Parkinson Disease: Role for Gut Microbiome

A new study has revealed ground-breaking research suggesting that the gut microbiome may play a role in the pathogenesis of Parkinson disease (PD). Results were published online in the journal Cell.

The study is the first to show that changes in gut bacteria may impact the etiology and progression of PD. 

PD belongs to a group of diseases called synucleinopathies. In such diseases, a defective protein - α-synuclein in the case of PD -- forms insoluble aggregates within neurons. These aggregates disrupt cellular functioning and cause the motor dysfunction typical of PD: tremors, muscle rigidity, bradykinesia, and impaired gait. 

Because fewer than 10% of PD cases are hereditary, scientists suspect that the environment, or gene-environmental interactions, may feature largely in PD etiology.

“Our findings provide a completely new paradigm for how environmental factors may contribute to Parkinson’s disease and possibly other neurodegenerative disorders. The notion that these diseases may be impacted by pathology in the gut and not only in the brain is a radical departure from conventional research in neuroscience. Parkinson’s disease is complex and there are several genetic predispositions and environmental risks that play a role, but we believe our findings shed light on a previously unrecognized and potentially important part of this puzzle,” lead author Sarkis Mazmanian, PhD, of the California Institute of Technology, Pasadena, CA, said in a press release.

Evidence of GI pathology in PD patients may also point to a role for the gut in PD pathogenesis. Some PD patients suffer from gut inflammation and GI problems like constipation years before motor dysfunction appears. Past studies have also suggested that PD patients have a different array of gut microbes than healthy individuals, though whether dysbiosis results from PD or plays a role in its development is unclear. 

In the study, scientists used a transgenic mouse model of PD, in which mice were engineered to over-express α-synuclein. Mice were also bred in germ-free settings in order to study the impact of introducing gut micriobiota on PD pathophysiology and symptoms. Results from a series of experiments suggested that gut microbes interact with genetically-susceptible α-synuclein over-expressing mice to produce the α-synuclein aggregates, motor dysfunction, neuroinflammation, brain pathology, and GI dysfunction of PD.

Key findings:

• Treatment with microbial metabolites called short chain fatty acids (SCFAs):

♦ Increased α-synuclein aggregation in SCFA-treated compared to untreated mice

♦ Significantly more neuroinflammation, motor dysfunction, and GI abnormalities in SCFA-treated vs untreated mice

• Fecal transplant from PD patients:

♦ Mice that received transplants from PD patients showed a different array of bacteria than those with transplants from healthy patients

♦ Mice transplanted with fecal samples from PD patients showed more severe motor deficits and neuroinflammation than those with transplants from healthy individuals

♦ Treatment with antibiotics improved symptoms

The research may impact how we think about other disorders long thought to originate in the brain, like Huntington disease and Alzheimer disease, especially in light of recent research suggesting bidirectional feedback between the gut and the brain in other neuropsychiatric disorders, such as autism. 

“Gut bacteria provide immense physiological benefit, and we do not yet have the data to know which particular species are problematic or beneficial in Parkinson’s disease. It is important to note that there are currently no antibiotic or microbial treatments available for human use that can replicate the effect we observed in mice,” Dr. Mazmanian stressed in the press release.  

The next step in research is to identify specific gut microbes that may play a role in PD. This knowledge could be used to develop biomarkers for identifying at-risk individuals or developing new therapies for PD.

Take-home Points

• Study in a mouse model of PD suggest the gut microbiome may play a role in the development of PD.

• Results from a series of experiments suggested that gut microbes interact with genetically-susceptible α-synuclein over-expressing mice to produce the α-synuclein aggregates, motor dysfunction, neuroinflammation, brain pathology, and GI dysfunction of PD.

• Mice treated with microbial metabolites called short chain fatty acids (SCFAs) showed increased α-synuclein aggregation, and significantly more neuroinflammation, motor dysfunction, and GI abnormalities than untreated mice.

• Mice treated with fecal transplant from PD patients showed a different array of bacteria and more severe motor deficits and neuroinflammation than those with transplants from healthy patients.

• The findings could be used to develop biomarkers and new therapies for PD.

Dr. Mazmanian is the scientific founder of Axial Therapeutics, which is involved in developing microbial-targeted therapeutics for neurological diseases like Parkinson disease.

Reference: Sampson TR, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167(6):1469-1480.e12.