Effects of a probiotic on Parkinson's disease symptoms

Dr. Valentina Leta is a movement disorders neurologist and researcher with a specific interest in gastrointestinal dysfunction in Parkinson's, and she currently works at the Instituto Neurologica Carlo Besta in Milan, Italy. And Dr. Ray Chaudhuri is the Director of Research and Clinical Trials at King's College Hospital, London in Dubai United Arab Emirates, as well as professor of King's Parkinson's Center of Excellence in Dubai, and professor at Dement Tech Neuroscience Clinical Academic Center in London.

We're going to be talking about [00:01:00] their recent article in the Movement Disorders Journal, Effects of Four Strain probiotic on Gut Microbiota, Inflammation and Symptoms in Parkinson's Disease. And this was a randomized clinical trial.

If our listeners have not done so already, I recommend that you go back to episode 111 of the MDS Podcast, which is a Hot Topic episode on the gut microbiome in Parkinson's disease.

And this relates very much to the conversation that we're gonna be having today. We'll start with you Ray. I just want you to let us know where the study came from. How was it conceptualized?

Dr. Kallol Ray Chaudhuri: Thank you, Sara, for having us on this podcast. Delighted to be here with Valentina. Yes. The work was actually initiated through the foresight and experience of a patient of mine who sadly has passed away recently, but had Parkinson's and had Parkinson's for many years.

And she had read about the gut and the [00:02:00] microbiota issues many years back and had asked me, whether or not she should try and use some probiotics works on the microbiota, and she'd found this particular probiotic and had been using it and came to me saying that since she's been taking this particular probiotic, she had felt much better in herself.

She's felt a lot of energy and specifically she said she was able to walk to my clinic for the first time which she hadn't been able to do before. It could be attributed to many things, but she directly attributed to this, to the power and the energy she had since she's been using symprove. And this was endorsed by her husband, who then, repeatedly asked me to see, why don't you do a trial? Why don't you do a trial? So that led me to then discuss this potential project with the makers of symprove, who I then approached and were very keen to put it through a rigorous clinical [00:03:00] trial. Which is how we arrived at the trial.

And of course, Valentina then led on the trial, which we then managed to get funding from independently to run the trial. So I think this is a real example when a patient based experience had led to the development of doubleblind placebo controlled international trial. And then subsequent data that we will discuss.

So the history is quite interesting that how patient experience could be very important for us to develop or even think about clinical trials of molecules or products that they might find beneficial.

Dr. Sara Schaefer: That's the ultimate goal, to end with the patient and I love that you're starting with the patient as well. Valentina, can you briefly take us through what's known about the body first subtype of Parkinson's, and the rationale for use of probiotics in this population.

What have animal and human studies demonstrated to date prior to your [00:04:00] study?

Dr. Valentina Leta: Thank you Sara, again for having us here. And yes you probably know that recently this news of typing classification has been proposed for Parkinson's disease. The body first versus the brain first Parkinson's disease. So in the brain first we hypothesized that the pathology might start the level of the central nervous system, the substantia nigra with the development of a Parkinsonism, and then the pathology might spread to the brainstem with the development of RBD and then to the peripheral nervous system with the other nonmotor symptoms such as orthostatic hypotension and constipation. While the body first Parkinson's disease, the pathology might start actually at the level of the peripheral nervous system early on with constipation and orthostatic hypotension as a prodromal feature and then spread to the brainstem with the locus [00:05:00] and having prodromal RBD and then affecting the substantia nigra with the development of a Parkinsonism. Now there are several limitations to this model mainly coming from postmortem studies. We can actually see these clinical phenotypes in our clinical practice.

There are some patient with a range of prodromal nonmotor features and some patients that they do not manifest any nonmotor symptoms prior to the development of the classic Parkinsonism. Now if we focus on the body first Parkinson's disease. Actually this subtype might have an early involvement of the gastrointestinal tract.

And we know that gastrointestinal dysfunction is quite common in patient with Parkinson's disease. Constipation, for instance, is one of the prodromal feature and a risk factor for the development of Parkinson's disease. [00:06:00] And this has set the ground for investigations of the gut microbiota in people with Parkinson. The gut microbiota is the pool of bacteria, fungi, viruses, protozoa, who live in our gastrointestinal tract, and they actually are quite important for human health. They can modulate metabolism, they can modulate the barrier function of the intestine. They can modulate inflammation, neurotransmission, and actually these aspects are also altered in Parkinson's disease.

Where we have a pro-inflammatory status, we know that is a multi neurotransmitter disorder affecting not only dopamine, but also serotonin, acetylcholine, and so on. And also we have the leaky gut condition. So a situation where we have an increase permeability of the intestinal mucosa. Now a variety of studies have looked [00:07:00] at the gut microbiota in patients with Parkinson's disease.

And essentially the common finding is a pro-inflammatory status where inflammation could trigger potentially alpha synuclein pathology. And among the variety of changes that have been replicated, there is the reduced abundance of short chain fatty acid producing bacteria. Short chain fatty acids are metabolites, which are beneficial because they r educe inflammation, and these are set the ground for the use of gut microbiota modulating interventions in Parkinson's disease, including probiotics. Which are defined by the WHOS live microorganism, which can provide a beneficial effect to the host.

Dr. Kallol Ray Chaudhuri: If I can just add one sentence to Valentina's conceptual points that the body first, brain first is [00:08:00] actually derived originally from the description by sour Beer etal in 2015. Where we were involved in that described three roots one was brainstem, one was limbic, another was the cognitive or neocortical.

And in fact, the body first embodies the limbic and the brainstem approach. And in fact, it's been described also via neurotransmitters, and Valentina and I, we both described a noradrenergic subtype, which overlaps with the body first hypotheses, but bottom line is that the gut is dysfunctional, as Valentina said. This particular project was aimed to see whether that could be addressed by using a non medicinal, probiotic compound, which penetrates the large bowel.

Dr. Sara Schaefer: And Ray, I wonder if you could expound a little bit on what has been shown in animals and humans regarding [00:09:00] probiotic use for Parkinson's or Parkinson's models.

Dr. Kallol Ray Chaudhuri: Yeah, so there's quite a lot of preclinical work actually showing, particularly in symprove, and Valentina can add to that as well, in rodent models showing that the, microbiota could be significantly enriched with certain protective sub bacteria population by using symprove. This has been shown in models for inflammatory bowel disorders and also for instance in in colitis group of disorder and probably in irritable bowel syndrome. And we have also published in collaboration with the preclinical group at the University College of London.

We published also the data that symprove itself in these rodent models had effect on enriching the gutmicrobiota and perhaps Valentina, do you want to speak a little bit more on that?

Dr. Valentina Leta: Yes, thank you Ray. Yes specifically [00:10:00] in relation to Parkinson's disease, we have reviewed the topic before setting up the study, and we know that from preclinical studies, the use of probiotics might have some neuroprotective properties in particular it has been shown that probiotics can increase neurotrophic factors, levels at the level of the central nervous system, but also dopaminergic neurons in the substantia nigra of animal models of Parkinson's disease.

They might have anti-inflammatory and antioxidant actions at the level of the central nervous system and also at systemic level. And finally, if we look at motor and nonmotor signs, probiotic use has been associated with improvement of motor agility and memory deficit among other nonmotor features in animal motor of Parkinson's.

However, [00:11:00] when it comes to clinical studies these findings have been only partly translated and in fact, at this moment in time, we have only level one evidence for the use of probiotics to manage constipation in people with Parkinson's disease.

Dr. Sara Schaefer: So taking all that we know so far how did you design your study and what outcomes did you look at? Valentina.

Dr. Valentina Leta: We decided to perform a randomized double blind placebo controlled trial investigating the effects of this specific four strain probiotic on gut microbiota composition on intestinal and systemic inflammatory markers and motor and nonmotor features of Parkinson's disease. We recruited the 74 patient with Parkinson's disease and constipation because we wanted to focus our study on patients [00:12:00] with a clear evidence of gastrointestinal involvement.

And the participants were allocated to the two groups, the active and the placebo group, and they were followed up for 12 months. So we had a baseline and a 12 week assessment, which was based on battery of validated scales and questionnaire for motor and nonmotor symptoms. We also collected stool and blood samples to perform, the analysis of these biological samples. And essentially we decided to focus the attention to the gut microbiota changes, which was our primary outcome. Then a secondary outcomes. We looked at changes in systemic and the external inflammation markers, and finally we wanted to explore the potential beneficial effects of this probiotic on motor and nonmotor symptoms, which represented our [00:13:00] exploratory outcomes.

Dr. Sara Schaefer: What did you find?

Dr. Valentina Leta: So first of all, we found that the two groups were very well balanced in terms of social demographics, clinical features, and gut microbiota diversity metrics. Which was very good because it means that the randomization was successful and the two groups were comparable. And focusing on the primary outcome measure.

We didn't observe any significant change between groups in terms of alpha and beta diverse metrics, which means that the intervention either didn't broadly change the gut microbiota of these individuals. Which is quite important because we didn't want to alter broadly this the gut microbiota composition, but a targeted intervention should change some taxa or function. So with the differential [00:14:00] abundant analysis, we identified that the active intervention, the probiotic, was associated with an increased abundance of some bacteria, which are quite known to have beneficial health related properties such as bacteria, Odoribacteraceae family, which is known to be associated with healthy aging.

Or for instance, Blautia faecicola, which is a short chain fatty acid producing bacteria, which is known to be reduced in patient with Parkinson's. So these were quite interesting results. And then looking at the secondary outcomes. We found a statistically significant decrease of the pro-inflammatory cytokine TNF-α and looking at the exploratory outcomes, there were some positive signals for reduction of the non-motor symptoms total burden, which we know it's quite strongly related to quality of life.

And this was [00:15:00] driven by improvement in constipation and fatigue, which was quite interesting to observe.

Dr. Sara Schaefer: So taking all of this data together, you gave me kind of a huge list of things that the probiotics are changing in this population. What do you think is actually happening pathophysiologically? What are the probiotics actually doing to help patients?

Dr. Valentina Leta: So I believe that the most reasonable explanation could be that by using probiotics we can improve constipation. So we can reduce this barrier to the transport and absorption of the gold standard treatment for Parkinson's disease, which is the oral levodopa. And so by absorbing better levodopa, we can have a reduction of the time to ON, which was also another finding that we did observe. So the time for the medication to kick on, to kick in and also of some nonmotor features that might be dopaminergic [00:16:00] response. Another possible explanation, which is a little bit more speculative, is that the probiotics could reduce intestinal inflammation by changing the gut microbiota, and this can result in a reduction of the systemic inflammation status, and these can finally lead to improvement of some nonmotor symptoms such as fatigue, which are known to be related to inflammation, partly at least. But this remains a little bit more speculative as an hypothesis.

Dr. Sara Schaefer: This all sounds very optimistic that there could be significant improvements, not just in non-motor symptoms, but even potentially in some motor symptoms in these patients. So are you running to your clinic and telling all of your patients to start probiotics or how do you think that this is translating into the clinical space at this time?

Dr. Kallol Ray Chaudhuri: I think this is now very much [00:17:00] personal, individualized prescribing trends in different physicians and healthcare professionals. In my own clinical practice, we have described and published on the the dashboard for Parkinson, which is some basic standards that needs to be met and improving gut health is one of them.

Addressing constipation, addressing levodopa absorption by reducing dairy intake with levodopa, et cetera. And I think the take home message from this trial and it's rigorously conducted, double-blind placebo controlled trial, is that it does seem that the four strain probiotic here appears to improve your time to ON.

So if that is the case, I often in dopa taking patients who are wearing OFF. I'm already asking them to take the probiotic, that additional advantage being at least here in the UK, probably in Europe and the US as well, that it is not a [00:18:00] medicinal compound. So you can have this without going to the rigor of prescribing for instance, many patients take supplements, many patients take vitamins, et cetera, and other probiotics from the general, supermarkets and so on. So the patients can use this particular probiotic. And given the data, it helps the time to ON which will have a clear motor implication. But in addition the improvement in non-motor aspects are very encouraging.

The constipation aspect of it, the fatigue aspect of it. And this very much goes back to the original patient's description. One of the key things she said to me before we talked about this trial is how once she was taking symprove, it has helped her fatigue, it had helped her general sense of wellbeing, which I think probably she was describing the fatigue.

So it's nice to see that's been reflected in the data that's come out of Valentina's study. [00:19:00] But also clinically, my view anyway, that it's a recommended product in the early stage or even the late stage of Parkinson's, whenever there is wearing OFF. No harm in giving it a try, particularly, it's also improving the gut health.

And as data shows also that there is the additional anti-inflammatory action, which seems very encouraging indeed with the cytokine data that we have.

Dr. Sara Schaefer: Anything that actually has data to support its use for fatigue in Parkinson's is a welcome addition to our regimens, right? 'cause that is just such a difficult thing to treat unless there's something else going on, like sleep apnea or low blood pressure. Once you rule out all that stuff, there's not a lot that we have in our toolbox.

It's great that this might be something to consider. Now, Ray, you keep mentioning that this is one particular type of four strain probiotic, but as we all know, there's a sea of probiotics out there, many [00:20:00] companies, many formulations, et cetera. Why was this particular probiotic chosen other than the fact that this patient presented to you that this was the one that she was on?

And how might you recommend a provider who treats Parkinson's patients or a person with Parkinson's kind of makes their way through the sea of probiotics that they have to select from?

Dr. Kallol Ray Chaudhuri: Excellent question, Sara. I think, important thing to realize here is that once the information was presented to us, both Valentina and I, we embarked on exactly as you said, looking at the evidence base that's already there. And we found that this particular four strain probiotic already had been used in other disorders, not necessarily neurological disorder, but in gut disorders. And also there is quite good evidence of this being used already in Clostridium difficile infections, where the difference with this particular [00:21:00] probiotic is that it has very good penetration into the large bowel and into the microbiota, which you don't seem to get with many other probiotics that have.

It may be that there might be some other probiotics which are able to do that, but we don't have the evidence base to support it. So the reason we've opted for improve for this particular probiotic is that we had evidence that of its efficacy in the Clostridium difficile group, we had its efficacy data from preclinical studies in inflammatory bowel disorders and also some preliminary patient based experience of Parkinson's patients saying that they feel better on it.

So that was the cumulative, a sort of force, if you will that sort of took us to this. Valentina, do you want to add to that?

Dr. Valentina Leta: Just to to say that the one of the most important challenges for a probiotic to work is really to survive the acid environment of the stomach. And there is an in vitro study [00:22:00] where essentially the researcher, they simulating the gastrointestinal tract with the acidity of the stomach, and this was one of the few probiotics able to survive the acid environment of the stomach with the strains of being alive essentially. So this is quite crucial. And also, let's not forget the preclinical evidence on the use of this specific probiotic in animal models of Parkinson's. This is that Ray previously mentioned. So there was a preclinical and clinical findings, which have led us to the selection of this specific four strain probiotic.

Dr. Sara Schaefer: That's so helpful. Valentina, you mentioned of course, that for this particular study you chose patients with constipation and Parkinson's disease. So clearly GI involvement. I wonder if you can tell us whether you think that there may be patients [00:23:00] outside of that narrow group that might benefit just because of anti-inflammatory things, or can we really assume that only patients with constipation have gut abnormalities in Parkinson's disease?

Dr. Valentina Leta: Thank you, Sara for raising this important point. There is evidence suggesting that even patient with Parkinson's without constipation might have some gastrointestinal abnormalities. They, their gut microbiota might be altered as well. So for sure even if constipation is not there, there might be some gut abnormalities.

However, we need to have further evidence to suggest the gut microbiota modulating intervention in this subgroup of patients because at this moment in time essentially we know that they might be beneficial for constipation. And there are some positive signals that we have mentioned.

The next step would be [00:24:00] essentially to set up larger clinical trials, looking at these specific motor and nonmotor features to confirm these exploratory findings, and maybe to be able to suggest probiotics to patients with fluctuations with delayed time to ON or with fatigue.

Now we need to confirm these exploratory findings.

Dr. Kallol Ray Chaudhuri: Yeah. In fact, we are in the process of doing so with Valentina and I, we are trying to put together now a open label, real life study across many centers around the world because we want to look at also different nationalities, different cultures, diet, different types of diet. How applicable is this data to perhaps Asian patients, to black African patients or et cetera, et cetera.

So we want to do a really large multiracial study just a tolerability study, but also perhaps addressing, as you pointed out, Sara, [00:25:00] fatigue. Which is such a problematic thing for us. People with Parkinson's, and also for us who are in the treatment sector. So we want to do something like that.

Dr. Sara Schaefer: Well, I really look forward to those next steps and next set of data. Do you have any concluding remarks either of you?

Dr. Valentina Leta: I believe that this is a area that needs to be further explored. There are. Some robust evidence suggesting that the gut microbiota plays a role in human health and diseases such as Parkinson's diseases. So it is crucially important to further explore the use of gut microbiota modulating intervention to clearly observe the potential impact of this interventions on motor and nonmotor symptoms of Parkinson's disease and to understand really what are the mechanisms underpinning these potential beneficial effects.

Dr. Kallol Ray Chaudhuri: I totally endorse that. But I would just also like to add that very [00:26:00] interestingly the Movement Disorder Society, as has a specific study group now on wellness in Parkinson, led by Idu Subramanian and her colleagues. And wellness of the key enablers of wellness is gut health in Parkinson's.

So we feel that this is a very significant step forward that by using a very easily available non medicinal, fairly safe product, which we use and most of us are very pro probiotic, if you will. Many of us are using gut health supplements even if you haven't got Parkinson's. So availability of such a product, which such good, evidence-based now level one evidence to support that is only a step forward towards the whole concept of wellness in Parkinson's in future.

And we very much hope that our further global study will further consolidate this data.

Dr. Sara Schaefer: That's wonderful. I didn't know [00:27:00] about that study group, but I feel like I wanna be on it. That holistic view of the patient and thinking about wellbeing. I love that viewpoint. Thank you both so much for joining us today and sharing these results with us.

Dr. Kallol Ray Chaudhuri: Thank you very much and thank you, Valentina for all your work.

Dr. Valentina Leta: Thank you, Ray, for your mentoring. [00:28:00]