Episode 143: Meet the Researcher: How Pesticides Impact Parkinson’s

Dan Keller 0:02 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.

We are all a composite of our genetics, the influence of our environmental exposures, and the microbes that live on and within us. Accumulating evidence shows that the microbes that live in our guts—bacteria, viruses, and fungi—are important in maintaining our health and affecting our disease states. Studies have shown that people with Parkinson's disease have distinct patterns of organisms in their gut microbiomes. Exposure to pesticides in the environment raises the risk for many neurological diseases, including PD.

Tim Sampson, a cell biologist at Emory University in Atlanta, a Parkinson's Foundation Center of Excellence, studies how genetics and Parkinson's-linked pesticides affect the gut microbiome with the aim of discovering how these interactions may trigger Parkinson's symptoms, and ultimately to gain insights to prevent PD and develop new therapeutic targets. I first asked him why he chose to study Parkinson's disease.

Tim Sampson 1:56 I've been largely interested in understanding how bacteria and viruses affect the human body, and so when I first got into science, I was really interested in those organisms that cause disease, but we know now that that's a really rare interaction. Disease doesn't happen very often from our interactions with bacteria, and instead, what we see is that our bodies are just colonized with numerous amounts of bacteria, and within this, these microbiome communities in our gut and in our mouths. And so I became extremely interested in understanding how those organisms that are on us throughout our entire lives could affect the body.

Dan Keller 2:40 You're a fairly young researcher, so I understand you've received the Stanley Fahn Junior Faculty Award from the Parkinson's Foundation. What does that allow you to do?

Tim Sampson 2:52 It's been really wonderful, and so it's allowed us to have the ability to springboard some of our ongoing research to generate some preliminary data to get some larger awards down the line, such as those from the National Institutes of Health. So it's really allowed us to take a little bit of a chance and develop some of these underlying questions that we have that aren't quite ready for prime time, but are percolating.

Dan Keller 3:18 What evidence is there that the gut microbiome under normal conditions contributes to Parkinson's disease symptoms starting in the gut and after that in the brain?

Tim Sampson 3:30 There's a lot of association studies between individuals with Parkinson's and those without that have really laid the foundation to show that the community of bacteria—the types of bacteria that are present in the gut—are different between those who have Parkinson's and those who do not. And so work from my lab and others now have shown that in experimental models, so using different mouse models, for instance, if we remove all the bacteria from the situation or add back new bacteria, we can change the progression of those disease models. And so sort of all together, this suggests that there is a role for microbes, and different communities of those microbes will have different effects, or may have different effects, I should say, on disease.

Dan Keller 4:19 So those experiments, I would think, put to rest the question of what's called reverse causality. I assume people test people with Parkinson's once they've been diagnosed and find different gut microbiomes. One could make the case that the disease causes the change in the microbiome, but by those transfer experiments, I guess you've really nailed down that the microbiome is the precipitating factor, is that right?

Tim Sampson 4:47 I don't think I would go that far. No. So I think that chicken-and-the-egg issue that you just described still exists. So, as you just mentioned, we could imagine situations where the disease itself is responsible for the change in the microbiome, and that's something that our lab and the field is becoming really interested in. So, what causes the change to the microbiome that we see in people with Parkinson's?

But we know from the animal work now, or at least have a good handle, that once that microbiome is changed, irrespective of how it's been changed, it can accelerate or exacerbate a disease condition. So we don't know yet what precedes disease. So, does the change in the microbiome precede diagnosis, or does that microbiome change occur upon the area of diagnosis? And so those long-term studies just haven't been done yet, but I'm hopeful that we'll be able to start—not necessarily my group, but others will be able to start doing some of that work soon.

Dan Keller 5:53 Does a person's genetics influence the mixture of their gut microbiome?

Tim Sampson 6:00 There is some evidence for this in the context of Parkinson's. However, it's not quite clear. And so work that is ongoing in my lab right now actually is trying to understand whether some of those genetic predispositions to Parkinson's—so for instance, changes in alpha-synuclein expression—whether that can change the microbiome, whether that's sufficient to drive some of the changes in the microbiome that we see in people who have Parkinson's disease.

Dan Keller 6:32 This is a fairly new field, everything having to do with the microbiome and many different diseases, or even in the healthy state. So, is your research at this point about where it stands, or where does the field overall talking about gut microbiome interaction and relationship to PD stand?

Tim Sampson 6:55 I think the experimental studies, so that is all the mouse experiments that we described where we can manipulate the microbiome and see changes in Parkinson's-like pathologies, I feel like that is still, you know, in the very early days. However, in my opinion, the studies now looking at the microbiome composition—so the differences in the microbiome between individuals with Parkinson's and those without—I think we've pretty much really nailed down what's happening there across numerous studies at institutions both in the United States and internationally.

Cohorts across individuals who have different lifestyles that sort of, irrespective of diet and other attributes that would change the microbiome, the disease status seems to be a driving factor for those changes. I think we really do know that Parkinson's disease has, as one of its characteristics, changes to the microbiome, and so I think that's sort of the foundation where we are now. You know, this is thousands of individuals across more than three or four dozen studies that have clearly indicated differences in the microbiome during Parkinson's disease.

Dan Keller 8:12 What evidence, if there is evidence, is there that pesticides and other toxic compounds known as toxicants in the environment influence the gut microbiome?

Tim Sampson 8:24 There's some very intriguing preliminary data in experimental models that have shown discrete changes to specific microbes—so microbes that might be more or less sensitive to certain toxicants. And so some groups have looked at things such as Gulf War chemicals, and exposing mice to those, and seeing particular changes in microbes, which, incidentally, we know that exposure to Gulf War chemicals is one of the epidemiologically linked factors to Parkinson's disease as well. And so my group is hoping to build on some of those studies and really relate how natural exposures to some of these toxicants and particular pesticides that are linked to PD can change the microbiome. The studies are so new and so early that we don't know exactly how the microbiome changes.

Dan Keller 9:16 Is the Department of Defense interested in funding any of this?

Tim Sampson 9:21 I personally have not applied. The Department of Defense does have a neurotoxicant exposure program that is devoted to Parkinson's-linked toxicants and how those interact to cause disease.

Dan Keller 9:35 How do organisms in the gut cause symptoms? Are they affecting nerves? Are they affecting water balance, motility of the gut? What do they do?

Tim Sampson 9:45 I think the contribution of the microbiome is going to have many different ways in which the microbiome is going to influence disease. In some cases, there's evidence in experimental models that certain bacteria can actually instigate the aggregation of alpha-synuclein and turn it into that pathogenic structure that is so detrimental. And so we and others believe that triggering that pathology in the gut by certain bacteria might be responsible for then spreading it and getting that pathology to the brain.

There's also other studies proving that certain microbes can influence immune responses, and so we know that Parkinson's disease has a very inflammatory component, so there's a hyperactive immune system that arises in Parkinson's disease, and we know that certain microbes are necessary for instigating those responses. And so there's likely a multifactorial response by the microbiome to influence different aspects of disease, and likely not just one, but many.

Dan Keller 10:52 That sounds like the inflammatory compounds that the microbiome causes the body to produce may be circulating, but is there also evidence that these compounds, or even the bacteria themselves, could reach the brain by, say, the vagus nerve? This is a nerve that innervates just about everything between the brain and the gut. So, is there a traffic highway through it?

Tim Sampson 11:19 Certainly, so, as you mentioned, with the vagus nerve, there's currently no evidence, to my knowledge, that microbes, or some of these particular compounds that we think instigate pathology, that those specifically can traffic through the vagus nerve. However, we know that alpha-synuclein can, and the vagus nerve interacts with particular cells in the gut that are then interacting with the microbiome. And so we think that one way this might all be happening is by instigating synuclein to aggregate in those cells, which is then passed on to the vagus nerve and travels up it to the brain. So not that the microbes are traveling to the brain, but that the initiation of synuclein pathology is traveling to the brain.

That said, there is some evidence in Alzheimer's disease, which is very different, that some microbes can actually cross the nasal barrier—so some microbiome in the nose—and enter nerves in those neurons that are involved in smell, and so it's not outside of the realm of possibility that microbes are traveling from the gut directly to the brain or from other surfaces into the brain. There's just currently, to my knowledge, no evidence that that is happening in Parkinson's disease.

Dan Keller 12:38 The aggregation of alpha-synuclein seems to be almost a domino effect, where if you have an aggregate, it causes more things to aggregate. So is that how it may sort of transmit itself up the vagus nerve?

Tim Sampson 12:54 Yes, I would say that that is currently sort of one of the major hypotheses in the field—that sort of that domino effect, that ability to template other synuclein molecules, other proteins itself can drive and spread the pathogenic form of that protein.

Dan Keller 13:13 Can the gut recondition itself or repopulate good bacteria and other organisms if pesticides are avoided, and can that alleviate symptoms such as constipation?

Tim Sampson 13:27 Yeah, so there's some interesting case studies. When we talk about case studies, these are very low numbers of individuals who these have been performed on, but it seems that fecal microbiome transplant therapy, which is commonly used for things like diarrheal infections—now, one in particular, Clostridium difficile—but when that has been performed on individuals with Parkinson's disease, the constipation effects are diminished. So, it does seem that there are ways to restore the microbiome, but certainly, you know, these fecal microbiome transplants, they are not fully approved for something like Parkinson's disease. They come with a lot of risks, and they're not necessarily targeted, and we don't know, for instance, how long they'll last.

As for avoiding pesticides, right now, you know, once the microbiome has been changed by an environmental exposure or through a lifetime of diet and a lifetime of aging, there doesn't seem to be much to remove from one's daily life that might allow the microbiome to be restored. But that said, there's some pretty nice evidence that suggests if one changes their diet to have increased fiber intake, for instance, increased vegetables—those nice leafy greens—that has a beneficial effect by providing appropriate nutrition and substrates for the microbes in our gut to eat and live, and that that might be one way we can think about restoring the microbiome to a stage that may be considered a little bit healthier. That's not to say it's going to diminish symptoms at all, but certainly we know that those bacteria that eat roughage and leafy greens and fiber are beneficial for things like intestinal motility and regularity. So it stands to reason that there could be some benefit there. We just don't have the data for it yet.

Dan Keller 15:22 The brain itself is essentially sequestered behind the blood-brain barrier, so getting drugs to it can be tricky, but the digestive system is largely a tube open to the outside at both ends, so the gut microbiome should be much more accessible to therapeutic or preventive strategies. Maybe, can you foresee any therapeutic uses regarding Parkinson's or preventive strategies coming out of it?

Tim Sampson 15:47 Certainly, so this idea that the gut microbiome is modulating inflammatory responses, for instance, so we could envision future potential for changing the microbiome in a way that those systemic inflammatory responses don't happen. And so there, even though the brain is sequestered, it's still getting these inflammatory signals from the rest of the body and from the gut. So, if we can change that by either providing substrate for beneficial bacteria to grow or through the addition of particular bacteria that might be beneficial, we therefore might be able to change the inflammatory state of the brain.

And sort of on the other side, you know, thinking about identifying bacteria that might be antagonists, the triggers to pathology in the gut, if we can identify those, it stands to reason that we might be able to prevent their interactions with our bodies. So if we know that an individual is carrying some of these bacteria that might be detrimental or might instigate Parkinson's pathologies, then we can perhaps consider doing pharmaceutical interventions to remove those bacteria, or at least prevent them from interacting with our cells to prevent the instigation of pathology.

Dan Keller 17:05 It's probably a good idea to try to reduce in the environment pesticides and other toxicants, but they do have uses. Are there any that are particularly problematic that should be targeted for reductions?

Tim Sampson 17:21 Not quite sure I can say specifics here. There are certainly some chemicals that we have historical evidence for that their removal from the environment has been beneficial, not just for things like PD, but for sort of general environmental health and things. The prime example is DDT.

I think more recently there's been some push to remove some other chemicals from the environment that are just generally toxic, and so individuals talk about things like paraquat, which causes some pretty strong reactive oxygen responses—so some stress responses in our cells—as well as some others. So I think that conversation needs to keep going, but I'm not sure right now I could say explicitly which ones are horribly detrimental compared to the balance of needing to use some of these for agricultural use and for home use.

Dan Keller 18:15 Parkinson's disease is becoming more prevalent, and there's a lot of different toxicants in the environment. I suppose they may interact, or at least be additive on a geographic level or population level. Would a composite exposure score be useful, taking into account the relative amounts and relative potencies of many major toxicants?

Tim Sampson 18:40 Oh, extremely. So, I believe there's ongoing studies in California doing just this, and those are some of the most informative we have. And so the teams in California, using the Central Valley of California, which is agriculturally rich, are actually able to map—because California requires pesticide registration. They're able to map relative exposure amounts, and then turn that into risk ratios for disease, and so combining that with things such as genetics and microbiome composition, I think, is going to be extremely powerful.

But right now, that's just the state of California, and at least in the United States, there's not a lot of pesticide registration that occurs, and so we can do things such as ask an individual in our studies if they are exposed to toxicants and pesticides through their occupation or through their residence being in an agricultural setting or through acts of war, but we don't actually know exactly how much, or even a good estimate of how much they've been exposed, so we are still limited in our ability to collect some of that data.

Dan Keller 19:54 A while ago, I produced an agricultural video in Ventura County, California. And it was about this natural insecticide that's very specific for different pest species, and the farmers were very happy to have something like this, because they said, "We live in the middle of this stuff, we don't want pesticides, but if you have to use them to get a crop, that's what we do." But they were all in favor of much more, even genetically modified pesticides or natural pesticides. Is there anything we've missed or important to add on the topic?

Tim Sampson 20:30 We've hit a lot. I think one of the emphases should really, though, be on the fact that we have lots of intriguing experimental data, but there currently is nothing to say that the microbiome is causative of Parkinson's disease. We have evidence that it might contribute to disease, but we don't necessarily know that there are these specific organisms that in humans instigate the disease itself or trigger the disease. We haven't fulfilled Koch's postulates, to use the basic microbiology term, we haven't fulfilled Koch's postulates with Parkinson's disease and particular microbes yet.

Dan Keller 21:06 Koch's postulates say that you have to give someone what you think is causing a disease and see if the disease occurs, that would be kind of unethical.

Tim Sampson 21:17 Well, certainly in humans, but we could imagine situations where we can envision experiments where we can get those bacteria from individuals with a disease condition and place those into our experimental models.

Dan Keller 21:31 Exactly. Yes. Well, I really appreciate it. This has been wide-ranging and pretty informative. Thank you. Bye.

Dan Keller 21:40 To find out more about Tim's research, search for Tim Sampson and Emory when visiting parkinson.org. You may also be interested in two past podcasts on the microbiome. They are called The Role of the Microbiome in PD, Parts 1 and 2. If you search our website at parkinson.org for "microbiome," you can also read up on the gut-brain connection and on the microbiome imbalance seen in people with PD.

To learn more about what the Parkinson's Foundation is doing to better define genetic influences in PD, you can listen to our past podcast, called The Launch of the PD Generation Genetics Initiative. More information on pesticides is available by searching our website for "pesticides."

News and updates about future events and resources are available by joining our email list at the bottom of our website's homepage. If you 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. Till next time, 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.

Timothy Sampson, PhD, is an Assistant Professor in the Department of Cell Biology at Emory University. Trained as a microbiologist through both his undergraduate and graduate training, Dr. Sampson subsequently performed postdoctoral studies with Dr. Sarkis Mazmanian at Caltech. There, he began exploring how indigenous gut microbes modulate outcomes of neurological disorders, specifically in models of Parkinson’s disease. Joining the faculty of the Department of Physiology in 2019, and subsequently Cell Biology in 2021, Dr. Sampson’s lab investigates host-microbe interactions at the interface of Parkinson’s and other neurological diseases historically studied within the context of the central nervous system (CNS). Similar to how the study of pathogens has informed the field of immunology, his work aims to reveal new pathways at the microbe-CNS interface.