Clinical Phenotypes of Parkinson’s Disease Associate with Distinct Gut Microbiota and Metabolome Enterotypes Original paper

What was studied?

This study investigated the gut microbiota and metabolome profiles of Parkinson’s disease (PD) patients with different motor phenotypes to uncover microbial and metabolic signatures associated with specific clinical subtypes. The authors focused on distinguishing between tremor-dominant and non-tremor-dominant forms, the latter including akinetic-rigid and dyskinetic phenotypes. Using 16S rRNA gene sequencing and gas chromatography–mass spectrometry (GC-MS), fecal samples were analyzed for bacterial composition and metabolic products. The goal was to determine whether specific microbial taxa or metabolites could be linked to the heterogeneity in PD motor symptoms and to provide insights relevant for a microbiome signatures database. Notably, the study highlights the association of the gut microbiota and metabolome with clinical phenotypes of PD, using the focus keyphrase “gut microbiota and metabolome in Parkinson’s disease phenotypes.”

Who was studied?

The study recruited 56 idiopathic Parkinson’s disease patients, diagnosed according to the UK Brain Bank criteria, from neurology departments in Cagliari, Italy. The cohort was subdivided into three clinical phenotype groups: 19 (33.9%) with tremor dominant (TD), 23 (41.1%) with akinetic-rigid (AR), and 14 (25.0%) with dyskinetic phenotypes. Participants were carefully screened to exclude atypical Parkinsonism and other major confounders such as psychiatric illness, cognitive impairment, primary gastrointestinal disease, recent antibiotic/probiotic use, and significant dietary variations; all followed a Mediterranean diet. Demographic variables (age, sex, BMI), constipation, coffee consumption, and smoking status were balanced across groups. All patients received levodopa-based therapies for at least three years, either as standard oral therapy or intestinal gel, and did not use catechol-O-methyltransferase inhibitors. This careful selection minimizes confounding and ensures that observed microbiota and metabolome differences are linked to PD phenotype rather than external factors.

Most important findings

The study revealed that gut microbiota diversity and composition significantly differed among PD motor phenotypes. Patients with the TD phenotype exhibited the highest bacterial diversity, while AR and D subtypes showed reduced diversity. Beta-diversity analysis confirmed distinct microbial community structures, with TD patients clustering separately from non-TD (AR and D) patients.

At the taxonomic level, non-TD phenotypes (AR and D) showed a consistent reduction in several beneficial butyrate-producing bacteria, particularly within the Firmicutes phylum and Lachnospiraceae family (notably Blautia, Coprococcus, and Lachnospira), as well as Brevibacteriaceae. Conversely, there was an enrichment of pro-inflammatory taxa, such as Enterobacteriaceae (including Escherichia and Serratia), and an increased abundance of Sedimentibacter in non-TD groups. The D phenotype also had increased Lactobacillaceae and Lactobacillus compared to AR.

Metabolomic profiling supported these findings. Non-TD patients, especially the D phenotype, had decreased levels of nicotinic acid (vitamin B3) and increased levels of cadaverine and glucuronic acid. Nicotinic acid, sharing the anti-inflammatory GPR109A receptor with butyrate, is often produced by beneficial gut bacteria and its reduction may signal loss of protective functions. Cadaverine, a biogenic amine produced by Escherichia, can promote neuroinflammation and α-synuclein aggregation. Elevated glucuronic acid suggests increased microbial β-glucuronidase activity, potentially interfering with host detoxification and neurotransmitter availability. Collectively, these results identify a microbiome-metabolome signature in non-TD PD characterized by loss of anti-inflammatory, gut-protective taxa and metabolites, and enrichment of pro-inflammatory, neuroactive microbial products.

Key implications

The findings strongly suggest that gut microbiota and metabolomic profiles are closely linked to the clinical heterogeneity of Parkinson’s disease. The enrichment of pro-inflammatory Enterobacteriaceae and depletion of butyrate-producing and vitamin B3-producing taxa in non-TD phenotypes may contribute to gut inflammation, increased intestinal permeability, and more severe α-synucleinopathy. Metabolic shifts—such as reduced nicotinic acid and increased cadaverine and glucuronic acid—reinforce the pro-inflammatory and neurotoxic milieu. These microbiome-metabolome signatures may underlie the faster progression, greater severity, and increased gastrointestinal dysfunction observed in non-TD PD. Clinically, these insights could inform personalized interventions targeting the microbiota to modify disease course or symptom severity. For microbiome signatures databases, these taxa and metabolites offer high-value targets for stratifying PD subtypes and understanding their pathophysiology.

Citation

Vascellari S, Melis M, Palmas V, Pisanu S, Serra A, Perra D, Santoru ML, Oppo V, Cusano R, Uva P, Atzori L, Morelli M, Cossu G, Manzin A. Clinical Phenotypes of Parkinson’s Disease Associate with Distinct Gut Microbiota and Metabolome Enterotypes. Biomolecules. 2021;11(2):144. doi:10.3390/biom11020144