Gut microbes promote motor deficits in a mouse model of Parkinson's disease

"We have discovered for the first time a biological link between the gut microbiome and Parkinson's disease. More generally, this research reveals that a neurodegenerative disease may have its origins in the gut, and not only in the brain as had been previously thought," says senior study author Sarkis Mazmanian of the California Institute of Technology. "The discovery that changes in the microbiome may be involved in Parkinson's disease is a paradigm shift and opens entirely new possibilities for treating patients."

Parkinson's disease affects an estimated one million people and 1% of the United States population over 60 years of age. The disease is caused by the accumulation of abnormally shaped α-synuclein proteins in neurons, leading to particularly toxic effects in dopamine-releasing cells located in brain regions that control movement. As a result, patients experience debilitating symptoms such as tremors, muscle stiffness, slowness of movement, and impaired gait. First-line therapies currently focus on increasing dopamine levels in the brain, but these treatments can cause serious side effects and often lose effectiveness over time.

To address the need for safer and more effective treatments, Mazmanian and first author Timothy Sampson of the California Institute of Technology turned to gut microbes as an intriguing possibility. Patients with Parkinson's disease have an altered gut microbiome, and gastrointestinal problems such as constipation often precede motor deficits by many years in these individuals. Moreover, gut microbes have been shown to influence neuronal development, cognitive abilities, anxiety, depression, and autism. However, experimental evidence supporting a role for gut microbes in neurodegenerative diseases has been lacking.

The researchers raised genetically modified mice with a Parkinson's-like disease either in normal, non-sterile cages or in a germ-free environment. Remarkably, mice raised in the germ-free cages displayed fewer motor deficits and reducedaccumulation of misfolded protein aggregates in brain regions involved in controlling movement. In fact, these mice showed almost normal performance on tasks such as traversing a beam, removing an adhesive from their nose, and climbing down a pole.

Antibiotic treatment had a similar effect as the germ-free environment on ameliorating motor symptoms in mice predisposed to Parkinson's-like disorders. By contrast, mice raised in the germ-free cages showed worse motor symptoms when they either were treated with microbial metabolites called short-chain fatty acids or received fecal transplants of gut microbes from patients with Parkinson's disease. Taken together, the results suggest that gut microbes exacerbate motor symptoms by creating an environment that could favor the accumulation of misfolded protein aggregates.

It is important to note that, in this study, gut microbes cooperate with a specific genetic factor to influence the risk for developing Parkinson's disease. The researchers used a specific genetic mouse model that recapitulates motor symptoms through α-synuclein accumulation, and genetically normal mice that were not predisposed to Parkinson's disease did not develop motor symptoms after receiving fecal transplants from patients. Other genetic and environmental factors, such as pesticide exposure, also play a role in the disease.

The findings suggest that probiotic or prebiotic therapies have the potential to alleviate the symptoms of Parkinson's disease. However, antibiotics or fecal microbe transplants are far from being viable therapies at this time. "Long-term, high-strength antibiotic use, like we utilized in this study, comes with significant risk to humans, such as defects in immune and metabolic function," Sampson cautions. "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 therefore critical to identify which pathogenic microbes might contribute to a higher Parkinson's disease risk or to development of a more severe symptomatology -- a research direction the researchers are planning to take. They will also look for specific bacterial species that may protect patients against motor decline. In the end, the identification of microbial species or metabolites that are altered in Parkinson's disease may serve as disease biomarkers or even drug targets, and interventions that correct microbial imbalances may provide safe and effective treatments to slow or halt the progression of often debilitating motor symptoms.

"Much like any other drug discovery process, translating this innovative work from mice to humans will take many years," Mazmanian says. "But this is an important first step toward our long-term goal of leveraging the deep, mechanistic insights that we have uncovered for a gut-brain connection to help ease the medical, economic, and social burden of Parkinson's disease."