“We have shown that there is a widespread imbalance in the Parkinson’s metagenome, creating an environment that is permissive for neurodegenerative events and is prohibitive of recovery.”
- Haydeh Payami, Ph.D., Professor of Neurology and Genetics, University of Alabama
“Understanding the role of the gut microbiome in influencing PD is its infancy. These are important steps to determining what—if any—link may be between gut bacteria and PD.”
- James Beck, Ph.D., chief scientific officer, Parkinson’s Foundation
Over the past several years I’ve been following the emerging medical literature on the potential role of the gut microbiome in Parkinson’s disease (PD). So, when the article: “Common Gut Bacteria Linked to Parkinson’s Disease,” appeared in Medscape Medical News at the same time that I was watching the documentary, “STILL: A Michael J. Fox Movie,” I decided that the time is right for a Germ Gems post on the topic of the gut microbiome and PD.
Synopsis of PD. PD is named after James Parkinson, an English doctor who was the first to describe this chronic neurodegenerative disease of the brain in 1817. A hallmark of the disease is unintended or uncontrollable movements, such as shaking, stiffness, and difficulty with balance and coordination. More than 10 million people are afflicted worldwide (nearly 1 million in the U.S.). Although most people develop the disease after age 60, about 10% experience the onset before the age of 50. (Michael J. Fox was only 29 when he was diagnosed.)
Symptoms usually begin gradually and worsen over time. As the disease progresses, people may have difficulty walking and talking. They may also have cognitive and behavioral changes, sleep problems, depression, and fatigue.
The cause of PD is unknown. Many scientists think the etiology is complex involving both genetic and environmental factors. Key neuropathological findings include death or impairment of nerve cells (neurons) in the basal ganglia, an area of the brain that controls movement. Normally, these neurons produce an important brain chemical known as dopamine. When they die or become impaired, they produce less dopamine, which causes the movement problems associated with the disease. (It also explains why levodopa, a precursor of dopamine, is the most commonly prescribed medicine for PD.)
Another neuropathological abnormality in PD is the presence of Lewy bodies (clumps of the protein alpha-synuclein) in many brain cells of people with the disease. Scientists are trying to better understand the normal and abnormal functions of alpha-synuclein and its relationship to genetic variants that impact both PD and Lewy body dementia.
Infections linked to PD. As already mentioned, environmental factors are postulated to be involved in the pathogenesis of PD. In addition to a wide variety of toxins, such as the heavy metals iron, mercury, and lead, as well as the chemical compounds, trichloroethylene and polychlorinated biphenyls, a number of infectious agents have been implicated as a cause of PD (see “Infection and Risk of Parkinson’s Disease” in Journal of Parkinson Disease, December 2021).
The original hypothesis of an infectious origin in PD stems from the observation of PD-like symptoms in individuals infected with the 1918 influenza A virus who developed a neurological disorder called encephalitis lethargica. Since then, other influenza virus strains and other viruses, for example, hepatitis C, as well as bacteria (Helicobacter pylori) have been implicated as the cause of PD. While the infectious origin hypothesis remains valid, there is little convincing evidence that any of these microbial pathogens cause PD.
More recently, an alteration of the microbiota in the gut has captured increasing scientific attention as a possible cause of PD. Before getting to the studies that address this hypothesis, it’s worthwhile to summarize some of the key features of the gut microbiome.
Recap on the gut microbiome. In several Germ Gems posts over the past two years, the human microbiome, that is, the microbes that share our body’s surfaces, has been featured. Of the five microbiomes in the human body, the composition of the microbial ecosystem of the gastrointestinal tract (the gut) is the most studied.
Residing in the healthy gut are an estimated 40 trillion bacteria, countless numbers of archaea, fungi, parasites, and about 400 trillion viruses. A comprehensive review of the composition of the gut microbiome can be found in the January 2019 journal
Microorganisms, “What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases.” For the purposes of today’s Germ Gems post, suffice it to say the gut microbiome is incomprehensibly complex, and frankly, I find it humbling that so many microbiologists have the temerity to study it. But I am grateful for their work and am constantly amazed at how much we are learning about its potential involvement in health and disease.
Gut microbiome and PD. Per Erik Saris, Ph.D., from the University of Helsinki, Finland authored the study on the gut microbiome and PD published in this May’s Medscape Medical News that I cited at the beginning of this Germ Gems post. This study was built upon earlier work by Saris and his colleagues that showed the bacterium Desulfovibrio was more prevalent in the gut microbiome of patients with PD, especially those with more severe disease, than the gut microbiome of healthy controls.
In their recent study, these Finnish researchers found that when Caenorhabditis roundworms were fed Desulfovibrio bacteria from patients with PD, the worms expressed significantly more human alpha-synuclein than worms fed Desulfovibrio bacteria isolated from healthy controls. In a news release, Saris was quoted as saying, “Our findings indicate that specific strains of Desulfovibrio are likely to cause Parkinson’s disease.”
Obviously, a lot more work, including work from other researchers, is necessary before concluding that an ominous strain of Desulfovibrio bacteria is the cause of PD. Nonetheless, as a February 2020 article in Frontiers in Neurology, “The Role of the Gut Microbiota in the Pathogenesis of Parkinson’s Disease,” makes clear, the idea that a disturbed gut microbiome (referred to as dysbiosis) plays a key role in the pathogenesis of PD isn’t new.
In my opinion, Haydeh Payami, Ph.D. and her colleagues at the University of Alabama at Birmingham have provided some of the most promising research showing that the gut microbiome is involved in the pathogenesis of PD. They have actually demonstrated that the gut microbiome is involved in multiple pathways in the pathogenesis of PD. Recent findings from the group, published in Nature Communications, have shown a wide imbalance in the gut microbiome composition in people with PD.
Underscoring the complexity of gut microbiome studies, these University of Alabama researchers studied 257 species of organisms in the microbiome. Of these species, the analysis indicated 84 of them (more than 30 percent) were associated with PD. Out of the 84 PD-associated species, 55 of them were abundant/present in persons with PD at an “abnormally high” level, and 29 were at an abnormally low level, that is, depleted. In sum, their findings indicate that a widespread imbalance of the gut microbiota is a common feature of PD.
According to Dr. Payami, “This study created a large dataset at the highest resolution currently feasible and made it public with no restriction to promote open science. It includes extensive metadata on 490 persons with PD, the largest PD cohort with microbiome data, and a unique cohort of 234 neurologically healthy elderly, which can be used in a wide range of studies. We have shown that there is a widespread imbalance in the Parkinson’s metagenome, creating an environment that is permissive for neurodegenerative events and is prohibitive of recovery.”
Can these basic science findings be translated into new treatments for PD patients? Mounting evidence indicates that a dysbiotic gut microbiome is associated with PD. But the most pressing questions facing researchers (and patients) are if, how, and when these findings can be translated into sorely needed new treatments of PD.
A prime example of successful translational research is provided by earlier advancements in the field of PD. When Swedish scientist Dr. Arvid Carlsson began his studies of the neurotransmitter dopamine in the 1950s, almost nothing was known about its relevance. His discoveries of the key role of dopamine in PD over the next several decades led to his being awarded the 2000 Nobel Prize in Physiology or Medicine, which he shared with two other neuroscientists for their discoveries relating to the transmission of chemical signals in the brain.
Dr. Carlsson’s scientific discoveries were translated into the development of levodopa, a drug approved for the treatment of PD in 1975. Despite its shortcomings, e.g., loss of effectiveness over time and side effects, levodopa remains to this day the most effective pharmacologic agent for the treatment of PD.
Given the complexities of microbiome research, it is likely to take some time before the recent discoveries of gut microbiome dysbioisis can be translated into new therapies for PD. But as Michael J. Fox said, “ Medical science has proven time and again that when the resources are provided, great progress in the treatment, cure, and prevention of disease can occur.” (To date, the Michael J. Fox Foundation has raised over $1 billion for PD research.)
