10.3233/JPD-191693