Hot topic: The gut microbiome in Parkinson's

[00:00:42] Dr. Filip Scheperjans: Yeah. Thank you very much, Sara. It's a pleasure to be here. Thanks for having me.

[00:00:46] Dr. Sara Schaefer: We are going to start from the very beginning, the basics of basics. What is the gut microbiome?

[00:00:54] Dr. Filip Scheperjans: Yeah, so the gut microbiome, let's maybe start with the microbiome definition. So basically [00:01:00] we are talking about the community of microbes that live in a certain environment. So that encompasses bacteria, viruses, archaea, eukaryotes. And so if we really want to be strict, then one could say that the term microbiome would encompass also the environment itself in which those microorganisms live.

And then there's also frequently used the term of microbiota which then basically refers only to the actual microorganisms and not the environment or the matrix in which they are embedded. So essentially it's the whole community of microbes in a certain place.

[00:01:38] Dr. Sara Schaefer: How variable or how similar is the gut microbiome across people, across a lifetime, across species. How much do we know about that?

[00:01:48] Dr. Filip Scheperjans: That has been studied actually quite a lot over the last decade or so. So when it comes to the human microbiome, we know that actually the strongest determinant of composition is location. So the location of [00:02:00] the body part where you basically take a sample from. So a sample that you take from the skin will have a very different composition as compared to, let's say, a fecal sample or when you sample from the vagina, for example, or the nostrils.

So it is actually the factors like the local pH, the local nutrient, environment, and exposures that basically shape that microbiome. So the differences between the different parts of the body are actually stronger than the differences between individual human samples from the same body part.

So they're more subtle when it comes to inter-individual differences. However, they are clearly detectable. So, sometimes we're saying that everyone has his or her individual microbiome and that we could maybe even identify persons by the microbiome. Maybe in the future, yes. But we need very high resolution data for that. So it's actually also depending on the resolution of our assessment of the microbiota community. So when we actually look at very high hierarchical level. [00:03:00] So we only analyze the major groups of bacteria and their relative contributions.

That is actually rather stable let's say between humans, but as we go deeper in the taxonomy. So a higher resolution going to what we call genus level or species or even strain levels, then it would get a very higher variability. And so it really depends on how you look at the data.

Within an individual, we see changes across a lifetime. And actually, it is already dependent on your mode of delivery. So basically, there is a difference in the microbiota depending on whether you were born by a vaginal delivery or versus cesarean section.

So that makes already a difference from day one. And then basically you acquire your microbiome over the first couple of years of early childhood that there you see quite strong temporal changes then it seems to slow a little bit. And during adulthood, if you maintain or rather stable diet and stable lifestyle, we think that you have rather stable microbiota composition. [00:04:00] It depends a lot on your health and the environment that you live in. So what quality foods you're eating, if you have any chronic diseases, medications, and so on.

So we see that on average the, what we call diversity? So the number of different bacteria, for example, in the gut tends to increase after birth. Maximizes like in early adulthood and then towards senescence it seems to decrease, but we see a rather high variability there, depending, as I said on the health status and many other factors. 

[00:04:29] Dr. Sara Schaefer: So you discussed some of the factors that determine an individual's gut microbiome. You discussed diet, where you live. I imagine for kids it might have a lot to do with how much dirt they're putting in their mouths.

And what other factors are we aware of that can influence the gut microbiome in any individual?

And how easy is it to actually alter?

[00:04:52] Dr. Filip Scheperjans: Yeah. So as I mentioned, you inherit your microbiome basically already from your parents to a certain degree or from your mother to be more accurate. [00:05:00] The mode of delivery has an impact, and then it comes to the environment, as you say. The exposures that we get during the earliest three years of our lifetime are probably most important with respect to how much the microbiota can change and train, for example, our immune system and makes us resilient to environmental immunological challenges, for example.

And after that, obviously diet is a major contributor. So within one day, basically you can achieve significant changes of the microbiome through, let's say, an intensive dietary intervention. Putting you on a high fat, high sugar, high protein diet versus a very high fiber plant based diet, this radical change you can immediately see in the microbiome. And however, , when this, let's say when this intervention is stopped, then there is a tendency of the microbiota to go back to the initial state. So it depends on how long this is sustained. So diet is a major factor.

It seems that also that actually human genetics have a certain impact on the [00:06:00] microbiota. Possibly through interactions with, for example, the immune system. And also metabolic activity of the human body, so that favors maybe certain bacteria and eliminates others.

So genetics seem to also play a role, but when it comes to really major changes that happen over short periods of time, then we're talking about, I think dietary changes, but also, physical activity is an important factor. Obviously that is frequently also correlated with dietary patterns. So that's not necessarily easy to discern. And obviously I could also mention antibiotics that obviously can disrupt the gut microbiota in a very significant way. And there is individual variability and how well and quickly the microbiota recovers from such an incident.

[00:06:44] Dr. Sara Schaefer: And what do we know about the gut microbiome in Parkinson's disease and also when Parkinson's patients or future Parkinson's patients develop changes in their gut microbiome? Does it happen in the prodromal phase?

[00:06:59] Dr. Filip Scheperjans: Yeah. So this [00:07:00] has been studied in PD now for about 10 years. And so we now have over 20 studies from different populations, different ethnical groups that have assessed this mostly in a cross-sectional case control type of fashion. And what I can say with confidence is that on average it has been established that the microbiome of Parkinson's patients differs from that of healthy controls.

So when we then go into the details then we see a certain variability. So one of the, let's say problems with this rather young field is that the level of methodological standardization hasn't been very high in the early days, or it has improved over time, but still, we have a lot of variability in these studies in terms of sample size, analysis pipelines accounting for confounders and so on.

But since we have already [00:08:00] quite many of these studies, people have started publishing meta-analysis. And so I think yes, we can say that there is definitely a short list of bacteria that are altered in PD across several studies. And just to mention a few, probably the most robust finding has been a reduction of bacteria that produce short chain fatty acids, such as, for example, Roseburia.

And so those are bacteria that are considered beneficial for health in general. And they're, the short chain fatty acid that they produce are considered, for example, anti-inflammatory. A reduction of bacterial family or a genus that we call Prevotella. That has been also well reproduced.

And then an increase of certain bacteria. So a relative increase in the abundance of certain bacteria, such as, for example, Akkermansia, which is actually an interesting finding because Akkermansia, so all of these bacteria, basically commensal bacteria, so they can be found in a very [00:09:00] high number or let's say fraction of Human subjects. The question is the relative changes here. And so a relative increase of Akkermansia has been reproducible found which is interesting cause usually Akkermansia in other contexts, such as, for example, obesity, metabolic syndrome research, or also inflammatory bowel disease has usually been linked to a good state of gut health. There is even Akkermansia being actually marketed currently as a probiotic. However, in Parkinson's, it has been recently consistently been increased. And there is some, hypothesis what could be the reason. But obviously we don't know exactly. And also increases of for example, lactobacillus and bifidobacteria have been reproducibly found.

And also for that we don't have a clear explanation yet. It doesn't seem to be explained by a higher usage of, let's say, probiotic preparations because those don't really impact these abundances too much. With bifidobacteria. There may be a link to for example, entacapone.

It has been proposed. [00:10:00] So the exact reasons for or implications of those changes. We only are starting to slowly understand, but I think that those bugs that I just mentioned, I mean, those are the best reproduced ones. There are a couple of, let's say three to four other ones as well.

But definitely we can shortlist the changes of those bacteria. It has also been studied what we call alpha diversity, which is the, let's say a measure of the richness of the overall microbiota. So having many different species and how they're balanced which has been linked, for example, to obesity and a western diet that you would have a lower alpha diversity.

So basically losing bacteria by following this type of diet. But there hasn't been any consistent changes of alpha diversity in Parkinson's. So it's mostly about the composition and relative abundance changes that we see in Parkinson's. And most studies that have been done are just looking at the composition.

And so we are only now in the last couple of years getting more and more studies that [00:11:00] also look at the functional impact of those bacterial changes.

[00:11:04] Dr. Sara Schaefer: And you mentioned that some of these changes we think might be due to medications others maybe not. However it has been shown that even in the prodromal phase of Parkinson's, some of these changes are already happening, correct?

[00:11:19] Dr. Filip Scheperjans: Yes. Sorry, I didn't go into that. Yes, so, There is less papers out on the prodromal phase. There is a couple of papers on REM sleep behavior disorder. That according to one paper from Germany and Luxembourg that showed basically similar changes already in IRBD as compared to Parkinson's disease.

A more recent study in Japan suggested that there was less changes in REM sleep behavior disorder as compared to established Parkinson's disease. What we did with the colleagues from Germany was that we looked at the very large cohort it's called the trend cohort, over 600 individuals that are not diagnosed with any neurodegenerative disease, [00:12:00] but they have different degrees of risk factors for these diseases.

And, so we ran basically the microbiota data against established prodromal markers and risk markers of Parkinson's. And so what we saw was that markers such as RBD, such as constipation, such as physical inactivity for example, were clearly linked to microbiota composition whereas for other factors they were looking at using ultrasound for example, at the substantia nigra hyperechogenicity, that wasn't related.

 And several are other factors were neither. So that pointed To an important conceptual aspect that we need to take into account is that Parkinson's is a heterogeneous disorder. And so it seems to really depend on what subgroup of patients you are looking at and since our hypothesis at least, in certain subtypes you can see more changes.

And also, let's say in certain prodromal subtypes, you can see more changes as compared to others. Because the relative contributions of genetic and environmental [00:13:00] factors can be different between different types of Parkinson's disease. 

[00:13:02] Dr. Sara Schaefer: It's good that you brought up the heterogeneity of Parkinson's disease cause some of your research has also shown that signatures in the gut microbiome may also correlate to specific disease symptoms, correct?

[00:13:16] Dr. Filip Scheperjans: Yes. And so in our first study that was published in 2014. I mean, we took it from a, let's say, clinical point of view and looked at clinical sub classification into tremor dominant versus kinetic rigid patients. And so what we saw was that bacteria of the Enterobacteriaceae family that are pro-inflammatory.

Those were at higher levels in those patients that were akinetic, rigid or had this postural incivility gait difficulty phenotype as compared to trauma dominant patients. So that was like an initial analysis and other groups have also aimed to look into this with variable results.

And again, there may be problems with statistical power and so on. But, had to look also at, non-motor symptoms and found [00:14:00] that first of all, subjects, for example, that had IBS like symptoms, so irritable bowel syndrome like symptomatology, that they had lower levels of, prevotella in their gut as compared to Parkinson's patients that did not have gastrointestinal symptoms, so there may be a link to that in the same cohort we also saw an inverse correlation between short chain fatty acid producers and short chain fatty acids itself and depressive symptoms of the patients. So the more you had short-term fat acid producers, and the more you could find short-term fat acid in its stool the less were the depressive symptoms of our Parkinson's patients.

We did a longitudinal study we're interested in, in the connection between the microbiota and disease progression. And so in our cohort particular a low abundance of Prevotella was predictive of a faster disease progression. And that was reproduced after two years of follow up.

So that was an interesting finding because we are all interested in finding new ways to slow down Parkinson's progression. So if it would be still indeed the [00:15:00] case that a certain bacterium is low in Parkinson's patients, that progress faster. That could be, potential target for intervention.

An Italian study found that a similar finding in relation to short chain fatty acid producers. So lower short chain fatty acid producers were linked to a faster progression. Yes, of the disease. And we also saw now some meta-analysis that we're able to establish links between also cognitive symptoms, MoCA score and certain bacterial abundances.

But, we have to be cautious with that. This is all, for the most part cross-sectional correlational data. So we really need be cautious in terms of, causality here and we need obviously more extensive longitudinal and eventually interventional studies to establish such connections.

[00:15:42] Dr. Sara Schaefer: Absolutely correlation versus causation. It's really hard to tease out in this particular realm. What are some of the reasons that have been postulated for why the gut microbiome in Parkinson's is different from controls? What is the cause? What we've discussed so far makes me think about the [00:16:00] prodromal PD study that looked at the Mediterranean diet and the fact that the Mediterranean diet seems to be protective against even the prodromal phase of PD. Do you think that that is related or common genetic links? What other reasons have been postulated?

[00:16:16] Dr. Filip Scheperjans: Yeah. So, I think no one of course knows, but If we think that the microbiota let's say would be a causative factor in PD or a let's say a risk factor for PD, if it's altered in a certain way. I mean, then we need to basically look already before prodromal changes are established.

And I mean, we don't really know much about that. In Finland we were lucky to have large patient registries. And so we had a look at antibiotic exposure in relation to Parkinson's disease risk because I mean, we basically don't know what causes the microbiome changes, but at least for antibiotics, we know that exposure to those antibiotics can result in also permanent [00:17:00] changes of the microbiome.

And so, we saw actually quite strong connections between certain antibiotic classes such as, for example, macrolides and Parkinson's disease risk. So up to 40% increase in Parkinson's disease risk in patients that were exposed to multiple courses of, macrolides.

And when we look at it from a bit of a higher level. So we found that especially broad spectrum antibiotics and antibiotics that target anaerobic bacteria as compared to antibiotics that target only aerobic bacteria were linked to a higher Parkinson's disease risk as compared to narrow spectrum antibiotics and even though this is far from proving a connection, but at least it's based on that, it seems plausible because those are exactly the drugs that we know have the strongest impact on the microbiome with over 90% of the bacteria in the microbiota being anaerobic bacteria.

And so those are the drugs that have the most lasting impact. [00:18:00] An interesting finding was that actually this connection, it was not only dependent on the number of antibiotic courses but also on the delay. So the strongest connection was 10 to 15 years before the diagnosis of Parkinson's disease.

So basically that would fit the concept of some sort of hit or incident, that happens years before the disease is actually diagnosed. And we have a slow progression of the pathology in that period. So those were interesting findings.

It would be great if that could be reproduced in other countries as well. So I think such things that disrupt the microbiota or maybe pesticides, for example, can also have an impact on the microbiome. So these could have an impact. Then obviously one can also argue that could it be the other way around? So if you have a certain degree of neurodegeneration and your gut starts to function abnormally let's say of a slowdown of peristalsis, for example. That could also basically induce changes in the microbiota. So, That's [00:19:00] really the hen and the egg question. Whether it is actually the microbiome that starts the process or whether it's the neurodegeneration that results in the microbiome changes, or if it's like a triangle relationship. But, obviously diet. I think it's very intriguing to see the results about the Mediterranean diet because that is a diet that is high in fiber that should be related to higher levels of short chain fatty acids. And I mean, that is something that we universally, first of all think is healthy from the perspective of the gut microbiome.

But especially also in Parkinson's because lower levels of short chain fatty acids have also been consistently shown in Parkinson's disease cohorts. And so not necessarily in prodromal, but that gives some reason to believe that if this is already happening before the onset, then a diet that would increase the production of short chain fat acids, could be beneficial.

But we don't really have that much strong data about it. It's a lot of, maybe wishful thinking also associated[00:20:00] with that, that we really need to have harder data obviously to get to far stronger conclusions in that respect.

[00:20:07] Dr. Sara Schaefer: Yeah, I think that we could probably put one big asterisk on the entire podcast which is that this is a young field and that we don't know. A lot of these things are just observations that we're making of correlations and we haven't quite gotten to the cause and effect yet, but hopefully we'll get there.

Some of your responses segue really nicely into my next question, which is about the theories for this kind of interaction between the gut and the brain, the gut-brain axis, if you will, and how the gut microbiome actually might influence brain pathology. Particularly interesting what you said about the delay between antibiotic administration and development of Parkinson's.

Can you talk about some of the theories that have been put forth for this explanation?

[00:20:57] Dr. Filip Scheperjans: Sure. I mean, one could maybe start with, [00:21:00] splitting it into two parts. So one is the impact of the microbiome locally in the gut and how that could have an impact. And the other one is how the microbiome could actually maybe have a direct impact on brain pathology or brain function in PD when it comes to the local impact. 

So there is several studies that suggest that there is a low grade inflammatory state in the gut of Parkinson's patients. So you can measure that from biopsies. You can measure cytokine levels. You can measure calprotectin from stool, for example.

it's not huge changes, but it is a consistent finding of a slight elevation of inflammatory markers. At the same time, several studies suggest that alpha synuclein could play a role also with relations to the immune system. So there is, for example, one study that looked at recipients of gut transplants and found that children, because of their transplant they get regular biopsies to rule out rejection. [00:22:00] And so some of these kids got neurovirus infection during that, follow up period and recovered from that. And what they found was that during that period when they were infected with Neurovirus that there was a high increase of the expression of alpha synuclein in the enteric nervous system.

And that alpha synuclein persisted for several months after the infection was already resolved. They found evidence that alpha synuclein could have a chemoattractant properties for innate immune cells. So that is I think, a very interesting link between inflammation and alpha synuclein.

So there could be a link here, in the sense that this low-grade inflammatory environment could, predispose to a higher expression, for example of alpha synuclein and maybe we know less about that I guess, but maybe also predispose to confirmational changes and induced the seeding activity potentially.

But that is quite speculative. Let's say when it comes to androgynous alpha synuclein. What has been shown from other researchers is that bacteria themselves, so certain bacteria, for example, E. Coli can produce [00:23:00] proteins that can have amyloid like properties. So for example, curli is name of one of these proteins and they use these proteins for biofilm formation. So to protect the bacterial community from outside attacks basically. And apparently these proteins, they have similarities to aggregation prone human proteins such as alpha synuclein or tau. And there is evidence from animal models and also in vitro evidence that these curli proteins may show seeding activity and may basically induce a pathological change in alpha synuclein that makes it behave like a prion or showing this seeding activity. So it has been called cross seeding. So basically from one species to another to see the cross seeding of proteins.

And so that is another hypothetical pathway, that could induce this type of pathology. Another one is actually overall immune regulation. But that's probably the best established, let's say impact of the microbiome [00:24:00] across the board is the impact on the immune system.

So the microbiome has a huge potential to up or down-regulate inflammatory activity. And then also that is not only locally in the gut, but it's a systemic effect. And it all that reaches actually up to the brain with impact on microglia and astrocytes as well. So basically the microbiota can produce metabolites that interact with gene expression regulators that can then regulate the activity of innate immune cells. And so that has been shown in several animal studies. And I think that is also one of the, let's say pathways where we may see a direct impact from the gut microbiota to the brain. And then obviously we're talking about metabolites vast proportion of the metabolites that circulate in our blood are actually of microbial origin.

So there is a big potential of metabolic interactions. Yeah, I think those are probably [00:25:00] the short list that I would say the mechanisms that the field is currently mostly interested in.

[00:25:05] Dr. Sara Schaefer: So one big question clearly when we think about all of this is whether altering the gut microbiome could alter the course of Parkinson's or even prevent Parkinson's. What has already been explored in an attempt to modify the gut microbiome in patients or animals, animal studies, or alter the effect of the gut microbiome on brain pathology or brain function.

[00:25:29] Dr. Filip Scheperjans: Yeah, so obviously most of the evidence is from preclinical animal models. And so a lot has been done in that respect. But obviously before we evaluated these results. We need to consider is there some publication bias involved and so on.

So we need to be careful and obviously, the chronic problem of translating animal research to human PD. However, the most influential and most cited study obviously came from Timothy Sampson and from Mazmanian Lab 2014. So basically showing that in an alpha synuclein [00:26:00] overexpressing mouse model when you generate a germ-free version of that model, so that doesn't have any exposure to bacteria, that those mice basically develop lot less alpha synuclein pathology, a lot less parkinsonian symptoms, less neuroinflammation. And so when you reintroduce that microbiota, then you see the pathology starting and see there's motor symptoms coming and so on. So basically that provided like proof of concept that in that animal model, by manipulating the microbiome, you can have an impact on Parkinson's pathology and other pathways that are linked to PD.

Since that there has been many studies that have exposed mice to probiotics or short chain fatty acids. Also fecal microbiota transplantation. So where you basically take the whole microbiota from a portion of feces and transfer it from one individual to another.

Those have been done. And well there have been encouraging results from these animal models. But it's difficult still, I think to [00:27:00] say what exactly is the impact? Because the interventions have been very different. The models have been different.

And I don't think that there is too much work being done with respect to what the mechanisms are. So I think, again, probably most evidence for short chain fatty acids, but in particular maybe butyrate that, has been able to induce beneficial effects, without actually manipulating the microbiota.

So basically suggesting that at least butyrate, could be one of these mediators or it's not that easy, the Samson study that I referred to before, their results suggested that short chain fatty acids could actually be deleterious. That could accelerate the pathology. So in that sense, the paper is standing still a bit alone and it has been discussed what the reason for that could be. Maybe it's related to the concentrations of different short-term fatty acids that were used. I mean, when it comes to human studies, I think we have consistently seen a decrease of short-term fatty acids and in human PD.

So that fits better to the evidence of supplementation [00:28:00] being beneficial. In terms of human studies. Well, there is quite some trials on probiotics for the treatment of constipation in PD. There is even a meta-analysis about it. So based on that, it seems that, let's say traditional probiotics which is a rather broad term because the probiotics that were used differ between studies, but basically meaning for the most part lactobacillus and or bifido bacteria in different combinations. May have a beneficial effect on constipation.

So increasing the amount of bowel movements per week versus placebo. And those were quite high quality studies. There are some studies on helicobacter pylori. So helicobacter has been linked to a worse motor state in Parkinson's patients and worse motor fluctuations. As with speculation as that is related to the inflammation in the gut, that could impair, for example, levodopa absorption.

We don't really know. And there had been promising small studies about eradication [00:29:00] of Helicobacter that showed a positive impact on time and motor fluctuations. However, the last study that I saw, which was actually the biggest study, really nicely done, that didn't show an impact.

So far we don't have really any strong evidence that Helicobacter eradication is beneficial in terms of motor symptom management. However, obviously we know that there is a higher prevalence of helicobacter in Parkinson's patients and helicobacters is a risk factor for gastric cancer.

So I think still that screening helicobacter and Parkinson's is probably a good idea and it should be eradicated when it's detected. So finally then coming to fecal microbiota transplantations. And so there has been publications on that in humans to my knowledge, two from China and one from Israel.

However, only small uncontrolled case series. And those showed a very profound impact on motor symptoms and also non-motor symptoms. But that is really something that we need to take very cautiously because those studies were open label and uncontrolled. So we are currently [00:30:00] actually finalizing an analysis of our fecal microbiota transplant study from Finland. So that has been a placebo controlled, double blind study in 44 Parkinson's patients. And so we hope to have an abstract and poster at the WPC in July. So stay tuned for the results from that trial.

[00:30:22] Dr. Sara Schaefer: Great. So. You had talked earlier in the theories portion about inflammation in Parkinson's, and you talked about a lot of possible interventions to changing the gut microbiome and its effect on the brain, but in the inflammatory side of things, we know that inflammatory bowel disease patients are at higher risk for Parkinson's disease, and although there are common genetic factors at play, there's also the interesting observation that those on TNF alpha inhibitors reduce the risk significantly.

Do you think that the gut microbiome is part of what we're seeing here? 

[00:30:57] Dr. Filip Scheperjans: Thanks for the question. Yeah, it is an interesting [00:31:00] connection. So I think it is determined by, microbiota host interactions. So let's say in general, when we're talking about the impact of the microbiome, it is not only the microbiome, but it is also how the host reacts to the microbiome.

 And that's the same with Parkinson's. We think that for Parkinson's , you need, let's say a certain genetic vulnerability and then environmental factors that basically together are the perfect storm to bring you Parkinson's. So this is the dynamics that we need to take into account here.

So, it's an intriguing finding that in those large studies, epidemiological studies, that found these links that treatment with biologicals was able, or let's say in the group that received that treatment that the risk of PD didn't seem to be increased.

And to my understanding, that has sparked new interest in looking at these TNF alpha inhibitors also in the context of PD. So, I think again, it boils down to is it one treatment or one finding across all patients, or do we just probably need to do a better job in identifying the patients or [00:32:00] trying to map the pathways and alterations and abnormalities that are relevant for the individual patients. So I think it is a very intriguing finding. But I would hope that when this is taken further in terms of clinical trials, that there will be attempts to enrich these trials with patients that, are the most likely to benefit based on certain biomarkers.

But when it comes to that connection between inflammatory bowel disease and PD we have an interesting finding that's related to epigenetics in that context. So we work together with, colleagues from the Van Andel Institute and they looked at epigenetics in our Helsinki cohort.

And what we found was that first of all, epigenetic loci, so the DNA methylation loci that were linked to butyrate levels in those patients, those had a very high correlation with GWAS loci that are linked not only to Parkinson's, but also to inflammatory bowel disease.

Butyrate is a strong epigenetic modifier. And so those results that [00:33:00] we got are obviously preliminary, but could point to a role of the microbiota and butyrate that is produced by the microbiota. Potentially in a way that the butyrate impacts the function of innate immune cells.

So we found also that the epigenetic changes were most pronounced in innate immune cells. And seeing that those patterns do not only map to loci that have been implicated in PD. But also strongly mapped to low side, have implicated in irritable bowel in inflammatory bowel disease.

That is obviously an intriguing finding that could place the microbiome as a link between these diseases. And those links were much stronger, for example as compared to when you map that to GWAS of Alzheimer's disease, so much less correlation with Alzheimer's disease genetics but much stronger links to PD and inflammatory bowel disease.

[00:33:54] Dr. Sara Schaefer: Fascinating, well we certainly don't know everything about this topic, but if you had [00:34:00] a crystal ball, how do you think that analyzing and managing the gut microbiome will be incorporated into the practice of movement disorders in the future?

[00:34:09] Dr. Filip Scheperjans: Well that is obviously a difficult question. So let's talk with the crystal ball. So I think one of the most important Let's say changes of our understanding or what we realized in recent years is that we cannot think as PD anymore as one disease, but we need to take into account that the contribution of genetic and environmental factors and the pathways that lead to Parkinson's disease are different between different patients and that must have an impact on how patients react or benefit from new treatments. So I would think that the field has universally accepted the fact that we need more biomarkers that allow us to stratify Parkinson's patients so that we can use these stratas, these subgroups of Parkinson's patients, study them [00:35:00] further. And try to come up with better treatments and hopefully disease modifying treatments for those specific subgroups. And I think one thing that I would definitely hope to see is that the microbiome and related omics, let's say broach the immune system and metabolomics, for example, would become part of this work so that the microbiota and its function and its interactions with the host are being seen as one of these factors that can be used and should be used to stratify our patients and to get better and more successful at getting these new disease modifying treatments to work So that's what I would hope to see it as a phenotype marker of the disease.

Then when it comes to treatment, yes I think we have reason to hope and believe that if we are successful in identifying the patients that have a significant contribution of the microbiome to their pathology for example, by regulating [00:36:00] neuroinflammation then there is good reasons to believe that by manipulating the microbiome we could have an impact on that disease process.

And hopefully also in neuroinflammation more generally. But so far we don't really exactly know how that would be done. And as I said, we still need to become better at understanding these interactions. And it may be that it is not that relevant for all Parkinson patients, but it could be very relevant for a significant subgroup of patients.

And in particular, when we're thinking along the lines of body first, brain first subgroups, and there may be even more subgroups and I think it is actually quite likely that there is a subgroup of patients where the microbiome has a significant impact on the disease and that could benefit from microbiota targeting treatments.

[00:36:46] Dr. Sara Schaefer: Precision medicine, everything's moving that way. 

[00:36:50] Dr. Filip Scheperjans: Exactly. 

[00:36:50] Dr. Sara Schaefer: Thank you so much for this comprehensive review of this very complicated topic. I really appreciate you taking the time.

[00:36:58] Dr. Filip Scheperjans: Thank you very much. It has [00:37:00] been a pleasure.