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Alzheimer’s and the Gut-Brain Superhighway

Samantha Mulrooney: All right, hello, everybody. Thank you for joining us here tonight. Welcome to those of you here in the building and to those of you joining us online. This is our Crossroads of Ideas: “Alzheimer’s and the Gut-Brain Superhighway.” So, this is the second part of our three-part miniseries on the microbiome. My name is Sam Mulrooney. I am the outreach program manager for WID, Wisconsin Alumni Research Foundation. Sorry, oh, my gosh. Wisconsin Institute for Discovery and the director of the Wisconsin Science Festival.

The Crossroads of Ideas is a collaboration between the Wisconsin Institute for Discovery, the Morgridge Institute for Research, and the UW-Madison Strategic Communications. It’s an opportunity to foster dialogue between the community and UW-Madison researchers. The series addresses issues that matter to all of us and are also the subject of research at UW-Madison. Since 2014, Crossroads has been a staple of public programming offered at the Discovery Building on UW-Madison’s campus.

So, before I say a little bit more about this evening’s event, we’ll take a moment to acknowledge the land that we occupy here at the Discovery Building. The Wisconsin Institute for Discovery at UW-Madison acknowledges that it occupies the ancestral lands of the Ho-Chunk Nation, known as Dejope, which means four lakes. The Ho-Chunk have stewarded this land and its waterways, Mendota, Monona, Waubesa, and Kegonsa since time immemorial, maintaining deep cultural, economic, and spiritual ties. We honor their sovereignty and the shared strength of standing together with all First Nations of Wisconsin. Thank you.

So, tonight, we are here to continue the journey of this exciting three-part miniseries, like I mentioned, featuring the gut-brain superhighway and the complex interplay between gut microbes and brain health. So, we have two wonderful researchers here with us tonight to help us dig into this topic, Dr. Barb Bendlin and Dr. Federico Rey. They will each take a few minutes to talk about their work, and then we’ll finish with a shared conversation and time at the end for audience Q&A.

So, as a quick introduction to both of our presenters today, Dr. Bendlin is a faculty member in the Division of Geriatrics and Gerontology within the Department of Medicine. She is a member of the Wisconsin Alzheimer’s Institute’s Executive Committee and the Alzheimer’s Disease Research Center executive committee, leads the research education component in the Wisconsin Alzheimer’s Disease Research Center, and directs the UW-Madison Neuroscience and Public Policy Program. Dr. Bendlin is a recipient of the 2019 Distinguished Honors Faculty Award and is an associate editor of The Journal of Alzheimer’s Disease.

Dr. Federico Rey started his independent research program in bacteriology at UW-Madison in 2013. A major focus of his group is to understand how variations in the gut microbiome composition modulate the effects of diet and the host’s susceptibility to cardiometabolic and cognitive diseases. The contributions from his team are helping move the field from associations to causal relationships and shedding light on the mechanisms by which gut microbes modulate health.

So, with that, please welcome first to the stage Dr. Barb Bendlin.

[audience applauding]

Barbara Bendlin: Thank you, Samantha, and welcome, everyone. It’s wonderful to see some old friends in the audience and new friends as well. I’ll be talking today about some of our work in aging and Alzheimer’s disease.

But I wanted to start off by just talking a little bit about lie Metchnikoff, going back in history to the early 1900s. He was a Russian zoologist and is well-known for his pioneering work in immunology. So, he found an immune cell called a phagocyte, and he won the Nobel Prize in Physiology and Medicine for his discovery.

But what else is interesting about him is that he was interested in aging and longevity, and he noticed that there were some individuals in Eastern Europe who lived to be very old, who were centenarians, and he was curious about what factors led them to live to this old age. And he noticed that they ate a lot of fermented foods and that they were consuming yogurt. So, he himself started to, with his interest in microbes and interest in immune function, he started to eat a lot of fermented foods, sour milk, yogurt, and in fact, he had this theory that if you ate these microbial-rich foods that potentially, they crowd out toxins.

And he believed it to the extent that when there was a cholera epidemic, he actually consumed cholera to see what the effect would be on him. And he survived it. And he had this idea that the good bugs were potentially protecting people against bad bugs. And so, he was interested in longevity. He actually coined the term gerontology. And I just thought this was such an interesting story, because I’m also interested in aging and diseases that increase with aging. It’s kind of this idea between microbes and aging and immune function is really something that myself and my colleagues are interested in as well.

So, I study Alzheimer’s disease, and the key pathological features you see in Alzheimer’s, we’re looking at them here actually under the microscope in a human brain. So, on the left, we have beta amyloid plaques. And on the right, we have neurofibrillary tangles. We see these when somebody comes to autopsy who has Alzheimer’s dementia, but we can actually see these in living people as well using brain imaging. We can also use cerebrospinal fluid analysis. And, most recently, we can even find out if someone has these pathologies using a blood sample.

When we’re thinking about factors that contribute to aging, healthy aging, or risk for disease, we know that human genetics plays a role. However, there’s also another idea beyond just genomics, and that’s the idea of the exposome, or all of those exposures that we have over the course of our lives, from when we’re in utero until we’re in old age. And we know that those also have an impact on our health outcomes. In fact, even there’s been cases of identical twins who have the exact same genetics where one individual develops Alzheimer’s disease dementia, but the other person does not or develops it much later.

So, when we think about some of those factors, some of those exposures, those can include things like the environments that we live in, the jobs that we work at, perhaps how much sleep we’re getting, whether we smoke cigarettes, et cetera. So, there’s all these kinds of things that happen in our daily lives that can influence our risk for disease. And microbial exposures can be another one of those things that are part of the exposome. So, those could be viruses that we’re exposed to. For example, there’s quite a large literature on herpes simplex virus and whether that impacts the brain. The jury is still out on that, but also potentially Lyme disease or coronavirus. We do know that coronavirus, for example, impacts the brain.

Some of these other so-called lifestyle factors may also operate through the microbiome. So, for example, what we eat impacts the gut microbiome, or for individuals who work and are exposed to pesticides, that could deplete the healthy microbes in and on their body.

So, the microbiome, when we’re talking about the human microbiome, that’s all the microbes in and on our body. Most of them are in the gut. And sometimes we think about microbes as being pathogenic, but often they’re benign, and very often they’re also beneficial. And we know that in individuals with disease, they can be different. And we’ve been really interested in understanding whether microbes are different between people with and without Alzheimer’s disease.

So, about 10 years ago, I started working with my friend and colleague Federico Rey in bacteriology, and he had done some pioneering studies showing that the gut microbiome is not only different in disease states, but using animal models, he showed that certain microbes might even drive disease or health outcomes, and he was working in obesity and Type 2 diabetes. So, we started a project to see whether the gut microbiome was different in Alzheimer’s disease. And potentially, could we figure out what the mechanisms might be linking the gut and brain in neurodegenerative disease?

So, how do we do this? In Wisconsin, we have actually very wonderful research participants who join our studies, who undergo brain imaging so we can see if they have that pathological protein associated with Alzheimer’s disease. They undergo MRI, positron emission tomography, cognitive testing. Many of them undergo lumbar puncture. So, I’m showing you a participant here whose permission we have to show this. The reason why we take the cerebrospinal fluid is because it bathes the brain. And we can see proteins related to Alzheimer’s disease.

But perhaps their greatest contribution has been stool. So, in order to study the gut microbiome, we can actually look at stool, because everything that’s in the gut eventually comes out in the stool. So, we added this as a procedure so that we could look at the gut microbiome in people either with Alzheimer’s disease dementia or without Alzheimer’s disease dementia. We also had participants who were actually asymptomatic, but we knew if they had pathology in the brain based on their cerebrospinal fluid.

We were interested in abundance and diversity of gut microbes. So, if you think about a healthy ecosystem, there’s lots of different kinds of plants, compared to, like, a monoculture. So, we wanted to see how many different things there are and then also how much of different kinds of microbes were present.

When we looked at people with Alzheimer’s disease dementia, they had reduced diversity. So, not as many different kinds of microbes in the gut. Some of the microbes were elevated, but much more were reduced in Alzheimer’s disease dementia. And we, after we published these findings, a number of other studies actually confirmed our original observations of reduced diversity.

We also saw that the abundance of certain bacteria was associated with how much brain pathology people had, even among people who were asymptomatic, suggesting that there could be an early relationship between the gut and brain in dementia.

So, how do we potentially change the gut microbiome? So, there’s a number of different factors that shape our gut microbiome. Many of them shape our gut early in life. We’re, as scientists, interested in potentially harnessing ways to change the gut microbiome to improve health. And you’re gonna hear about some of those from my colleague, Dr. Rey. But, for example, diet has a large impact on the gut. We’re also interested potentially in probiotics. We might even explore microbial transplant to see if that can have a benefit for individuals, for their healthy aging and for their brain.

I did want to tell you a little bit, kind of to bring it back to Dr. Metchnikoff. There was a clinical trial that looked recently at supplementing diet with fermented foods. And so, in this clinical trial, the participants who had previously not been eating a lot of fermented foods started a diet with fermented foods, including yogurt, kombucha, brined vegetables, and kimchi, for example. And what the investigators found was that those individuals who ate more fermented foods actually had changes in their gut microbiome. So, they had increased diversity, and it appeared to positively impact their immune function.

What was interesting was, there wasn’t just more diversity because they were eating microbial-rich foods, but that eating the microbial-rich foods actually kind of made their intestines more hospitable to different kinds of microbes, suggesting that this could be potentially beneficial for health.

So, the takeaways are that gut microbiome is important for health. It’s been implicated in longevity, healthy aging. We do believe that it may play a role in Alzheimer’s disease dementia. But the caveat is that these are still early studies. We need more mechanistic studies, more clinical trials. And you’re gonna learn a little bit more from my colleague, Dr. Rey. And I’ll stop there. Thank you.

[audience applauding]

And I’ll welcome Dr. Rey to the stage.

Federico Rey: Thank you, Barb. Thanks for the invitation. And so, yes, I’m a microbiologist, and I’m interested in how the metabolism of bacteria influence disease and sort of what I’ll be telling you about, the work that we’re doing with regards to Alzheimer’s disease.

And so Barb did a great introduction to the gut microbiome. And there are a couple of aspects that I would like to sort of remind everybody. And one of those is that the genomes of the microbes that colonize our gut represent an enormous genetic repository that encode for functions that we did not have to evolve on our own and endowed us with capabilities, metabolic capabilities, for example, to digest fruits and vegetables and so on.

And that sort of metabolic capability has some features that are conserved among all of us. But there are also sort of quite a bit of variability among individuals in those capabilities in our microbiome. So, we have a unique set of microbes, each of us, in our gut. And the other sort of aspect that I wanted to mention is that sort of the idea of that the microbiome is quite plastic, so we can change, you know, through diet or through some other interventions, we can sort of change the composition of the gut microbiome. However, the up to date, we can make broad changes, but to make sort of precise changes of specific taxa, we’re not there quite yet.

And so the other aspect that I wanted to mention is that, even though we can, you know, we have the idea of the notion that we can change the microbiome through diet, most microbes that colonize us stay with us for very long periods of time. You know, the studies that are published today that look at up to eight years, but about 60% of the microbes that we detect today, we’re likely gonna see in sort of colonizing you eight years from now.

So, my lab is interested in understanding sort of the consequences of our gut microbial differences. So, you know, there are about thousands of microbes can colonize our gut. And each of us sort of ends up with a collection, a unique collection of 100 to 200 different species of bacteria. So, we’re interested in how these microbial differences influence the metabolism of the food that we consume and how these in turn impact our health. So, the central hypothesis that drives the research in my lab is that the gut microbiome is a key determinant of how we respond to the diet that we consume.

So, think about your favorite meal. This is my favorite meal, and the point that I wanna drive from this slide is that everything that we consume, this is a microbe, or there are many microbes out there that can process it into something else. And so they are gonna go through the different components of this meal. You know, we have a salad rich in fiber and plant polysaccharides, which are sort of great food for our gut bacteria. And they use it as a substrate for growth. And they generate energy. And as a product of their metabolism of this fiber, they produce small molecules called short-chain fatty acids. These short-chain fatty acids, you know, the predominant ones are acetic acid, like vinegar, propionate, and butyrate. They have been linked with many benefits on health.

A good red wine is a rich source of antioxidants, and antioxidants, there has been a lot of studies on antioxidants and the protective effects on cardiovascular health. What we’re learning is that some of us harbor bacteria in our guts that can turn those antioxidants that are in wine and other fruits into compounds that are way more potent than what is present in the red wine or fruit.

And then we look at the steak. It’s a great source of essential nutrients or key nutrients for our health, like choline and carnitine and histidine. But what we have learned over the last few years is that there are bacteria in our guts that like these substrates as much as we do and can turn it into compounds or metabolites that maybe are not as good for us. And I’m gonna tell you a little bit about that.

So, this is sort of the pipeline that we have, our discovery pipeline sort of from correlation to causation in trying to understand how bacteria metabolism influences AD progression. So, through our collaborations with ADRC and with Dr. Bendlin, we start usually with populations of humans, large populations of humans that are fairly well-characterized in terms of the AD-related phenotypes. We have data on cognition for these individuals. And we take their fecal samples, we measure their, we look at their bacteria. We look at the metabolites that are in their blood and cerebrospinal fluid. And then we sort of run correlations to identify metabolites or bacteria that track with disease.

And so that sort of leads us to generate hypotheses about the function of these metabolites or the relation of these bacteria or these metabolites with disease, which we then go into animal models or in vitro models to test whether these metabolites that track with disease track because they influence disease or track because they are produced as a consequence of disease. So, we do these tests of causality and then try to understand if they are causal, if they have an effect of disease, how, and we try to understand the mechanisms. So, this is sort of the central or conserved sort of studies that we do for many, for a lot of our work.

And so I’m gonna tell you about one metabolite or sort of gonna tell you about two groups of metabolites. But this one, I’ll tell you before, is called imidazole propionate. I’ll tell you more about that metabolite. But we see it is a bacterial metabolite that we see in the blood of people that is increased in individuals that score lower in the cognitive test.

What I’m showing you here are three graphs where we look at different cognitive tests, where we assess executive function, memory, vocabulary, and so on, sort of different types of tests, and we correlate the scores on those tests with the abundance of this metabolite ImP in their blood. And what we see is that individuals that tend to score better in this test have lower levels of the metabolite in their blood, whereas individuals that score worse, they have higher levels in their blood.

And we also see that the abundance of bacteria capable of making this bacterial metabolite are associated, are positively associated, with markers of neuron damage. So, more bacteria that makes ImP, more neuron damage.

So, a little bit about this metabolite ImP. It’s a metabolite that bacteria make from histidine. Histidine is an essential amino acid that is present in the steak that I show you. And humans or mammals can metabolize histidine to some extent. But bacteria can metabolize histidine to imidazole propionate. And only bacteria can do that. So bacteria, whereas humans can do some conversions of histidine and be able to utilize histidine, we get only imidazole propionate from bacteria, and there’s only a small set of bacteria that can actually do this conversion.

So, because of the correlation that we observe between imidazole propionate and cognition, we decided to test whether imidazole propionate exacerbates AD pathology in a mouse model of AD. And so what I’m showing you here are slides, cerebral slides of brains of mice, that were either treated with ImP, to your right, or that have low levels of ImP. So, you know, the slide to the right are mice that have very high levels of ImP in their blood. And what we see, and so, you know, and just to guide you here, so we have the cortex and the hippocampus there of the mice. And what we see is that mice that have high levels of ImP accumulate a lot of amyloid plaques on their brains compared to control animals.

Here’s more histology. So, looking at a different type of cells here, these are called astrocytes, that they look like stars, and these cells’ response to damage in the brain or to the accumulation of plaques. And we see that in mice that have high levels of ImP sort of the abundance of these starlike cells called astrocytes is more abundant compared to control. And here’s some of the statistics. We do this in multiple mice to get statistical body.

Okay, so, I told you about one metabolite that is potentially sort of not good for us and may sort of exacerbate progression of disease. There are other bacterial metabolites that might be good for us, and such is the case of these compounds called short-chain fatty acids. And so, as I told you, these are mainly produced by bacteria from dietary fiber. And there are a number of studies where sort of scientists dose mice with these short-chain fatty acids, specifically butyrate, and they were able to, sort of the similar study I mentioned earlier with imidazole propionate. In this case, they increased the levels of butyrate. And what they see is that increasing levels of butyrate reduces disease progression. And so some of the mechanisms by which this might be happening is sort of butyrate might have anti-inflammatory effects and be protective in the brain.

So, what we are doing, so, all of this was done in animals. And so we were on mice. So, we are testing this whether this is true also for humans. So, in the human cohorts that Barb mentioned, we collected fecal samples and we are measuring short-chain fatty acids in feces of individuals that are either negative or positive for amyloids. So, individuals that have AD pathology in their brain and, you know, the findings that we’re getting is that individuals that are positive for amyloid tend to have lower levels of short-chain fatty acids, consistent with what we’re seeing in mice, and maybe suggesting that these metabolites might be protected or might slow down the accumulation of amyloid in the brain, but more study is needed.

Okay, so, the take-home messages from what I was telling you, we see these associations between the abundance of gut bacteria and their metabolites with AD pathology in humans. And for some of these metabolites, we see a causal role of these sort of bacteria and metabolites in mice. And what I’m sort of trying to say here is that these metabolites may potentially change the trajectory, may not be the cause or the cure to the disease, but just sort of change how fast or slow the disease develops. And, you know, these are just two examples. There are other examples in the literature, but I think this is just the tip of the iceberg. There’s a lot more metabolites to explore and discover. And with that, I’ll thank you for your time and thank the lab and the funding sources.

[audience applauding]

Barbara Bendlin: So, now we’re going to have our fireside chat.

Federico Rey: Okay, so I will probably start. So, I mentioned sort of the probiotics. And I’m sure there’s a lot of people interested in learning whether we’re finding out what’s the evidence of probiotics and AD, what has been done. Are there strains that are good? What do we know?

Barbara Bendlin: Yeah, so, there have been some small number of studies with small numbers of participants, mostly looking at people who already have some memory impairment. And the studies have shown some positive effects on cognitive function. And most of those studies use probiotics like Lactobacillus, Bifidobacteria. But we’re lacking kind of large, gold-standard clinical trials, and there haven’t been any studies that have looked at impacts on those neuropathological features that I showed. So, looking at, say, at amyloid plaques or neurofibrillary tangles, and you and I have talked about this. I don’t think necessarily that probiotics would stop the spread of those pathologies once they get going. But potentially, they could still have beneficial impacts on the brain. But we don’t know. We have to do those studies.

Federico Rey: Yeah, probably to look at change of sort of, you know, changes in amyloid or tau, sort of, maybe the length of those studies need to be, I mean, I don’t know how long were these studies that you describe.

Barbara Bendlin: Yeah, so, I mean, the studies that have been done mostly looked at memory, and those were over, kind of short periods of time. But using the biomarkers, like the brain imaging or even maybe the blood biomarkers, we could see if probiotics have an impact on the actual biology of the disease. Yeah.

So, I think one question I have for you, and we were talking about it before we started the session, has to do with diet. And I personally don’t think that there’s, like, one diet for everyone. And we know, for example, even, you know, ketogenic diet can have beneficial impacts for some people, for example, reversing insulin resistance. But you showed a lot of evidence for fiber-rich diets. So, I’m curious. A, is there a good diet for everyone? And B, can you speak to fiber specifically?

Federico Rey: Yeah, so I mean, the answers are, well, they also, what the literature says with regards to diet is, and there’s quite a bit of variation in responses to specific diets. Some people respond great to Mediterranean diets, and people respond great to ketogenic diets. So, there’s no universal diet that is beneficial for health, as most studies suggest. However, I would say that fiber, the sort of evidence for fiber being beneficial, I think is really strong and for multiple diseases. I’m not speaking about AD specifically, but, you know, sort of particularly metabolic diseases.

So what, sort of the tweak there is that there are specific fibers. There are people that respond better to specific fibers, where other people respond better to other fibers. And there’s quite a bit of variability when you look at, you know, start sort of looking at specific fibers. There’s quite a bit of variability. But if you consume a large sort of good proportions of fiber and, you know, the recommended numbers are quite high and hard to achieve, of sort of a diverse source of fibers, I think sort of, that would be my recommendation so as to sort of what diet would be good. And this is something that over the years, I have become obsessed with sort of my diet and tweaking the amount of fiber.

And so, what I say is the recommendation of fiber is about 30 to 35 grams of fiber a day for an adult man and about 30 for women. And it’s really hard. You have to eat, like, 20 oranges to get the… [Barbara laughing] So, getting the values of fiber that are recommended is not easy. And so you have to be very conscious about, you know, incorporating fiber in every meal and every snack to reach those levels that are recommended, you know, sort of for beneficial effects.

Barbara Bendlin: What’s the best fiber-rich snack?

Federico Rey: Orange. [both laughing]

There are some good cereals out there that have astronomical amounts of fiber and that sort of have, you know, very diverse sorts of fibers that are good, but in general, eating, you know, sort of grains and vegetables and sort of can get good fiber intake combined.

Barbara Bendlin: Yeah, okay.

Federico Rey: So, all this evidence about our microbiomes changing as we age. And, you know, sort of talk a little bit about what’s happening with the microbiome and aging and sort of what’s the literature on that and what you think is sort of happening there. Why does it change?

Barbara Bendlin: Yeah. So, as we get older, generally speaking, there does seem to be reduced diversity as we get older. And then another thing that we’ve found in our studies is as people get older, there’s also increased intestinal inflammation. We see that as well. So, there could be lots of different reasons that other people have studied, not necessarily us, but the, you know, Westernization of the diet reduces diversity. Taking antibiotics over the life course probably reduces diversity. I think probably medications are also playing a role. And we have seen some impacts of proton pump inhibitors, even, in increasing intestinal inflammation. So, those are very useful medications. I take one myself. But sometimes, you see that literature and wonder, is there ways that we could potentially promote increased diversity with aging? What would be the ways that we could do that as opposed to just losing microbes? I don’t know, are there other things that you think are having a negative impact?

Federico Rey: Changes in mastication. Sort of probably, you know, sort of change the access to sort of some of those substrates and, you know, how they get metabolized.

Barbara Bendlin: The kinds of foods we’re eating as we get older.

Federico Rey: The kind of food, yes.

Barbara Bendlin: Yeah.

Federico Rey: That also has an impact.

Barbara Bendlin: I mean, oranges we can masticate, though, so…

Federico Rey: Absolutely.

Barbara Bendlin: Yeah, what do you think are kind of the big opportunities in terms of better understanding of the microbiome and then in terms of our work for healthy brain aging? You know, what do you see as things on the horizon?

Federico Rey: I do think sort of, you know, and sort of obviously I have a biased answer on this because of my interest in bacterial metabolism, but I feel like sort of there’s a lot of opportunity to sort of, as I was alluding to everything that we eat gets processed or metabolized by bacteria, resulting in compounds that enter in our circulation and affect our biology. And so identifying, you know, sort of cases like ImP and other metabolites. I think ImP and short-chain fatty acids are just the tip of the iceberg, and there’s a lot of opportunity to find sort of metabolites that impact disease. And maybe they sort of, I imagine sort of a constellation of metabolites impact disease in different conditions and maybe impacting disease in opposite direction and in unique ways for each individual.

So, a role for personalized nutrition in sort of impacting the ability of those metabolites. And yeah, so I think sort of, and then sort of the idea, yeah, sort of the idea that, you know, maybe early interventions, you know, being mindful about what we eat and sort of trying to promote the production of those beneficial metabolites maybe might have a role in sort of changing trajectory of disease. But there’s more metabolites to find. And who knows? Maybe there are some that are more potent than others.

Barbara Bendlin: Can I ask you, though, so, do you think that the best way to change our microbiome then will be through diet? Or do you think there’s like a, people will do some kind of probiotic cocktail in the future?

Federico Rey: Yeah. So, I mean, I do think that diet and sort of diet using information of, you know, of our gut microbiomes to inform, you know, to design our diets with, you know, with sort of microbiome-centered sort of a strategy to change our diets. Sort of increasing the production of beneficial metabolites is one way to go. However, I would say that in recent years, the number of academic labs and companies that are studying, sort of studying the idea of, you know, producing these cocktails of bacteria, these are defined sets of bacteria that have specific properties and can be changed with specific nutrients. And, you know, sort of, this would be like a more advanced version of, you know, regular general probiotics that you get in the store. This would be prescribed and that would target specific conditions, you know, to change the abundance of specific metabolites or to sort of talk to the immune system in a specific way with specific bacteria.

I feel like that’s sort of one of the directions that this field is going with, you know, moving from those fecal transplants that are very core sort of changes in microbiome to cocktails of bacteria with specific functions.

Barbara Bendlin: Do you take any probiotics?

Federico Rey: I drink kefir every day, that has probiotics, but I don’t take pills with probiotics. And I should say that probiotics, I mean, they are very general. And while there’s amazing data for some, you know, in some cases for some strains of probiotics, there’s quite a bit of variation on the responses, depending on the strain. And so, the data out there is quite messy. They are good sources to look at specific strains of bacteria and what clinical trials have been done sort of to try to match your need with the right strain. But I say that right now sort of the field is quite, you know, the data is quite messy with very disparate effects. However, I don’t think they are dangerous. So, you know, if they work, why not? I would take them.

Barbara Bendlin: Yeah.

Federico Rey: Okay, so, over the years, I have heard you sort of talk about Alzheimer’s and sort of have learned how complex this disease is and sort of how challenging it could be to find a cure. So, can you sort of summarize some of the… I mean, is there hope, and what are the recent successes in this area?

Barbara Bendlin: Yeah. So, I would say that, you know, we’ve been studying Alzheimer’s for, you know, over a hundred years since it was identified. But I would say in recent years, the last 5 to 10 years, there’s been some really, truly major breakthroughs. Some of them I mentioned, which includes things like being able to see the disease developing in the brain early, you know, not waiting until someone has passed away to be able to see that, see what is causing their dementia.

There have been some promising breakthroughs in terms of drugs that have been developed. So, there’s new monoclonal antibody therapies that people can take that you can now, you know, actually get at the hospital here in Madison. You know, I have friends who are clinicians who are prescribing these new medications that remove amyloid from the brain. And then we also, you know, we have some great things going on. I think even in our research, as well. And a lot of this has been possible, you know, through the funding that we’ve gotten. But then, also, even more importantly, our partnerships with participants. So, we’re really fortunate that we have so many people who are engaged in the topic of dementia and have participated in these studies and have made these discoveries possible. So, I see that as very, very hopeful.

Federico Rey: I agree.

Barbara Bendlin: Yeah. We are open for questions from the audience as well. I believe there will be some microphones. So, just raise your hand, and someone will bring you a mic.

Attendee 1: So, how far are we away from having people donate a sample of feces and analyzing their microbiome? And you say they react different to fibers based on what the microbiome is. So, is that gonna be in a clinical scenario?

Barbara Bendlin: I mean, I don’t know how long, but I’ll say, like, that is the vision. So, I know people and I think there’s private companies that are pursuing this as well, but that you would send your stool sample and then find out, you know, what kinds of microbes you have present, maybe how those influence your risk for disease, maybe give you some suggestions for different diets or probiotics. I think there’s even, like, ideas for “smart” toilets in the works. But how far away are we from that?

Federico Rey: I don’t think so, not very far. Already, you know, as Barb mentioned, there are companies working on this and there are publications, you know, sort of where they use information from the microbiome and sort of some, you know, other metadata to predict responses, glucose responses to diet with high accuracy. And so, the microbiome information sort of aids into those predictions to a great deal. So, I think that we’re not that far from that sort of becoming more, the evidence still developing, but sort of developments on AI and those type of sort of approaches is also accelerating how we mine the microbiome data, the very complex microbiome data, and apply it to these type of questions.

Attendee 2: Okay. So, you were mentioning about the various metabolites that increase the incidence of a-beta plaques. Do you think that those are directly interacting with the monomeric amyloid beta and influencing the aggregation, or it’s just a downstream effect?

Federico Rey: So, this is sort of, specifically sort of for ImP. So, this is sort of work in progress. So, the evidence that we have suggests that maybe, so ImP seems to be interacting or disrupting blood-brain barrier function and maybe sort of impacting the clearance of amyloid. So, we don’t have sort of definitive data on that, but it doesn’t seem, we don’t know whether ImP sort of how, you know, the exposure, how much gets into the brain. So, I would think that the effects might be due to the effects on the vasculature. And we have data sort of suggesting that it does impact the vasculature.

Any other questions?

Attendee 3: Hi, great talk. I’m wondering how do you address the interindividual variability that you showed both with the data and what we know when you design a human study?

Barbara Bendlin: Mm. That’s tricky. [laughing] It’s true, with the animal, you know, the animal studies are so easy because all the animals are kind of the same. And with humans– Go ahead.

Federico Rey: They’re less similar than we hope.

Barbara Bendlin: Okay, okay, yeah, that’s true. You have a whole other body of research on that. That’s true.

Federico Rey: But not like humans.

Barbara Bendlin: But I guess you might have seen some of the, some of the pictures that Federico showed. Even those relationships between ImP and the cognitive function, all those little dots are everywhere, right? And so there’s a lot of different things that are impacting trajectories. And, you know, maybe we’re going about it wrong. I mean, ideally we would find probiotics, for example, that would reduce risk for dementia across the board. But maybe it’s not going to be as simple as that. I mean, and just to add one more complexity, usually when people develop dementia, there’s a lot of different pathologies that are accumulating in the brain. I talked about amyloid and tau, but there might be other things going on. There might be vascular dysfunction. There might be other abnormal proteins. So, it does get really tricky.

All that said, we still try to figure out what’s the effect of the probiotic or the drug that we’re testing. And if we know what the effect is, what the effect size is, then we can calculate, for example, how many people we need to have in a study to see the effects, but it’s not simple, yeah.

Federico Rey: Maybe what I can add to that is sort of the idea that we don’t think, at least from the perspective of the microbiome, there’s not gonna be one metabolite that, you know, that is the metabolite that we have to– It’s gonna be different from different people. So, the idea that we have to think about, instead of thinking about individual metabolites, we have to think about constellations of metabolites that are different. You know, like our microbiome is very different among different people.

Attendee 4: Hi, thank you for the talk. I have a personal question. So, if I wanted to kind of do an experiment on myself, how can I, I guess, compare diets to see which one would work best for me without being a research participant?

Barbara Bendlin: Yeah, okay. So, I’m not advising that you experiment on yourself. That’s the first caveat. But, you know, we have done studies where, for example, people wanted to know how they responded to different foods, just even this, like, idea of monitoring your glucose. You know, you could get a glucose monitor, and you could try different diets and then see how it affects your glucose levels. That would be a very simple thing to do.

I think that some people maybe who have access to the technology also collect stool samples and monitor their stool to see how, for example, higher-fiber diets might impact their composition. But that could get expensive, right?

Federico Rey: It can get expensive. And also, I think sort of, we don’t have at this point, you know, we look at microbiome composition of a person and we cannot tell you, “Oh, this is healthy.” You know, we can say how far you are from healthy if you’re not. But it’s hard to define healthy or healthier, you know? So it’s just sort of challenging to do from the microbiome perspective. But maybe like what you said, tracking the phenotype of interest. I mean, I think of mice most of the time. So, I don’t have a good suggestion.

Barbara Bendlin: You could, you know, maybe it wouldn’t be unbiased, but you could track how you subjectively feel, you know? Are you sleeping better? Do you have more energy? Those kinds of things, yeah?

Attendee 4: I have a follow-up question. So, with glucose, I can look at my HbA1c, and I kind of know how that’s trending. Is there a similar metric or metrics for gut health?

Barbara Bendlin: Mm, again, I think it would be, you know, some of these things that we collect in the lab. But then, because it’s not, like, so easy to do, for example, an analysis of your stool sample. There is a Bristol stool scale you could see just what your stool looks like and see how the effects of fiber are impacting you. See what happens after you eat your 20 oranges. [both laughing]

Attendee 5: Hi, thank you, great talk. I have a question. You guys talk a lot about how diet influences your microbiome. I’m curious if you guys have explored how stress or other lifestyle factors change your microbiome and to what extent in comparison to diet?

Federico Rey: I mean, I have not explored that. We have not done sort of in our studies. There are studies out there suggesting that it does. We sort of have looked at. We did a collaboration many years ago looking at social interactions and, you know, ourselves and there are studies suggesting that social interactions sort of have a large impact on microbiome, and, including sharing of taxa among people that have close interactions, sort of like spouses and the sort of the quality of the relationships, you know, correlated with the number of taxa they correlated. So, there are many sort of aspects of our life that, you know, including stress that sort of impact the microbiome, absolutely.

Barbara Bendlin: And I think if you are following this series next month, there will be a talk on microbiome and mindfulness. So, we might learn more about how reducing stress can potentially impact the microbiome through mindfulness. I’ll be looking forward to that one.

Federico Rey: Yeah, absolutely, flip side.

Attendee 6: Hi. Thank you so much for your talks. You said that there are some companies trying to associate benefits of having certain type of microbiota or the whole thing, microbiome and some metabolites. And you said that they’re publishing this. My concern or my question is, are they really assessing food intake?

Federico Rey: Well, I cannot speak for every study, but most, you know, microbiome studies, they do collect, or many, or at least the intention is to collect these sort of, diet information is very useful and informs greatly changes in microbiome. I think many studies do, but I don’t know for the specific companies. But I do, I mean, maybe I wanna add to that that I think sort of the field is evolving. We don’t have the answers to everything. And I’ll be skeptic somewhat that today will make you recommendations on how to change your microbiome based on what you already have. I don’t think the field is there today. So, I’d be skeptic of a company sort of making such suggestions.

Attendee 6: Yeah, me too, thank you so much.

Attendee 7: I’m just curious. How long does it take to change your microbiome if you were gonna change your diet or take probiotics?

Federico Rey: Maybe I can take that. So, studies in mice show that the changes happen overnight, really quick. You know, overnight, you see changes. By week, two weeks, you see very dramatic changes. In humans, the story is a lot more complicated. you know, as it always is. And unless you do very dramatic changes of diet, you know, let’s say you become vegetarian. You, like, you go from carnivorous to vegetarian or become, or start doing ketogenic diet. So, the changes are very subtle in humans and take very long time.

And what you typically see is sort of changes of abundance of bacteria, but not so much disappearance or, you know, new members coming in, and that takes much longer. I don’t have a sort of time scale, so the changes, you know, I’ve seen studies where, you know, someone takes antibiotics, for example, and there’s a huge depletion of the microbiome, and then they track that person over months and, you know, and they put it in different diets and the microbiome doesn’t change very much. So, it’s very slow to change in humans.

Attendee 8: Hi. I’m wondering if that’s the same in the case of fecal transplant.

Federico Rey: A fecal transplant is, well, it all depends. If there’s a previous antibiotic treatment, engraftment, it can be better, but they are transient, too. So, usually sort of with, you know, in cases, for example, with C. difficile infection, which is when the fecal transplant is prescribed, usually you see significant engraftment because that microbiome is lacking a lot of bacteria. But if you do sort of a fecal transplant in a healthy individual, you’re not gonna see much engraftment of new taxa from the donor sample because there is a robust community there preventing the colonization of what comes in.

So, the fecal transplant sort of, and we have sort of, you know, we had intentions of doing these studies, and we have this castle of the fecal transplant trials, and there’s a lot of poop that has to be given to the individual to have sort of some level of engraftment. But it’s not great, though. You can change a few taxa, but you don’t have a complete reconfiguration of microbiome.

Barbara Bendlin: We started a fecal microbiota transplant study in Alzheimer’s disease. We started it before the pandemic, and then it stopped when the pandemic started. But I will just say that we had sourced the material from a company that carefully screened the stool for harmful microbes. And it’s not a recommended do-it-at-home type of activity like some people in the audience might want to experiment with. But, yeah, so, we did a few transplants. But I would say that again, yeah, in healthy older adults, there’s not that much known about how quickly that would happen and whether it would have beneficial impacts or maybe even negative impacts. We don’t know.

Federico Rey: We don’t know.

Host: We have one final question from online. Is there a standard blood test for ImP that my rheumatologist, neurologist, or PCP can order?

Federico Rey: No. No, I want to sort of answer that. I would say the data is very preliminary, and we don’t know the side effect that might have in humans. But there’s absolutely, these are metabolites that we measure in academic or commercial labs, but they are not in the clinic yet.

Host: Thank you.

Samantha Mulrooney: All right. Thank you, everybody, for joining us here tonight and for those of you online, and just a reminder. Thank you for the plug before. Our next Crossroads of Ideas will be on March 4, featuring mindfulness and the microbiome. So, that will conclude our three-part miniseries. So, be sure to check that out on our Crossroads of Ideas webpage. There’s also recordings of our previous Crossroads as well, if you want to check those out. So, one more final round of applause for our presenters. Thank you guys for being here.

[audience applauding]

Excellent, all right, have a good night. Thank you.