Current microbiome research for Parkinson's disease • 2025 MDS Congress

And today I have the pleasure of interviewing Professor Paul Wilmes, a professor of systems ecology at the Luxembourg Center for Systems Biomedicine in Luxembourg. Paul gave a lecture on October 6th at the Congress on the microbiome gut brain axis in Parkinson's disease. So Paul, thank you for joining us on the podcast.

How are you enjoying the Congress so far?

Dr. Paul Wilmes: It's a pleasure Tiago. First of all, yes, I'm very much enjoying the Congress. So far, it's been very stimulating on a number of different levels. It's of course a beautiful location, but the science that I've been exposed to has been just remarkable.

Prof. Tiago Outeiro: Have you seen any interesting presentations that you would like to highlight?

Dr. Paul Wilmes: I thought that yesterday, the discussions over alpha [00:01:00] synuclein and its role in the pathogenesis was very interesting in the context also of having to consider other amyloid proteins. So that was something that I hadn't been exposed to in that in that way. And I thought that was very interesting.

And that is also important I think, in the context of guiding our own work on the gut microbiome in Parkinson's disease.

Prof. Tiago Outeiro: I'm very happy to hear that because of course, as I work a lot on this field of alpha synuclein, so I'm always happy to hear people are excited about the topic. And I know you work a lot on this as well. Can you tell our listeners what you covered in your presentation?

Dr. Paul Wilmes: Yeah, so in my presentation what I covered was basically from the initial studies that had been conducted on the gut microbiome in Parkinson's disease. All the way to the latest studies of which we've conducted a few to really look at what is functionally relevant in the context of the gut microbiome in Parkinson's disease.

So I basically initially elaborated also on [00:02:00] why one would want to look into the gut microbiome in Parkinson's disease. How might the enteric nervous system then be impacted by changes in the microbiome, for example, as we've touched on alpha-synuclein or other, for example, amyloid proteins that will be produced by the gut microbiome that can cross seeded alpha synuclein leading to its aggregation and then spreading up via the vagus nerve into the brain stem. So those are elements that I covered. And then I specifically also highlighted from, the earliest studies about a decade ago on the gut microbiome. What have we learned what are the common organisms to be found? As elevated in the context of Parkinson's disease, such as, for example akkermansia bacteria.

So there are quite a few common signatures that over the course of the last decade we've learned about. But then critically I think what is important is that one gets to the point of actually understanding what is, cause or consequence [00:03:00] of the disease, and specifically if there are pathogenic microbiomes especially in the context of Parkinson's disease.

So how can we actually identify what are causal molecules, pathogenic agents that would cause for example, the misfolding and aggregation of alpha synuclein. And so there we've conducted also a number of studies, where we've looked at also prodromal.

So Parkinson's disease, so idiopathic REM sleep behavior disorder. So what are changes vary early on. And in particular, what are functional differences and how may those then link to the actual disease? And so there we've seen interesting functional shifts especially in relation to glutamate biosynthesis as well as for example, in the expression of flagellins. So those are of course the constituents of flagella, of bacteria and they are highly immunogenic and we see very clear differences there. And so key question there is of course, whether those differences are then also tied to [00:04:00] intestinal inflammation and potentially neuroinflammation. Those are the main elements that I covered through the course of my presentation.

Prof. Tiago Outeiro: No, of course. 

It was amazing. I was there and I really enjoyed and I think it's such a fascinating field. And I wanted just to touch on something because we talk a lot about the gut microbiome, but of course we have other microbiomes as well, the mouth microbiome, the skin microbiome.

As a specialist, how do you see these other microbiomes as being possibly relevant also in the context of Parkinson's and even other diseases of course. But is this something you're, thinking about as well, or are you only focusing on the gut microbiome for now?

Dr. Paul Wilmes: We are very much interested also in other body habitats and the microbiomes that we find there we've worked for example, a lot on the oral microbiome and looking at transmission of specific microbial strains from the oral cavity into the large intestine. And, there have been epidemiological links of [00:05:00] course, for example in the context of oral health and then a whole panoply of chronic diseases, including neurodegenerative diseases and that might be also an important body habitat to look at. So we are considering that, of course we are also studying that we haven't not yet published on these topics, but we are in the process of testing hypothesis there as well.

So absolutely the other body habit habitats also very relevant. I know that there is also quite a lot of interest, for example, looking at organisms on the scalp for example, and whether there might be also there shifts in the microbiota. And so yeah, I think it is understandable that we've focused first and foremost on the gut because that's where we have the most microbial biomass.

But it is also clear that there are other body habitats that we have to look into. And then finally what we have in particular, very early on, what we had looked into is the nasal microbiome. Also [00:06:00] that together with Mollenhauer and what we had not seen, there were very conclusive shifts. So that was a little bit blurry, I would say, in terms of the results, there were no coherent signatures in stark contrast to the gut for Parkinson's disease. So this is certainly something that we're still interested in and pursuing, and is of course, highly relevant, not least in relation to, for example, the dual-hit hypothesis.

Prof. Tiago Outeiro: Yeah. And of course this is very relevant in the context of these diseases because of dietary habits. So could potentially be a way to also interfere with the microbiome and maybe gear it towards more beneficial microbiomes. Do you have any thoughts on this?

Dr. Paul Wilmes: Yeah, so I basically briefly touched on this also in the context of my presentation. What is interesting to observe is that we see organisms enriched in Parkinson's disease that are often associated with for example, diets that are low in fiber. So you [00:07:00] get enrichments in those organism. As they are actually feeding off other complex carbohydrates. And in that context, they are feeding off the outer mucus layer in the large intestine. And so those are, for example, akkermansia basically mostly akkermansia muciniphila. But there are a number of now, strains described within that species.

So you have enrichments in those in Parkinson's disease. You have also enrichments in other mucolytic organisms. And so diet indeed is a potentially compelling intervention. One could potentially advocate there for a high fiber diet. We also have there some work together with Brit that is currently under revision.

So I can't speak too much about it, but what we find there is that recalcitrant starch does appear to be beneficial. And then finally. We've also done some interventions, for example, with therapeutic fasting and also that seems to be beneficial in the context of Parkinson's disease, even leading to an improvement in motor symptoms.

There [00:08:00] are potential ways whereby via the microbiome we can potentially modulate disease symptoms. But of course there's much more work yet to be done there. And then finally also, of course, what has to be finally proven is that there are causal relationships between the microbiome and Parkinson's disease.

And if those are established, then that would lead to specific targets, how we can then manipulate the microbiome beyond dietary interventions. There are, for example, researchers that are harnessing CRISPR Cas, for example, to actually edit or engineer the microbiome. So those are very, early, I think in terms of the development, but they are very exciting.

I think prospects as to how we can modulate the microbiome. And in the case of Parkinson's, then hopefully leading to beneficial outcomes.

Prof. Tiago Outeiro: So there's a lot to look forward to in the future, but a lot of hope as well. 

And Paul, that's what we wanted to cover. Is there anything else you would [00:09:00] like to mention that we may have not covered?

Dr. Paul Wilmes: What I am specifically again interested in are possible pathogenic agents that are basically yeah, coming in essence from the microbiome, one particular area. That I am currently working on are actually small proteins produced by the microbiome of which the vast majority, according to our analysis, are actually immunogenic.

And this is opening up a whole new area that we are very excited about. And that obviously also is immediately tied to potential novel targets. Yeah, I'll have to say that. I'll keep you posted on developments there. Thank you very much Tiago. Again, it was really fantastic. to talk to you. 

Prof. Tiago Outeiro: Thank you Paul. It was a pleasure talking to you. And I invite all our listeners to go and look for your work. Beautiful work and I'm sure they will learn a lot and we will all learn a lot from you. So I hope you can join us again in future MDS meetings as well to tell us about your progress.

Dr. Paul Wilmes: I will be delighted to. Thank you.

Prof. Tiago Outeiro: Thank you. So [00:10:00] thank you all for listening. Join us in our upcoming podcasts. Bye for now.