Dan Keller 0:08
Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller. At the Parkinson's Foundation, we want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research—the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow. Many factors may influence the development of Parkinson's disease and its progression: one's genetics, the environment, and even the microorganisms inhabiting a person's body, known as the microbiome. A major part of that is what is in the gut—the bacteria, fungi, and viruses in the intestines—and in most cases, living peacefully and beneficially within us. It does not only function locally in the gut in terms of digestion and nutrition, but it influences other parts of the body. Researchers studying various conditions in the brain have found influences of the gut microbiome there as well. Unfortunately, at times, it may essentially malfunction and contribute to disease. Dr. Ali Keshavarzian of Rush University studies the relationship between the gut microbiome and inflammation, including when this occurs in Parkinson's disease. We spoke at a Parkinson's and movement disorders conference in Hong Kong, where he told me about how the microbiome may influence the development of PD and how it may be manipulated to potentially help manage the disease. You're a gastroenterologist. We're here at the Parkinson's disease and movement disorders meeting. What's the connection?
Dr. Ali Keshavarzian 2:08
Yeah, it's the question I get asked very frequently. The reason is that for the last decade, we have been studying the impact of gut-derived inflammation and, in particular, intestinal microbiota in Parkinson's disease in collaboration with the movement disorder division at Rush University.
Dan Keller 2:38
Now you're doing basic science studies. So what does that imply? You're not looking at people directly, but you're using animal systems? Or how are you studying the microbiome?
Dr. Ali Keshavarzian 2:48
No, we are doing it both. Our first study was in patients with Parkinson's disease, and that was followed by animal study as well as basic science cellular studies to better understand how the microbiome impacts Parkinson's disease.
Dan Keller 3:06
Can you give me some examples of what you found—how it does impact Parkinson's?
Dr. Ali Keshavarzian 3:12
Before that, let me explain why even we thought about the microbiome. In fact, in the last 30 years, my research has been concentrated on a better understanding of the impact of environmental factors, and specifically factors associated with Western lifestyle in chronic diseases. Initially it was gastrointestinal diseases, and in the last 20 years in non-gastrointestinal diseases that are chronic, and experimental studies suggest that inflammation is a major factor for either initiation of a disease or progression of the disease, and Parkinson's disease is one of those potential disorders. And the reason is that there is now compelling evidence, both experimentally as well as in humans, that loss of brain cells in Parkinson's disease is a consequence of inflammation in the brain, so-called neuro-inflammation. And the question was, what is that source of inflammation? And we reasoned an intestinal microbiota is a reasonable candidate for a trigger of that inflammation, because we carry 10 kilograms of bacteria in our intestine. In fact, we are more bacteria than human. We initially thought 10 bacteria compared to one human cell. That is probably exaggerated, but at least two bacteria to human cells; we have 100 bacterial genes compared to one human gene. And more importantly, those bacteria are highly diverse and capable of producing inflammation when they are put in a position to be mischievous, and the many factors associated with Western lifestyle are those that make intestinal microbiota to become so-called pro-inflammatory. And Parkinson's disease, like many chronic diseases—whether it is obesity, diabetes, just to name a few—is more common in Western societies and became more common in developing countries when they adopted a Western lifestyle.
Dan Keller 5:57
How does the microbiome in the gut interact with the brain? Is it releasing factors that circulate? Is there transmission through nerves, back and forth? What's going on for the cross-talk?
Dr. Ali Keshavarzian 6:11
We don't know for a fact, but all of the above: that it can lead to inflammation in the intestinal wall, affecting the nerve cells in the gut. By the way, we have more than 10 millions of nerve cells in the gut. In fact, it is said that the gut is a small brain, and therefore there's plenty of nerve cells in the gut. And when they get inflamed, they have direct communications with the nerves in the brain, but that is one potential. But I believe that the effect is more systemic, that so-called abnormal intestinal microbiota can do two things or three things. One is impact the intestinal lining, so-called intestinal barrier, and disrupt the barrier, make it more leaky and make it more possible for bacterial products to penetrate into the intestinal wall and systemic circulation, and those products can eventually reach the brain and cause inflammation in the brain. The other part is that those bacterial products, because of the intestinal leak, get access to the nerve cells within the intestinal wall, and that inflammation either, again, by producing factors into the systemic circulation to reach the brain, or directly through the brain and cause nerve inflammation, leading to loss of nerve cells in genetically susceptible individuals, leading to Parkinson's disease, or at least result in progression of Parkinson's disease.
Dan Keller 8:07
It sounds like what you're finding now is really what leads to Parkinson's disease, what leads to progression, things like that. Does it have any implication yet for treatment or prevention of progression?
Dr. Ali Keshavarzian 8:21
Quite honestly, we don't know for a fact whether it leads to Parkinson's disease or progression of Parkinson's disease. At least in animal study, in a genetically susceptible mouse, it can, in fact, lead to Parkinson's disease. What we have found first in humans: in patients with Parkinson's disease, they have abnormal microbiota, so-called pro-inflammatory. And also we find in the same group of patients, they have disruption of the intestinal barrier, the leaky gut, and also evidence that those pro-inflammatory factors derived from the bacteria reach the circulation in patients with Parkinson's disease. Also there was association between those leaked factors and progression of a disease—more severe disease, higher level of those pro-inflammatory factors. And then we followed those human studies in animal models, and we showed that in animal models of Parkinson's disease, indeed, the same phenomenon happens, and factors such as stress and the type of food worsen that abnormal bacteria, intestinal leak, and inflammation in the brain and loss of nerve cells, very similar to patients with Parkinson's disease. Therefore, that provided opportunity to find a novel means to at least modify disease progression in those that they already have Parkinson's disease. And more exciting: that even prevent or delay the onset of Parkinson's disease in those at risk of Parkinson's disease, and that can be done by so-called microbiota-directed intervention. There are now primarily experimental, but also human studies outside Parkinson's disease, that we are able to change the composition and function of intestinal bacteria through diet, through supplements. And we have also data that when we took the stool of patients with Parkinson's disease and demonstrated that they have that abnormal bacteria and they have abnormal bacterial products, predominantly less amount of so-called anti-inflammatory products, short-chain fatty acids. When we incubated the stool with a series of supplements—prebiotics—we were able to change the composition of the bacteria to so-called less inflammatory bacteria, and we were able to increase the production of those putative anti-inflammatory products, such as short-chain fatty acids. It remains to be seen whether the use of those supplements or change of diet could also lead to this similar beneficial effect on bacteria—that is the first step. And secondly, whether that beneficial change will lead to improvement of symptoms of patients with Parkinson's.
Dan Keller 11:56
Anything important to add or words for people with Parkinson's today?
Dr. Ali Keshavarzian 12:02
We feel that the work we have done and others—in fact, now there are 13 studies from all over the world, from different parts of the United States (ours was obviously Chicago), in Europe (both northern, eastern, southern, and western Europe), as well as Asia—that patients with Parkinson's disease have abnormal bacteria. Whether it is a cause or consequence of Parkinson's remains to be seen, and therefore it is opening up a new avenue to add treatments such as diet or supplements to see whether we will benefit patients with Parkinson's disease. It remains to be seen through high-quality clinical trials, but in the meantime, that is what I suggest to my patients that come to see me. I'm a gastroenterologist, but because of my work, I have a large number of patients with Parkinson's disease, many of them with GI symptoms, that come to see me. And I tell them that there is no direct study in patients that change of microbiota will impact, but I provide dietary and what I call sleep circadian hygiene to improve their intestinal macro-environment and their microbiota. These are what I call common-sense recommendations: to try to avoid what is known as junk food, to try to be as organic as possible. Have food such as fresh food and vegetables, and have so-called Mediterranean diet with berries and legumes, and try to eat most of their food during sunlight to improve that circadian rhythm—that is breakfast and lunch—and try to have a regulated sleep-wake pattern. These are the factors, and we and others have shown that clearly improve microbiota in other diseases such as obesity or cardiovascular disease. Those common-sense dietary advice have shown to be beneficial; the hope is that that will also be beneficial in Parkinson's disease. But I'm eagerly waiting the opportunity to do clinical trials in Parkinson's patients to see whether those gut-directed interventions benefit the disease course.
Dan Keller 14:34
Very good. Thank you. You can find much more about the gut-brain connection, and specifically how it relates to PD, by going to parkinson.org/blog where you will find several articles on gut bacteria linked to PD symptoms, nutrition, and the PD gut-brain connection. You can also find an expert briefing on nutrition and PD at parkinson.org/eb by Dr. John Duda of the University of Pennsylvania, in which he discusses how the gut microbiome may be involved in PD and explores the possibility that sound nutritional choices may provide disease-modifying effects. Along that line, Professor Bas Bloem talks about how diet can help improve some of the symptoms of Parkinson's and optimize the effects of medication. In podcast episode four in this series, as always, our PD Information Specialists can answer questions and provide information in English or Spanish about this topic or anything else having to do with Parkinson's. They can help you find dietitians in your area or other resources having to do with diet and nutrition. You can reach them at 1-800-4PD-INFO. If you have questions or want to leave feedback on this podcast or any other subject, you can do it at parkinson.org/feedback. If you enjoyed this podcast, be sure to subscribe and rate and review the series on Apple Podcasts or wherever you get your podcasts. At the Parkinson's Foundation, our mission is to help every person diagnosed with Parkinson's live the best possible life. Today, to that end, we'll be bringing you a new episode in this podcast series every other week. Until then, for more information and resources, visit parkinson.org or call our toll-free helpline at 1-800-4PD-INFO, that's 1-800-473-4636. Thank you for listening.
