Microbiome and Parkinson’s
Many people with Parkinson’s disease experience gastrointestinal symptoms such as constipation. In some individuals, these gut symptoms can seriously impact their quality of life, particularly early in their disease trajectory. Indeed, there is accumulating evidence that constipation may appear in people with PD before their movement disorder, sometimes by many years prior to a diagnosis. Certainly not all people who experience severe and prolonged constipation will develop PD in their lifetimes, and we still don’t know how to use this information to predict those who will progress on to motor symptoms. However, studies are underway to learn more about this “prodromal” stage of PD, which also includes surveying for other non-motor symptoms such as REM sleep behavior disorder or loss of smell (hyposmia), as well as advances in molecular biomarkers which may also help identify people at risk of developing PD. The benefits of predicting who may develop PD may enable early treatments to slow or perhaps even halt disease progression.
So how is the gut involved in PD? Are gastrointestinal symptoms part of PD itself? We don’t know, but clues to this mystery go back over 200 years to the Essay on Shaking Palsy by Dr. James Parkinson where he describes patients who had hallmark PD symptoms, and the high rate of co-occurrence of gastrointestinal issues. While the field of neurology has made strides in understanding and treating fundamental aspects of movement disorders, gastroenterologists have largely not become interested in researching this problem. The consequences are that we currently have no validated approaches to provide symptomatic relief for PD-associated constipation, which is treated with traditional laxatives that often do not work or in some cases, make symptoms worse! We need to do better.
Recently, there has been increased focus on peripheral, or body, issues in PD that includes new research into gut problems. Our laboratory became interested in this area about 15 years ago based on a perplexing question: why is a classical neurologic condition linked to gastrointestinal issues? And, we viewed the puzzle not from the perspective of gastroenterologists (which we are not), but as microbiologists who study the gut microbiome, the diverse collection of mostly bacteria, but also viruses, fungi and archaea that inhabit the human digestive system. We wondered if the gut microbiome was somehow involved in triggering or worsening PD symptoms, and if so, was it connected to just the gut problems or was there even a link to the brain? Our laboratory researches mouse models of PD, which allow testing of unproven ideas that may not be feasible or ethical to first test in humans. We performed a very simple experiment: we tested motor behavior in mice prone to showing PD symptoms side-by-side with the same mice missing their gut microbiomes. The result was a true eureka moment, as the mice without microbiomes performed better in every test we tried. Also, not only did the “germ-free” mice not have constipation, but they didn’t display motor deficits either! Something about the microbiome was contributing to PD-like outcomes in mice, so we set out to find out what it (or they) may be.
The human gut microbiome contains about 100 trillion cells comprised of several hundred bacterial species. Other laboratories had begun sequencing the gut microbiome of people with PD and matched non-PD individuals, generating a blueprint for differences between the two groups. Many studies have now replicated these findings, and there are numerous leads to follow. One result is that the PD microbiome is enriched in the expression of certain bacterial amyloid proteins. This was very interesting to us, since it is believed that a human amyloid protein named alpha-synuclein contributes to PD and may even cause it. Amyloids are self-aggregating (i.e., clumping) proteins that form large inclusions that build up inside of neuronal cells, and if not cleared out, ultimately lead to death of those neurons, i.e., neurodegeneration. We found it curious that in a disease that involves a human amyloid, there is an increase in a gut bacterial amyloid in the microbiome. Time for another simple experiment: we added only the bacterial amyloid to the intestines of germ-free mice, and again tested gut and motor performance. Indeed, this one gut bacterial protein, out of the approximately half million bacterial proteins we have in our microbiome, was enough to make the mice show all PD-like symptoms. Further, it was sufficient to cause aggregation of alpha-synuclein in brain cells of the mice. In essence, we had discovered a gut-brain connection that may explain Parkinson’s disease.
To be clear, we do not know if this interaction contributes to PD in humans. We also don’t know what else about the microbiome or what else about the person with PD is playing a role (for example, genetic predispositions, infections, chemical exposures, etc that make people vulnerable to the harmful effects of the gut microbiome). But we had uncovered a target, and finding a target is half the battle in making a new treatment. The other half is formulating a drug that engages, and in this case blocks, the target.
While we are hopeful this research will help people with PD, it is still too early to know if the treatment will work. But we are trying, and if we fail, then we will try again and will continue to learn along the way.
I hope this story inspires curious and industrious scientists to look at medical problems from different angles, bringing new skills and perspectives that may at first seem strange. I recall healthy skepticism when our research was first presented to colleagues. But occasionally, the answers to longstanding or new questions are not immediately obvious even in research fields that are mature and have set clear directions. There is always room for discoveries by investigators who are not experts in a given topic area, such as in our case where microbiologists began studying a brain disorder. This is because biology, and the human body itself, is comprised of complex and sometimes unintuitive inputs and interactions, most of which modern medicine still doesn’t understand. While explorers can get lost, hit dead ends, and may even be injured during their journey, my gut feeling is that it’s better to take risks and fail than digest the status quo.
Sarkis K. Mazmanian, PhD works at the California Institute of Technology, Division of Biology and Biological Engineering. He has spoken at past World Parkinson Congresses, and will be presenting on this topic at the upcoming WPC 2026 discussing Gut-mediated therapeutics in preclinical models on Sunday, May 24. He will also be speaking about this topic in our July 14th Research Spotlight. Register for the spotlight HERE and get your questions answered about the gut.
Ideas and opinions expressed in this post reflect that of the authors solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®