There is a missing link between genetic and environmental causes of Parkinson’s disease, scientists at the University of Alabama at Birmingham speculate, and armed with a four-year, $2.5 million grant from the U.S. Army Medical Research and Materiel Command, they intend to find it.
Parkinson’s disease, which affects nearly 1 million Americans and 10 million people worldwide, occurs when dopamine-producing neurons in the brain are damaged or die. The loss of dopamine leads to tremors, stiffness and trouble walking and balancing. There is currently no preventive treatment, or a cure. In most cases, the damage has been accumulating for decades before symptoms appear. But what if it were possible to get an early warning about trouble in the brain based on turmoil in the gut? Or, better yet, what if some simple tweaks to intestinal bacteria — the gut microbiome — could interrupt Parkinson’s progression in the first place?
The grant will allow UAB researchers to launch a major investigation into the role of the gut microbiome in Parkinson’s disease. The gut microbiome refers to the 100 trillion or so bacteria and other microbes that live in the human intestines. Their combined DNA is 100 times larger than the human genome, says Haydeh Payami, Ph.D., professor in the UAB School of Medicine Department of Neurology and John T. and Juanelle D. Strain Endowed Chair, who is the principal investigator for the study.
At this point, only a handful of studies have looked at the microbiome in Parkinson’s disease; Payami’s paper in the journal Movement Disorders, in 2017, was one of the first. This research has uncovered tantalizing clues that could explain a puzzling problem in Parkinson’s research. What we know about the role of genes and environment in Parkinson’s does not add up, according to Payami.
“Large patient studies have searched for genetic variations and environmental triggers shared by people who have Parkinson’s disease,” Payami said. “Dozens of genetic risk factors have been identified, but each only increases risk by a small amount. There is a significant link between exposure to pesticides and herbicides, as well as repeated head trauma, and Parkinson’s risk; but again, not all people who have a genetic susceptibility and are exposed to these factors get the disease. There has to be something more than genes and environment.”
That is where the microbiome comes in. In 2016, researchers at CalTech removed the gut microbiome from mice bred to exhibit Parkinson’s symptoms, and the symptoms improved. Then they transplanted microbes from human patients with Parkinson’s into the mice, and the symptoms returned.
The 2017 study from Payami and colleagues drew on the patients enrolled in the NeuroGenetics Research Consortium, which has one of the world’s largest datasets of Parkinson’s patient information. Payami is lead investigator for the consortium, which includes both genomic and environmental data. By collecting additional fecal samples from those patients, the researchers found that the types of bacteria in the guts of people with Parkinson’s differed significantly from healthy controls. The researchers also discovered that Parkinson’s medications were linked to changes in gut bacteria as well.
“The microbiome metabolizes drugs,” Payami said. “It can turn harmless drugs toxic, and vice versa. Exposure to pesticides and insecticides may be mediated by the microbiome as well. And because the microbiome is easily modifiable, it could offer a way to predict, prevent and even treat Parkinson’s disease.”
There are several other intriguing lines of study pointing toward the microbiome. In a number of small studies, eradicating Helicobacter pylori infection in the gut of Parkinson’s patients increased the effectiveness of levodopa, the most commonly used Parkinson’s medication. Scandinavian studies (here and here) found a link between cutting the vagus nerve — a physical connection between the gut and the brain, which was sometimes severed to treat peptic ulcer — and a lower risk of Parkinson’s.
The microbiome connection is still only a hypothesis, Payami cautions, and there is unlikely to be a single cause for Parkinson’s found. Instead, there are probably many different routes that all end in the same outcome.
“There’s no question that the gut microbiome is changed in Parkinson’s disease,” she said. What isn’t clear is whether the microbiome is changed as a consequence of the disease, or whether it contributes to the disease process itself. The same is true of drug-microbiome interactions: Could the makeup of a patient’s microbiome affect his or her response to treatment, or do medications alter the microbiome?
Payami suggests that the answer is all of the above. If so, it could be possible to manipulate the microbiome to prevent Parkinson’s in people who are at risk, slow or stop progression in people who have the disease, and use the microbial composition to prescribe the right drug to the right patient to maximize efficacy and avoid side effects.
The new Department of Defense-funded study will address a number of crucial questions. Its aims are to identify the specific microorganisms that contribute to the pathogenesis of Parkinson’s; to identify any micro-organisms that interact with the dozens of known genetic risk factors for the disease; to test the effects of two neuroprotective factors, cigarette smoking and caffeine consumption, on the microbiome; to look for early microbial changes in patients with REM sleep behavior disorder, a sleep disorder that is strongly linked with eventual Parkinson’s diagnoses; and to investigate the interaction between micro-organisms and Parkinson’s progression in animal models of the disease.
Many studies that look at the microbiome in patient populations are too small to produce statistically valid results. That is why the current study will include 1,000 Parkinson’s cases and 600 healthy controls, drawn from UAB and the other members of the NeuroGenetics Research Consortium, including Emory University, Oregon Health and Science University, the University of Washington in Seattle, and Albany Medical Center in New York. The study will also enroll 100 individuals with REM sleep behavior disorder from UAB and Montreal, Canada.
“Eighty percent of people with REM sleep behavior disorder go on to be diagnosed with Parkinson’s or another neurodegenerative disease,” Payami said. “If we can see changes in the microbiomes of these patients decades before they develop Parkinson’s, we could take action. That’s what’s exciting.”
Co-investigators on the project are David Standaert, M.D., Ph.D., professor and chair; and Amy Amara, M.D., Ph.D., assistant professor, UAB Department of Neurology; and Ron Postuma, M.D., a neurologist from McGill University, Montreal, Canada.