Parkinson’s disease is a progressive neurodegenerative disease that causes combined motor symptoms of tremors, slowness in movement, stiffness, abnormal posture and gait, loss of balance, and non-motor symptoms as well. It occurs when brain cells that produce dopamine, a chemical messenger that helps coordinate smooth and balanced muscle movements, become damaged and die. Despite advances toward understanding what causes Parkinson’s disease, there is still no cure. Current treatments mainly focus on managing symptoms rather than slowing disease progression.
In recent years, the explosion of interest in the so-called “gut-brain axis,” the link between microorganisms living in the digestive tract and the central nervous system, has led scientists to look for links between the gut microbiome and diseases of the nervous system like Parkinson’s. Researchers have already uncovered interesting connections between the gut and Alzheimer’s disease, depression and anxiety, and even macular degeneration in the retina.
Now, a new grant will help a team of researchers from the University of Chicago study the gut microbiome’s role in Parkinson’s disease as well. The five-year, $3.4M award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health, is part of a larger consortium created to collect data from patients, in hopes of developing treatments to slow or prevent the disease’s progression.
“A better understanding of the gut microbiome during the development or progression of Parkinson’s disease could lay the foundation for us to develop microbiome biomarkers and treatments in the future,” said Tao Xie, MD, PhD, a Professor of Neurology and Director of the Parkinson’s Disease and Movement Disorder Program at UChicago.
Tao Xie, MD PhD
Professor of Neurology
Xie is one of the lead investigators for a new research project supported by the grant, which will collect and analyze data from hundreds of patients treated in his clinic over five years. This includes a wealth of data tracking their disease symptoms, severity, and progression, along with genetic data, demographic information, diet, physical activities, environmental exposures, and fecal samples for measuring gut microbes, their genetic activity, and the metabolites they produce.
The team deliberately designed their study to include more Black patients, who make up a only 3% of Parkinson’s disease patients overall. The number of Black Parkinson’s patients treated at UChicago is about 30% of its total population, however, filling a crucial gap where this study can provide more data on clinical and environmental factors that affect their experience with the disease.
Eugene B. Chang, MD, the Martin Boyer Professor of Medicine and Director of the Microbiome Medicine Program at UChicago, is another lead investigator for the project. As an expert on the gut microbiome and its contribution to digestive diseases like inflammatory bowel disease, he said it was surprising at first to see the NIDDK support research on a neurological disorder. Given what he has learned over the years about the microbiome’s role in the body, however, he says it makes sense.
“We now think of the gut microbiome as another organ in the body, which is just as important as other vital organs,” he said.
Eugene B. Chang, MD, Martin Boyer Professor of Medicine
Director of the Microbiome Medicine Program
Up to 90% of Parkinson’s disease cases are “sporadic,” or not linked to genetic causes. This means that it is likely to be linked to different variables that change based on a person’s lifestyle, social and economic conditions, and exposure to toxins in the environment. Perhaps the single most important way that lifestyle can affect health is diet, so Chang says it’s crucial to recognize the gut microbiome’s role in that process.
“It is so integrated with every organ system of our body that you have to think that any perturbation created by modern society, high fat Western diets, or lifestyle change is going to impact the microbiome,” he said. “The consequence of that is that it could contribute somehow to the neurodegenerative condition associated with Parkinson's.”
One means of measuring the gut microbiome is a metabolic panel developed in Chang’s lab that provides a scorecard of microorganisms and their activity. Just like standard bloodwork at a hospital shows a patient’s cholesterol or blood glucose levels on a range of healthy values, this microbiome panels shows the abundance of different strains of bacteria or metabolite levels on ranges that are known to contribute to overall health.
A key element of this analysis is not just taking snapshots of a patient’s gut microbiome, but also understanding what it is doing at a given time during their care. RNA levels serve as a measure of gene activity, as they transcribe their genetic instructions and build proteins.
Tao Pan, PhD, Professor of Biochemistry and Molecular Biology at UChicago, is a co-investigator for the project who specializes in developing tools to sequence RNA, especially a number of small RNA molecules like transfer RNA that make up more than 90% of RNA molecules. Pan’s techniques for analyzing these molecules will help the team track genetic expression at timescales as brief as days or hours, providing a more comprehensive and detailed view of gut microbe activity.
Tao Pan, PhD
Professor of Biochemistry and Molecular Biology
of Committee on Genetics, Genomics and Systems Biology
of Committee on Microbiology
Finally, Xiaoxi Zhuang, PhD, Professor of Neurobiology, Neurology and the Neuroscience Institute at UChicago, another co-investigator, will help tie these data to brain and nervous system functions. He studies the molecular machinery involved in brain plasticity, or how connections change during learning, especially in relation to motor control. He has also developed animal models of Parkinson’s disease that will help the team analyze their findings and test different hypotheses.
Xiaoxi Zhuang, PhD
Professor of Neurobiology
Professor of Neurology
Professor of Neuroscience Institute
of Committee on Computational Neuroscience
Crunching all the data collected from patients over several years is a tall order, and the team will make use of machine learning models and artificial intelligence. These computational approaches are especially effective at finding connections and spotting patterns. The team hopes to identify biomarkers that might predict, for example, what type of Parkinson's a person is going to have or how the disease is expected to progress. They will also contribute the data to a repository managed by the NIDDK so other researchers can make their own analyses.
Xie said he is excited that the data will continue to fuel research beyond the life of this project. “Even before we applied for this award, we thought that if there was any study we really wanted to put our hands on, this would be the one that we wanted to try,” he said. “We feel really excited about the potential.”
With experts in Parkinson’s patient care, the microbiome, genomic sequencing, and neuroscience working together, the project is also another example of “team science” bridging several disciplines that plays to the strengths of UChicago, with its tightly integrated basic science programs and hospital system.
“You put all this together and you get something that none of us could do alone,” Chang said. “It's really an example of the strength of the University of Chicago. We're very collaborative, and there's synergy created by the interactions that we have among faculty.”
