"For the first time we identify bacteria in the gut of people with Parkinson's that can also be found in those with a genetic risk for the disease, but before they develop symptoms."
— Professor Anthony Schapira, Lead Investigator
Recent research has identified specific changes in the gut microbiome associated with Parkinson's disease (PD) and has explored potential mechanisms by which the disease may spread from the gut to the brain. These studies were published in journals including Nature Medicine, Neuron, and Nature.
Gut Microbiome Signature Identified
Study Overview
A study led by researchers from University College London (UCL) and collaborators analyzed clinical and fecal data to identify a distinctive gut microbiome signature in individuals with Parkinson's disease and those at genetic risk. The research analyzed samples from:
- 271 people with Parkinson's disease
- 43 carriers of the GBA1 gene variant (which increases Parkinson's risk) without symptoms
- 150 healthy control participants
Key Findings
The study found that 176 different microbial species differed in abundance between Parkinson's patients and healthy controls. Of these, 142 species also showed consistent abundance differences when comparing healthy controls to GBA1 variant carriers without symptoms. The gut microbiome composition in genetically at-risk individuals without symptoms displayed an intermediate pattern between healthy individuals and those with diagnosed Parkinson's disease.
The researchers corroborated these findings using additional cohorts comprising 638 Parkinson's patients and 319 healthy controls from the UK, South Korea, and Turkey.
A small proportion of healthy control participants had gut microbiomes similar to those at risk of Parkinson's disease.
Dietary Observations
Dietary data from participants indicated that those with more balanced and varied diets were less likely to have gut microbiomes suggesting elevated Parkinson's risk. Individuals with the abnormal microbiome signature consumed more processed foods and saturated fats compared to fruit, vegetables, fiber, fish, and lentils.
Expert Statements
Co-lead author Professor Stanislav Dusko Ehrlich stated: "Gut microbiome analysis can enable us to identify individuals who are at risk of developing Parkinson's disease, so that we can suggest ways for them to reduce their own risk, such as through dietary adjustments."
Potential Mechanism
Professor Schapira explained that changes in the microbiome could alter the production of a protein called alpha-synuclein: "Certain bacteria cause inflammation in the gut wall that increases alpha-synuclein, which is then transported up the vagus nerve from the gut to the brain and then into the brain cells affected in Parkinson's."
Commentary
Claire Bale, an associated director of research at Parkinson's UK, stated the study adds to evidence that the gut microbiome is important in Parkinson's: "The findings indicate that changes in the microbiome may occur in the very early stages of the condition and that the extent of these changes may correlate with disease progression."
Mechanism for Spread from Gut to Brain
Research on Immune Cells
Researchers from the UK Dementia Research Institute at UCL published a study in Nature identifying a mechanism by which Parkinson's disease may spread from the gut to the brain involving immune cells. The research was conducted in mice.
Scientists have theorized that Parkinson's disease might originate in the gut due to the early involvement of the dorsal motor nucleus of the vagus nerve, which directly connects to the gut.
Key Findings in Mice
- Scientists isolated misfolded alpha-synuclein from the brains of deceased Parkinson's patients and inserted it into the small intestines of mice.
- Gut macrophages, a type of immune cell, engulfed the alpha-synuclein and showed signs of lysosomal dysfunction.
- These macrophages then signaled to T cells, which migrated to the brain.
- When the number of gut macrophages was reduced prior to alpha-synuclein injection, a decrease in toxic protein levels in the brain was observed, along with improved motor symptoms in mice.
Therapeutic Implications
The findings suggest that targeting these immune cells could offer a new therapeutic approach for Parkinson's. Researchers plan to further investigate the immune system's role in neurodegeneration and explore inflammation markers in the blood for early diagnostics.
Monoclonal Antibodies Targeting GPNMB
Study Overview
A study published in Neuron by researchers at the Perelman School of Medicine at the University of Pennsylvania reports that monoclonal antibodies targeting glycoprotein nonmetastatic melanoma B (GPNMB) can block the spread of alpha-synuclein pathology in cultured neurons.
Key Details
- The study identifies microglia, the brain's resident immune cells, as a major source of GPNMB in Parkinson's disease.
- In preclinical experiments, antibodies that block GPNMB prevented the spread of alpha-synuclein pathology from cell to cell.
- Analysis of brain tissue from 1,675 individuals in the Penn Brain Bank showed that genetic variants associated with higher GPNMB production correlated with more extensive alpha-synuclein pathology.
Statement
Alice Chen-Plotkin, MD, lead author, stated: "These results suggest Parkinson's disease may be driven by a self-reinforcing cycle—alpha-synuclein accumulates in neurons, damaging the neurons. The injury to the neurons initiates the release of GPNMB, which accelerates the spread of alpha-synuclein, leading to further damage. Interrupting this cycle would hopefully slow, or even stop, the spread of alpha-synuclein through the brain."
Background on Parkinson's Disease
Parkinson's disease causes progressive brain damage, including the death of neurons in the substantia nigra leading to a fall in dopamine. Symptoms include tremors, slow movement, and stiff muscles. Cases of Parkinson's have doubled in the past 25 years, with more than 8.5 million people globally now living with the condition. The disease affects over 1 million people in the United States with approximately 90,000 new diagnoses annually.
The GBA1 gene variant can increase Parkinson's disease risk by up to 30-fold, according to the study.
There is no cure for Parkinson's disease, but medicines that bolster dopamine, physiotherapy, and surgery can help manage symptoms. Current treatments do not slow disease progression.
Prodromal Symptoms
Prodromal symptoms, such as loss of smell, REM sleep behavior disorder, and constipation, can precede motor symptoms by 10 to 20 years.
Funding and Next Steps
The gut microbiome study was supported by the Michael J. Fox Foundation for Parkinson's Research and the Medical Research Council. The study on GPNMB was supported by the National Institutes of Health, SPARK-NS, the Parker Family Chair, and the Lipman Family Fund. The study on gut-to-brain spread was funded by the Chan Zuckerberg Initiative.
Further research and clinical trials are needed to understand how gut microbes are linked to Parkinson's and whether reshaping the microbiome could shield against the disease. UCL researchers are involved in a phase 3 genetically stratified Parkinson's trial and clinical trials testing treatments to slow or stop Parkinson's progression.