Expert Briefing: Parkinson's and the Gut-Brain Connection

Dr. James Beck 00:00:00
Hello everyone, and welcome to our Expert Briefings. I'm Dr. James Beck, Chief Scientific Officer of the Parkinson's Foundation. Our expert briefing today will be centered around Parkinson's disease and how the gut is connected to the brain. While stomach or intestinal distress can lead to anxiety or depression, gut-brain connections go much further. New research strongly suggests a link between the gastrointestinal system and Parkinson's disease. Today, we will learn a lot more about the gut's potential impact on symptoms and progression.

Before we begin with the formal briefing, let me share a little bit about the Parkinson's Foundation. The Parkinson's Foundation is a nonprofit focused on bettering the lives of those living with Parkinson's through improving care and advancing research.

Importantly, everything we do is done in close concert with our community to ensure that our actions are aligned with the needs and priorities of those living with Parkinson's disease. We're focused on improving care for those living with PD, advancing research toward a cure, and empowering our global community. Today's briefing is an example of just how we reach our goals.

Before we do that, I want to highlight what's going to happen next Wednesday, on October 18. We're hosting a special program designed for people living with Parkinson's who have not shared their diagnosis publicly. As we all know, this is an issue, and we'll highlight the challenges many people face when deciding how and when to share their diagnosis. You can learn more about this webinar at our website, www.Parkinson.org/PDHealth.

As our next step, what I would like to do is get a chance to know who's on the call today. We've got a lot of people today, and there's a poll that just appeared. Go ahead and select whether you're a person with Parkinson's, a scientist or researcher, someone else who's joined, or you have a friend or family member with Parkinson's disease. This is really helpful for us to get a sense of who our audience is today and also for our speaker, so they can have a sense of who's on the call and make adjustments to their presentation. Let's give a few more seconds, and then we'll see what the poll comes back as. Great.

Not surprisingly, a lot of people here have Parkinson's, and a lot are partners of those living with PD. A fair number of healthcare professionals too, which is great, and scientists and researchers. I think we're going to have a great talk today that will cover a lot of ground and have something for everybody.

For your convenience, I want to highlight that we are recording this episode. If you've missed this or you need to step away, or you have friends and family members you think could really benefit from watching this episode of Expert Briefings, know that it will be made available at our website, and we'll also be emailing a link of the recording and other resources related to today's topic to all those who registered for today's briefing.

Dr. James Beck 00:02:52
Now I'd like to go on and introduce our expert presenter, Dr. Carley Rusch. Dr. Rusch recently became a medical science liaison in medical affairs research at Abbott Nutrition and specialized in adult therapeutics. Before that transition, she was an instructor in nutritional sciences and a neurology dietitian at UF, University of Florida Health, Norman Fixel Institute for Neurologic Diseases, for many years. Dr. Rusch completed her master's degree in food science and human nutrition and completed her dietetic internship at the University of Florida. During her training, she was involved in research studies on a number of topics, including gastrointestinal dysfunction, inflammation, pre- and probiotics, and the gut microbiome.

Dr. Rusch earned her PhD in Nutritional Sciences, also at the University of Florida, where her research investigated the effect of the Mediterranean diet on improving constipation and intestinal inflammation in Parkinson's disease. Dr. Rusch's work appears in numerous peer-reviewed journals, and she has been invited to present her research on nutrition-related topics at both state and national conferences. Her clinical experience spans a variety of disease states, such as cancer, gastrointestinal and neurologic disorders, malnutrition, and critical care. Dr. Rusch, it's a real pleasure to have you, and thank you for sharing your time and knowledge with us today.

Dr. Carley Rusch 00:03:59
Perfect. Thank you, Doctor.

I am really honored to be invited as a guest speaker for the Parkinson's Foundation for these Expert Briefings. I've had a long relationship now, I think, with the Parkinson's Foundation doing some more local work and speaking, so again, I'm really honored to be invited to chat with everyone here today. Just taking a look at the number of people that we have so far, we're up to 850 people and growing. This is amazing. Welcome.

Before beginning, I just have a couple disclosures that I do want to share. As you heard, I am now an employee within Medical Affairs and Research at Abbott Nutrition. While the program today is not intended for any individual medical advice or continuing education for healthcare professionals, I hope that you will find that it is an evidence-based review of the literature on this topic.

Here are my objectives for today. We're going to talk a little bit more about how the gut microbiome is altered in someone with Parkinson's disease and discuss the role of the gut-brain axis and how diet may impact Parkinson's symptoms and gut health too.

Before beginning, I just wanted to share very briefly with you a little bit of my background in Parkinson's. It was approximately almost five years ago now that I was invited to join the Norman Fixel Institute for Neurological Diseases at the University of Florida. I've done a number of work with them, partnering with their Parkinson's Foundation Symposium that was locally held in Gainesville, Florida. I saw numerous patients in our outpatient clinic that you see there with my photo in the middle. Maybe some of my former patients and caregivers are here on the line, and maybe some clinicians that I've worked with in the past too.

Then, of course, like I mentioned earlier, I have given multiple talks for the Parkinson's Foundation on diet and Parkinson's disease.

Dr. Carley Rusch 00:06:02
Let's talk a little bit about the gut microbiome and the gut-brain axis. I will preface my talk today: I know there are a lot of people with Parkinson's and care partners on the line, and we also have a really great number of healthcare professionals and researchers too. What I do want to say is that the content of the program today is probably going to be a little more on the technical side, but with my experience with people with Parkinson's and their care partners, you guys are all very smart individuals and a very smart group of people. I hope my job today really takes a complex topic with a lot of nuance and simplifies it down together.

All right. Now, before diving into the meat and potatoes of my talk today, I want to start off by sharing this image. This is a cross-sectional image of the colon in a humanized mouse model. The blue fluorescent color is a stain that shows both food and tissue. The yellow represents the mucus in the colon, and purple is going to be the bacteria. This paper was published in 2017 in the Proceedings of the National Academy of Sciences, and it was an important paper because it captured the structure and relationships between bacterial microbes and their host.

These relationships are significant because we know our resident bacteria are more abundant than even our human cells too. The genetic capability of our resident bacteria is enormous. Even though I'm showing you an image highlighting bacterial microbiota, we're beginning to learn even more about other members that reside in the microbial community, such as fungi, which we call the mycobiome, and viruses too.

What I really enjoy about this image is, when you magnify it a little bit further, you can really appreciate the ability of our bacteria to break down food from the diet that I have on the photo here on the right.

What is the microbiome? I always love to start this conversation off by just giving some definitions because we use a lot of these terms interchangeably, so I think it's really important to set some groundwork too. The microbiome, when we hear that, is referring to the totality of microorganisms and their collective genetic material present in the intestinal tract. We know that the microbiome can really span from the mouth all the way down to the colon. The gut microbiota are microorganisms of the intestinal tract, and these could be bacteria, viruses, fungi, and even protists too.

Dr. Carley Rusch 00:08:50
When we think about the gut microbiome, we often think about the colon, right? That's because we have the greatest density and diversity of bacteria in particular located in the colon. For the purposes of today's presentation, I'm going to primarily focus on the microbiota composition and metabolism that's located within the colon, but certainly, especially within Parkinson's disease, there are some papers out there that do refer to the microbiome in the oral cavity too.

What is a healthy microbiome? We might want to first consider that too when we're talking about this type of topic. It's really something that researchers have debated and really struggled to specifically define, even someone like myself. However, it's generally accepted that a healthy microbiome is a diverse one. We see lower diversity associated with different disease populations. We can measure diversity within individuals called alpha diversity by measuring the number of species present, called richness.

This figure that I have here on the left shows richness of samples from people with IBD, including ulcerative colitis and Crohn's disease, compared to healthy controls. You can see that blue line, that as we sequence more bacteria, people without irritable bowel disease have a higher number of species present than those with ulcerative colitis or Crohn's. When we quantify this, you can see that there is a trend toward lower diversity in people with Crohn's compared to healthy controls, which I have in that little shadow box here at the top left. We can also show diversity in a 3D space too and compare diversity between different populations. This is known as beta diversity.

Each dot that you see here on the right is an individual, and the closer those dots converge, the more similar they are to each other. You can see in this figure how similarities between healthy controls without irritable bowel disease group together in that red shaded area, and how diversity changes or becomes less similar from one another with active or inactive irritable bowel disease. Diversity isn't only affected by specific disease states like Parkinson's disease; it's also influenced by other factors like diet and lifestyle too.

Dr. Carley Rusch 00:11:18
When it comes to our gut microbiota, we know that there are several different inputs or factors that shape our microbiome. These factors are stress, whether intentional like physical activity or unintentional such as metabolic or psychological stressors. Pharmaceuticals such as antibiotics, we classically know, will shape or even remove some of our microbes. We understand that diet is important, which we will discuss a little bit more later. Some other additional factors to consider are geography of the host or the person and potential pollutants in the environment. I know that's still talked about very frequently within the Parkinson's community. Even other lifestyle stages can contribute to individual variability. As we age over time, our microbiome may also change too.

We know that the gut microbiota can produce signaling metabolites such as short-chain fatty acids. These short-chain fatty acids can be broken down by bacteria to produce acetate, propionate, and butyrate. We'll talk a little bit more about those short-chain fatty acids later.

These bacteria can also produce inflammatory molecules such as lipopolysaccharide, or endotoxin. They can even deconjugate some of those bile acids and influence cholesterol metabolism, and even produce other nitrogenous metabolites like TMAO, which you may hear a lot about within the cardiovascular disease realm. All of these signaling metabolites can communicate and influence not only the GI tract and immune system, but also the liver, the adipose tissue, the brain, of course, which we're going to highlight a lot today, the cardiovascular system, lungs, and even the skeletal muscle too, we're learning more about.

There is so much interest that has developed in specifically human nutrition and the microbiome. You can see on this graph here, I have a number of published studies that's growing exponentially each year.

Documented studies have really been described as early as actually the 1400s on the benefits of bacteria in yogurt, for example, for treating diarrhea. But we had this inflection point that occurred in the early 2000s with the development of high-throughput sequencing, in which we could take someone's stool sample and identify thousands of bacterial DNA present. What was exciting for me personally is that I actually began my research career in the microbiome during this bloom of current studies that were coming out. It's really exciting to see how far we've come in even the last decade too.

Dr. Carley Rusch 00:14:00
What I thought was really fascinating, and what I can kind of compare on this graph, is when we actually look at the number of published studies on Parkinson's and the microbiome, we're truly only in the infancy of our understanding. But what have we learned, right?

How this came about was we started to notice that there was pathology occurring along the GI tract in people with Parkinson's disease. We know people with Parkinson's have a progressive loss of dopamine neurons in that substantia nigra of the midbrain. It's estimated that between 60 to 70% of those neurons are lost when those motor symptoms appear. That's what they refer to as that motor stage.

The pathology that's found in the brain is an accumulation of Lewy bodies, so an aggregated alpha-synuclein, that are found in the neurons of people with Parkinson's. Now, there's a lot of debate when it comes to proteins in the neuroscience community like alpha-synuclein, but it has been postulated that this accumulation of alpha-synuclein may trigger loss of those dopaminergic neurons. We can also find these proteins in other neurodegenerative diseases, so they're not very specific.

What has got us thinking more about the gut as it relates to Parkinson's is that we have actually been able to find alpha-synuclein pathology all along the GI tract of someone with Parkinson's, whether that's the submandibular gland, the oropharyngeal region, the stomach even, the appendix, and of course, the colon too.

When we think about those non-motor symptoms of Parkinson's disease, I know probably one of the most common ones that I'm sure plenty of people with Parkinson's and those care partners who are here on the line experience daily is some type of gastrointestinal dysfunction. That's because it is fairly common in someone with Parkinson's. Whether that be dysphagia, it's estimated that up to 77% of people with Parkinson's have some type of dysphagia. Current treatments available, of course, would be speech therapy, surgical treatments if necessary, and then potentially even some dopaminergic medications too if it's indicated.

Dr. Carley Rusch 00:16:22
Gastroparesis, or delayed stomach emptying, is another one that's highly prevalent in about 70 to 90% of people with Parkinson's. Right now, most of the treatments that we have for gastroparesis involve dietary interventions, whether that's modifying fiber sources or fat, potentially using certain types of prokinetic agents if it's indicated, and other types of therapeutics too. Then, of course, which was the focus of my research, was constipation. Constipation may affect up to 70% of people with Parkinson's. Of course, we have current therapies like increasing fiber, fluids, and physical activity, as well as other therapeutics that are over the counter or prescribed, like laxatives, stool softeners, et cetera, too.

Shifting back to the microbiome, knowing that we have this gastrointestinal dysfunction that is highly common in people with Parkinson's, and knowing that alpha-synuclein pathology also can be found along the GI tract, a lot more researchers over the years have started actually sequencing the microbiome of different people with Parkinson's. This image that I have here is actually a systematic review that really looked at the number of studies and tried to find any trends of specific bacteria that were altered in people with Parkinson's.

What I will highlight is that beneficial or commensal bacteria, such as Prevotella, Faecalibacterium, and Roseburia too, are found to be reduced in people with Parkinson's when compared to someone without Parkinson's. These bacteria are important because they produce beneficial signaling metabolites like those short-chain fatty acids I mentioned earlier. We'll talk a little bit more about that later too. They've also found Parkinson's is associated with increases in other specific bacteria, like Bifidobacterium and Lactobacillus too, and these are actually known commensal microbes. It's suspected that these might be increased due to the high prevalence of constipation.

Dr. Carley Rusch 00:18:27
We also have increases in pathobionts like Bilophila and even Akkermansia too, which is an interesting one that I won't touch on too much right now that might be beneficial or not, depending on how abundant it is in the GI tract.

We've also had some studies published over the years looking at different markers for intestinal permeability and inflammation in someone with Parkinson's. On the left here, I have an image showing you measures of fecal zonulin. What zonulin is, is essentially a protein or a marker of intestinal permeability. We know that this marker is increased in GI inflammatory conditions like celiac disease, IBD, type 1, and even other autoimmune diseases.

You can see when we compare fecal zonulin in people with Parkinson's to controls, that is significantly elevated, indicating increased intestinal permeability. On the right here, I have calprotectin. This is another marker of intestinal inflammation. It's actually very highly sensitive but low specificity as a fecal marker for other irritable bowel diseases. But again, you can see in people with Parkinson's, calprotectin, and this is just one study, but there have been a couple others that have been published too, is significantly increased compared to those without Parkinson's, signaling some type of intestinal inflammation going on.

With our knowledge of these changes in the GI tract occurring in someone with Parkinson's, it's led to this early hypothesis about 20 years ago by Braak et al. that we call the Braak hypothesis. What Braak and his colleagues postulated was that the alpha-synuclein pathology may actually spread from the GI tract via the vagus nerve to the brain. This is just an image here showing that hypothesis too. There's still a number of researchers trying to investigate this hypothesis, but this is the origination of this gut-to-brain spread in someone with Parkinson's disease.

Dr. Carley Rusch 00:20:46
We do have some recent preclinical models that do suggest this type of gut-to-brain spread via the vagus nerve. This was a study that was published in Neuron, and it was a fabulous study. It's a very technical paper, so I'll do my best to simplify it down for you all. What they did was they injected mice with these exogenous preformed fibrils, or PFF, is how I'll refer to it, and the alpha-synuclein within the GI tract of mice.

What they aimed to do was measure the amount of that pathologic or aggregated alpha-synuclein accumulation in the brain. They saw that mice with intact vagus nerves accumulated that aggregated protein, that alpha-synuclein, in the brain, specifically in that substantia nigra region, and they did develop PD-like symptoms.

However, when these mice, when they actually performed a vagotomy to cut the actual vagal nerve and they injected with those preformed fibrils, the mice did not develop that pathologic alpha-synuclein or PD-like symptoms.

To prove that you actually need to have this endogenous alpha-synuclein to develop these PD-like symptoms, they actually did perform the same experiment in mice that didn't have a gene, which is the SNCA gene, to code for that endogenous alpha-synuclein. Ultimately, this study demonstrated that you do need aggregated Lewy bodies or that alpha-synuclein to develop PD-like symptoms, but it also established again that connection between that gut-brain axis and its development of Parkinson's disease.

This is just kind of a summary slide to put together this Braak hypothesis and the gut-brain axis. You can see here, it's postulated that we have maybe some environmental, genetic inputs that cause maybe some immune dysregulation and inflammation, leading to a reduction in beneficial microbes, those beneficial short-chain fatty acids, and an increase in those pro-inflammatory cytokines or signaling molecules, an increase in that LPS, zonulin, and calprotectin, as well as that increase in intestinal permeability.

Dr. Carley Rusch 00:23:07
This leads to potentially what we refer to as leaky gut, right, that you see here down at the bottom. That communication may spread from that enteric glia within the GI tract through the vagus nerve to that central nervous system in the brain for PD-like symptoms. This is just a theory, but this is to summarize this gut-to-brain axis spread in someone with Parkinson's. Particularly for me, as a dietitian by training, I've always been interested in how diet may modulate this mechanism. Can we utilize dietary interventions to increase those beneficial microbes, short-chain fatty acids, and decrease that inflammatory response?

We know that the influence of diet on low-grade inflammation and intestinal barrier function is becoming more relevant to our understanding of metabolic diseases. The gut barrier consists of beneficial microbes, the mucus layer, the intestinal epithelium, immune cells, and dendritic cells, which are those purple cells that you see here on the picture, are continually sampling the lumen of the GI tract to promote immune tolerance through proliferation of regulatory T cells and mediate pathogen evasion via secretory IgA.

We also have Paneth cells, which are that red cell that you see there, that can actually secrete antimicrobial peptides, or AMPs, in response to immune signaling induced by the gut microbiota. When we consume fibers and prebiotics that are added to the diet, we actually have conversion of those fibers to those short-chain fatty acids by the microbiota, which supports mucus production by the goblet cells, expression of tight junction proteins to hold those epithelial cells tightly together, and reduce inflammation.

We know that low-fiber diets are associated with a decrease in the mucus layer and reduced expression of tight junction proteins that promote intestinal permeability, leading to inflammation and further contributing to the development of metabolic diseases and potentially Parkinson's disease too.

Dr. Carley Rusch 00:25:27
Just to give you a little bit more information on short-chain fatty acids, like I mentioned, short-chain fatty acids are produced by the microbiota through fermentation of fibers or non-digestible carbohydrates. One of the short-chain fatty acids that I love to talk about and a lot of microbiome researchers are very interested in is butyrate. That's because butyrate is a major energy source for colonocytes. But despite this, it's actually the least abundant short-chain fatty acid produced by those intestinal microbes through fiber fermentation. We know that butyrate-producing microbes frequently rely on the cross-feeding of others, which I'll show a slide on a little bit later. Butyrate has the ability to influence immune function and even gene transcription too, so primarily this anti-inflammatory effect.

Recently, just last year actually, researchers have looked at the relationship of fecal butyrate and how it correlates in someone with Parkinson's. This study was a case-control study where they compared someone with Parkinson's and those without. They found that people with Parkinson's had significantly less fecal butyrate in their stool samples that you can see on the figure on the left. When they compared that butyrate to those MDS-UPDRS Part III scores, for those that aren't a movement disorder neurologist, these are going to be those motor symptom severity scores that our movement disorder neurologists are testing on visits.

You can see this inverse relationship. As butyrate decreases, motor symptom severity potentially increases too. But again, this is a correlation study, so our interpretation of this evidence is pretty limited and preliminary at this point right now.

Now we're going to shift gears in the presentation and really dive a little bit deeper on dietary interventions that can modulate the gut microbiome.

Dr. Carley Rusch 00:27:29
Bringing it back to this figure that I showed you earlier that describes those different inputs, as a dietitian, you can probably expect I've always been fascinated by how dietary interventions can modulate the microbiome to improve our overall health and quality of life. Initially, this interest definitely began with fiber, prebiotics, and probiotics, but it's now even expanding into others like synbiotics and postbiotics. We'll discuss a little bit more on that later. Again, with these inputs of diet like fiber, for example, that microbiota can ferment to produce those short-chain fatty acids like acetate, propionate, and butyrate.

When we look at how specific diet factors influence diversity, which I mentioned earlier is important for the microbiome, this was a recent study that actually further attempted to explain these factors that influence diversity using both stool and blood samples across thousands of people. This was over 3,400 people in this study. What I want to do, because I know this is a very nuanced and small slide, is when we blow this image up to show some of the beneficial factors on diversity of the microbiome, you can see in these green boxes here that higher consumption of plant foods such as fruits and vegetables are associated with higher microbial diversity. This is likely due to the high content of dietary fibers found within these foods.

When we look at our intake of fiber just as a population here in the U.S., you can see dietary fiber is actually frequently under-consumed here in the U.S. We compare intake of dietary fiber using this adequate intake that comes from the DRIs, and it's recommended that we should be consuming 14 grams of fiber per 1,000 calories. For example, if you are someone that consumes a 2,000-calorie diet, it would be recommended to get in about 28 grams of fiber in your diet. Where this information comes from is actually its benefits on cardiovascular health and outcomes too.

Dr. Carley Rusch 00:29:40
When we actually look at how fiber intake changes over different age groups, you can see overall most people are only consuming probably about 14 to 18 grams of fiber per day, or about eight to nine grams of fiber per 1,000 calories.

When we look at older adults, especially because a lot of our people with Parkinson's are over the ages of 60 and above, but even my young-onset Parkinson's too, you guys can see both of these intakes still not meeting those fiber recommendations. Again, we know that dietary fiber can aid in both GI health, but also providing that energy source for beneficial bacteria in the microbiome.

Dietary fibers, just to give a brief overview of that, are very known for their ability to promote laxation, right? We hear about it a lot when we think of constipation management. They can even decrease the rate of absorption of cholesterol and glucose from the diet too. Dietary fibers promote microbial diversity through fermentation.

Prebiotics such as fructooligosaccharides, galactooligosaccharides, and inulin are actually another class of fibers that are selectively utilized by host microorganisms to confer a health benefit. This benefit is usually due to increased abundance of beneficial bacteria, like Bifidobacterium, for example, that can lead to increases in those short-chain fatty acids, like acetate, propionate, and butyrate. These short-chain fatty acids can actually be used as an energy source for other microbes and colonocytes, and even modulate that immune function and colonic pH too.

Short-chain fatty acids can increase secretion of gut hormones like GLP-1 and PYY. These are peptides that are related to gastric emptying, appetite, satiety, and even glycemic control. Increased secretion of these peptides via short-chain fatty acids are also implicated as targets for treating other metabolic disorders too, like type 2 diabetes. I know there's a lot of work in this area as it relates to the gut-brain axis on how increases in these peptides may also impact appetite and satiety too.

Dr. Carley Rusch 00:31:58
Just to give you a brief, quick summary of how that fermentation occurs by the bacteria. We have this dietary fiber, which is that non-digestible carbohydrate that's seen in that green chain there. I have an example of different types of fiber that may be used. When that fermentation occurs, we have normally a primary fiber degrader, maybe it's Ruminococcus bromii, that can break down that fiber into smaller fiber units and even those short-chain fatty acids like acetate, propionate, and butyrate.

And then we also have cross-feeding by secondary fiber degraders. That could be, for example, Eubacterium hallii, which can further break down those smaller fiber fragments into short-chain fatty acids like butyrate that can work as a signaling molecule on the GI tract, the immune system and potentially the gut-brain axis too.

Moving on to talk a little bit more about prebiotic fibers, these are substrates, again, that are selectively utilized by host microorganisms to confer a health benefit. What I really want to point out is that not all fibers actually meet this definition. We have some foods that naturally contain prebiotics, like bananas, onions, garlic, chicory root, which is a source of inulin, artichokes and even beans too.

We know that prebiotics can also be added to food products in the form of GOS, FOS, oligofructose, chicory root or inulin. You might see this, for example, in different food products like fiber bars, or lately I've been seeing this a little bit more with protein shakes and other types of drinks too.

When we look at the recommendation for how much prebiotics we should be getting in our diet, we actually can look to the International Scientific Association for Probiotics and Prebiotics. This is an expert consensus working group of researchers in this area that came together to establish these definitions of what is considered a prebiotic, a probiotic, a synbiotic, et cetera. I have this figure here just to use as a reference to show you how prebiotics are different than dietary fibers and other fibers that aren't prebiotics too.

Shifting gears, I've spent some time discussing the prebiotic effect of fermentable fibers. However, we know that other compounds, like polyphenolic compounds and, for example, proanthocyanidins found in grapes or cranberries, can also be considered a prebiotic, and they're important for that intestinal barrier function of the GI tract. We have bacteria like Akkermansia muciniphila that resides in the mucus layer of the GI tract and is a potential biomarker for barrier integrity.

I will say that, especially within the neurological and Parkinson's disease world, Akkermansia can be a little bit more nuanced and complicated. We see people, for example, with obesity and diabetes actually have low counts of this microorganism, and it's associated with intestinal permeability. But it's interesting: we actually see the opposite in someone with Parkinson's, where they have this overabundance of Akkermansia in the GI tract. There's really more work to be done in this area, and maybe it's just a signal that there's this balance occurring.

We know that Akkermansia can metabolize those polyphenolic compounds down to other phenolic metabolites as well, and that can be reabsorbed back into the liver and enter systemic circulation too.

In the GI tract, they can also signal production of mucin by the goblet cells, which is used as that energy source for Akkermansia to bloom. An abundance of Akkermansia can have this bidirectional effect on stimulation of mucin secretion. To show what it looks like when Akkermansia is at work in the colon, this is just a cross-sectional image here of an obesogenic mouse model that was fed a standard chow diet, a high-fat, high-sugar diet or a high-fat, high-sugar diet with polyphenols.

You can see, at the same magnification, the mucosal thickness was drastically reduced with the high-fructose, high-sugar diet compared to controls. The thickness was normalized when supplemented with polyphenols, and it was associated with a bloom of Akkermansia. Again, these investigations really need to be further confirmed in humans, and their relevance to improving clinical outcomes, especially as it relates to someone with Parkinson's who actually might have some overabundance of Akkermansia, but that can also have some variability there too.

I definitely predict we're going to see a little bit more of Akkermansia and polyphenols even as therapeutic targets for different disease states, like people with Parkinson's.

Dr. Carley Rusch 00:37:10
Moving on to probiotics. You probably hear about probiotics very frequently. These are going to be those live microorganisms that, when administered in adequate amounts, can confer a health benefit to the host. But one of the things I always want to keep in mind, especially within the Parkinson's community, is that benefits of probiotics are going to be species- and even strain-specific. Not all probiotics are going to function the same way. They're not going to function the same way in everyone with Parkinson's, and they're definitely not going to function the same way between different individuals too.

When we think about the differences between probiotics and fermented foods, there's evidence for a health benefit, but that's not required for fermented foods. Examples of that would be yogurt, kefir, kimchi, even cheese and some breads too could be a fermented food, but not a probiotic. You might have also heard the term synbiotic, which is a combination of a probiotic and a prebiotic. One of the things to keep in mind is that there really isn't a general recommendation that exists for consumption of probiotics.

I do have this clinical guide that I'll reference here for you all. It's a website for probiotics in the U.S. I find it really helpful. I have the link here at the bottom where you can actually search the different types of probiotics that are available on the market in the U.S. and take a look at the strain and its potential application that's been found in research too.

When we think about diet for someone with Parkinson's, what I always am communicating right now is that we're not there yet as it relates to what's the best diet for someone with Parkinson's, but we are getting closer. The majority of research has focused on identifying risk factors for Parkinson's, and trials haven't actually shown strong results in humans unless you have a clinical deficiency. So a lot of the research, especially in Parkinson's, and for my scientists on the line, I'm going to challenge you all to think about this too: we've done a lot of research looking at single food components, but we know that we don't just individually eat one specific vitamin or protein, et cetera, each day. We eat a whole pattern of foods. You really want to consider this as we move the research forward too.

Just to briefly share with you some of the evidence that we do have right now in the literature as it relates to probiotics and someone with Parkinson's, this was a synbiotic drink that a research group out in Italy did back in 2016, showing that a synbiotic drink increased the number of complete bowel movements in someone with Parkinson's after six weeks.

These results were also similar in a multistrain probiotic that increased spontaneous bowel movements after four weeks in people with Parkinson's. This was, I believe, an Asian, maybe Japanese group that was published back in 2021.

One of the things about these studies that you really want to keep in mind is: what does the diet look like when you're adding the supplement? When we actually take a further look at this study, we find that average fiber intake at baseline, before intervening, was about 30 grams per day. When you think about someone in the U.S., we're consuming half of that too. So it's interesting to think how these results might actually differ here in the U.S.

We also have a new area of dietary interventions that can modulate our gut microbiota, which are called postbiotics. This is a new definition by ISAPP. It's basically a preparation of inanimate microorganisms that can confer a health benefit to the host. I know I'm getting short on time, so I'll just briefly review this. If you look at the figure here, at the top, it's the live and active form of a common probiotic, Lactobacillus rhamnosus GG. At the bottom, you can see it's an inactivated form.

There's been some evidence for efficacy of even postbiotics in treating conditions like infections and other disease states, like IBS and even COPD too. However, we do have some limited safety studies published in this area and really no regulatory guidance from the FDA in this category. But I anticipate you may see some new research down the line as it relates to postbiotics in the gut-brain axis even too.

Dr. Carley Rusch 00:41:41
Finally, we're going to end by talking about the Mediterranean diet. We know that the Mediterranean diet, and the health benefits it provides, includes antioxidants from plant foods that act as scavengers to help prevent or slow damage to our body cells. It also provides a high level of omega-3s from the fish and seafood in the diet that can influence brain health and function, and even dietary fiber from plant foods too.

There have been a number of different studies that have looked at the Mediterranean diet and how that changes microbial composition in healthy populations and some other disease states too. It's also been associated with higher levels of those beneficial short-chain fatty acids like butyrate, which I mentioned earlier.

When we think about how the Mediterranean diet might actually influence brain health, the PREDIMED trial is really that classic trial that demonstrates this. This was done in Spain and published in 2015. They took older adults, over 65 years, who were at high risk of heart disease and assigned them to either a Mediterranean diet with extra virgin olive oil, a Mediterranean diet with nuts or a healthy control diet, a low-fat diet. They actually intervened for four years, which is a very difficult thing to do in research. What they found was that a Mediterranean diet may slow age-related cognitive decline. This didn't matter whether you were supplementing with olive oil or nuts, but these tended to do better than that healthy low-fat diet group.

When we look at the Mediterranean diet's association with Parkinson's disease, we've had a couple studies showing that it's associated with lower risk of developing Parkinson's. For those in your family, this might be something to think about in terms of diet quality and risk of developing Parkinson's. Even prodromal symptoms too. That prodromal stage is going to be before that motor stage, where a Mediterranean diet is associated with fewer non-motor symptoms in that early phase.

Those flavonoids and flavonoid-rich foods that are found within the Mediterranean diet have also been associated with decreased mortality, or risk of death, in someone with Parkinson's as well.

Even a small study that we did here at the University of Florida found that a five-week Mediterranean diet altered some of those bacteria that we find are altered in someone with Parkinson's. For example, Roseburia and Bilophila here too.

When we put this all together, that brief take-home point is how this works: we really want to consume a diet rich in those plant foods, like a Mediterranean diet, or other prebiotics, fibers, et cetera, and really ensure that dietary fiber intake is between that 25 to 30 grams per day range to increase production of beneficial microbes and their byproducts, which are those short-chain fatty acids that can potentially modulate the gut-brain axis and brain health too.

In the future, we're definitely going to see this leverage of machine learning and AI, and precision nutrition for treatment of Parkinson's disease. In this old framework, we took a target population, gave them a dietary intervention, sequenced their stool samples, and we had lots of different heterogeneous outcomes. Where we're actually moving in the literature now is to a new framework of inputting the microbiome, metagenomics, diet, genetics and other clinical parameters into these machine learning models, in which we can use AI to predict and create precision nutrition strategies that will modify an individual's microbiome and further improve the response to a specific diet. This is definitely still in its infancy, but a decade ago, this model definitely seemed like a dream, and now it's actually becoming more of our reality. I'm really excited to see where this next decade of research in the gut-brain axis takes us.

In summary, we talked about how the gut microbiome and gut-brain axis are implicated in people with Parkinson's. Diet, like fiber, prebiotics, probiotics and even the Mediterranean diet, can shape the microbial diversity and metabolic capabilities of the microbiome. That response to the gut-brain axis is going to be host-specific. So we really need, and this is a callout to all the researchers who are listening in, those precision nutrition strategies to potentially differentiate responders to these dietary interventions as well.

With that, I am happy to take any questions that you all may have. Thank you again for your time.

Dr. James Beck 00:46:40
Thanks, Doctor. Gosh, I really appreciate that. That was an incredibly detailed presentation, and clearly the research in this area is evolving tremendously. Thanks for that tremendous overview. It seems like, given the technical nature of where we stand, how do we turn that into something that becomes really pragmatic for our listeners? I think one of the slides you showed began to get there. Part of it, and if I can summarize, it seems like a bottom line here is fiber. It's really something that people should be focusing on. We don't take enough of it. It greatly impacts our microbiome, and our microbiome, by giving off various chemicals, some good, some bad, certainly plays a role in gut health and then impacts brain health as a result of that. Is that a fair assessment?

Dr. Carley Rusch 00:47:34
Yes, it's definitely a fair assessment, Dr. Beck. When I was practicing as a dietitian in the clinic, I was always educating people to start with the basics. We're seeing the forest for the trees. I might have butchered that analogy a little bit. We really just want to go back to the basics of diet quality, which includes increasing fruits and vegetables, getting more dietary fiber in the diet and making some modifications from there. That's how we can really begin to customize and provide that individual nutrition strategy, because if we don't have the basics and that foundation set up, then it's really hard to supplement or determine what's going to be the right fit for someone with Parkinson's as it relates to the microbiome and the gut-brain axis.

Dr. James Beck 00:48:24
Fantastic. Let me just pause real quick and let our audience know to continue to submit questions using the Q&A icon below. If you're on Facebook, share your questions in the comments. My colleagues are organizing the questions as they come in, but a lot of them are coming in, so we're not able to respond to all of them as much as we would. Our Helpline is also a resource to answer questions that may not be answered and are still persistent as part of that.

Let me just kick off with some additional questions. I think we've established this brain-gut connection. It's both the physical one through the vagus nerve that may contribute to the development of Parkinson's disease, but it's also this less clear one, let's say through the circulatory system, where the impact of gut health, whether it be constipation or the microbiome itself, can have an impact.

A lot of people with Parkinson's are here on the line, and they're asking some questions. Let's just tackle a practical one as we think about gut health. People with Sinemet a lot of times experience nausea as a side effect of it. But is it all because of nausea? Can constipation lead to some of these issues? This gets to the idea again of when we talk about gut health and the microbiome, what can we do as part of that?

Dr. Carley Rusch 00:49:47
That's a wonderful question, definitely probably the number one question I always got when I was in clinic too, as it relates to taking Sinemet or that levodopa medication and how the influences of GI dysfunction impact it. I was first author on a review paper that was published earlier this year in npj Parkinson's Disease, which is a partner journal with the Parkinson's Foundation, that actually describes this interaction between GI dysfunction and levodopa. There are a few studies that have looked at the pharmacokinetics of when we take oral levodopa, and how GI dysfunction impacts those pharmacokinetics. Constipation certainly may impact the pharmacokinetics, reducing the efficacy of levodopa. Gastroparesis, or that slow gastric emptying, as well too.

For my providers who are listening in, and even my people with Parkinson's, when we think about when our levodopa isn't correctly working the way it should be, and we're not getting that good on-and-off time, oftentimes when we think about diet, we always think about the protein aspect because there are potential protein interactions with levodopa. One of the things I might want to challenge my healthcare providers and even people with Parkinson's and their caregivers is to think about the GI dysfunction and how that might also impact the pharmacokinetics of the medication too.

Dr. James Beck 00:51:11
Fantastic. Let me just say I'm going to post a link to your paper to my colleagues, and they can push it out. The great thing about npj Parkinson's Disease is it's an open access journal, so anyone listening can download it without a paywall as part of that process. Great stuff.

Thank you for that answer. Taking into account some of the things you were talking about today, butyrate and some of these short-chain fatty acids that are playing an important role, is the research suggesting that you take it exogenously, or is it better to spur one's microbiome to make more of it directly? Where are we headed with that?

Dr. Carley Rusch 00:51:47
That's a really great question. We definitely need more research on butyrate as it relates to how it can modulate, especially, the gut-brain axis. There are actual oral exogenous forms of butyrate on the market. I know, for example, I think tributyrin is one. The challenge with taking exogenous butyrate is that the taste is very terrible because it is a short-chain fatty acid. If anyone's tried exogenous ketones, for example, you might experience a similar flavor profile as well. It's just terrible.

That's been one challenge with oral butyrate. The other challenge is how to study it too. When we take exogenous butyrate, I mentioned that colonocytes are epithelial cells. They're constantly rapidly turning over and producing new ones. When we take something exogenously, whether that's by mouth or, actually, there are butyrate enemas that some studies have looked at, particularly in a critical care population, those enterocytes in the GI tract metabolize, I think the number is around 70% of that butyrate just for those enterocytes, and the remaining amount might get back into circulation.

It's really difficult to study how much of the butyrate that I gave you actually does end up in circulation. Usually you need a more sophisticated method, like radioactive labeling, to really investigate that type of mechanism too. That's why you've seen the literature really focus on these other interventions to increase butyrate production. So this indirect effect on the gut-brain axis, like fiber, prebiotics and probiotics too.

Dr. James Beck 00:53:34
Yeah, because it seems like you mentioned it as a food source for other bacteria in your gut, and they rely on it. It seems like it could be beneficial for that to help restore the microbiome. It leads to my next question. We talk about the microbiome. How stable is it? Using dietary fiber as an example, we're clearly not taking enough of it. If you take more of it, how long would it take to see a change? Then I guess the other point you bring home in your talk is that not all dietary fiber is the same. How do you do that? One of the things you mentioned is bananas, which, for a person with Parkinson's, is not exactly the fruit they reach for first because of the constipation factor.

Dr. Carley Rusch 00:54:20
Yeah, it's a really great question too. How to manage this? Actually, Dr. Beck, can you repeat the first part of the question because I think I'm blanking on it a little bit?

Dr. James Beck 00:54:33
I threw a lot in there, so no problem at all. How stable is the microbiome at all? It seems like, especially when we take probiotics, you're hoping to change, but I think, and this is my terrible analogy, if you have an unhealthy microbiome, it's like your yard covered with weeds. If you're taking probiotics, it's like throwing grass seed down. I still have weeds. What do I need to do? Clear house? Do you have to do that in order to really get probiotics to work? Do you need to take antibiotics in order to purge your gut and then start fresh? What are people thinking these days?

Dr. Carley Rusch 00:55:12
I really like that question. In terms of stability of the microbiome, our microbiome is very stable when we look at it over time. It can change in the short-term period. For example, if we give someone a short-term antibiotic or if we give someone a probiotic, we can see some short-term changes in that resident microbiota. But over time, especially as we come off the medication and there's some type of a washout period, now you're back in your normal environment, you're eating similar foods again, you tend to see that people tend to move back to their resident microbes.

When it comes to changing the microbiome, that's been one of the most difficult challenges that researchers have had. That's why particularly fiber can be a great strategy, because you're getting those broad-spectrum changes. Those fibers aren't specifically targeting one bacteria. They can be broken down by multiple types of bacteria that other bacteria that are resident to your microbiome can use for cross-feeding, et cetera.

When we give a probiotic, we're only increasing abundance of one bacteria in the community in the hopes that it creates a new niche and it takes residence in that microbiome. But often what we see is that when you take a probiotic, if you miss a couple of days, your microbiome kind of goes back to normal too. There have been some researchers who have been looking at whether we need to do maybe some short-term antibiotic treatment and then do a dietary intervention as well, whether that's a probiotic or another type of therapeutic too, and see how that changes the microbiome and whether that can create stability.

We're definitely in our infancy there. Even fecal transplants too. I know, in a lot of people with Parkinson's, there's been more interest in the community there, because again, you're changing someone's microbiome. But even with fecal transplants, you still may get some changes back to your original resident microbiota over time. The question becomes, do you need to do multiple fecal transplants? Again, definitely in its infancy. But I love the analogy that you made as it relates to the seed starter over the weeds, because you're right. That's a really good analogy for it too.

Dr. James Beck 00:57:45
Thanks. I think also about the fact that I could understand why it's hard to establish the change, because you really need to change the conditions for the bacteria to grow. You can take the probiotics, that's great, and unless something else fundamentally changes, then it may not help. Perhaps that could be fiber, because that really seems like a good food source for a lot of this stuff.

We talk about fiber, then, and I know we have just a few minutes left. How do you measure that on a practical level? You go out to eat, hopefully, and you're trying to have this, and not everything has labeling on it. How do you make these choices? Are there resources available, perhaps, that you could recommend as part of the process?

Dr. Carley Rusch 00:58:32
Yes. In general, your high-fiber foods are going to be plant foods: your fruits, your vegetables, beans, whole grains even too, and sometimes other types. Then you could also have additives as well.

If you don't have a label, those are going to be the things that I'm looking for to get more fiber in my diet. I'm going to be looking for plant foods. It's recommended by the USDA, MyPlate. You can actually go on to ChooseMyPlate.gov, where you can see more very simple nutrition education resources. What they recommend is actually using the plate method, filling half your plate with fruits and vegetables. That's one way, as a visual strategy, to get more fiber in the diet. Of course, if you do have labels available to you, you can take a look at labels as well.

It will actually have a daily value percentage next to that fiber. One of the questions is, well, how do I know if this is a high-fiber food? You can look to that daily value, and if it's over, I believe, 10%, it's considered a good source of fiber in the diet.

Dr. James Beck 00:59:47
Okay, awesome. Well, I think we've reached the end of our time. I appreciate all the questions that have come in as part of that. Again, thank you, Dr. Rusch, for offering your knowledge and time today and talking about the gut-brain connection. Big thanks to everyone who's joined us today. We again had a lot of questions and were not able to answer them all. If a question was not answered, please call our Helpline, 1-800-4PD-INFO.

I also want to highlight that we've completed a good chunk of our Expert Briefings today. We've got one left, and it's going to be one that's not to be missed on Wednesday, November 8. It's about hallucinations. This is something that people are concerned about, and some people have at various levels. I think it'll be a great one to register for and to learn about as part of that.

We are here for you as always. Our website, our Helpline via telephone or email, those are good ways to get in contact with us beyond questions regarding this gut-brain axis and other issues that you may be facing. But before you go, we're in the Zoom world, and it's just going to go to black when we end this webinar, but a survey will appear afterward, and we really want your input on this.

We use that survey to provide feedback to our speakers. We use those survey results to provide feedback on our program as a whole. So please just take a few minutes and complete that survey when it appears. Otherwise, we will look forward to speaking with you again come November. Take care.