Gut Feelings: The Links Between Gut Health and Alzheimer’s Disease

Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Welcome back to Dementia Matters. Today, I'm joined by both a returning guest on the podcast and a new guest, Dr. Barb Bendlin and Dr. Tyler Ulland. Dr. Bendlin is a professor in the Division of Geriatrics and Gerontology and deputy director at the University of Wisconsin Center for Health Disparities, as well as leader of the Research Education Component at the Wisconsin Alzheimer's Disease Research Center. Dr. Ulland is an associate professor of pathology and laboratory medicine at the UW–Madison School of Medicine and Public Health and leads the Ulland Lab, focusing on the role of innate immune responses in Alzheimer's disease. Both Barb and Tyler were senior authors on a paper published in November 2023, titled “Gut Inflammation Associated with Age and Alzheimer's Disease Pathology: A Human Cohort Study.” The study suggests a link between gut inflammation and changes in the brain related to Alzheimer's disease, further supporting a connection between the gut and the brain in Alzheimer's. Drs. Bendlin and Ulland, welcome to Dementia Matters. 

Dr. Tyler Ulland: Thank you for having us. 

Dr. Barbara Bendlin: Happy to be here, Nate.

Chin: Tyler, let's start with you. Your gut is the GI system, which includes your stomach, intestines and colon. How would you define gut health, and why does gut health matter?

Ulland: There's really a lot of different factors that shape gut health, but one of the main factors is the gut microbiome. That consists of all the bacteria, fungi, archaea, protozoa and viruses that inhabit the gut. These organisms really can shape how the gut functions overall because they're important in processing all sorts of nutrients from what we eat into usable proteins, usable vitamins, usable minerals, and things like that for us. Really, the goal is to have really really limited symptoms of digestive disorders. What we're after is having no real gas, diarrhea, heartburn—things like that—but also more serious conditions as well. The gut really can impact all aspects of our life—everything from our mental state, our mood, sleep—everything like that. Having a healthy gut really allows us to be in a really good space. It allows us to be able to live a really healthy and productive life.

Chin: I think some of us would have a hard time imagining the fact that our gut helps with our mood, helps with our overall well-being, because it's sort of this spot in our body. I also think it's interesting to think that it's actually the microbes in our gut that do a lot for our body, that without them, we might not get all of the nutrients or minerals or the things that you're talking about.

Ulland: Absolutely. Yeah, I mean, if you take a look at all of the things that the gut microbiome is important in either producing or the gut microbiome is important in modifying, without all of those things, you end up with organisms that really would have a failure to thrive. If you take our mouse models, where we have mice that are germ-free—and this is something that our colleague Federico Rey works on as well—those mice, their digestive system is not healthy by any means. They have a huge colon, their spleen is messed up, their immune system is messed up. It really impacts all those aspects of life.

Chin: Huh, so I guess the next time Barb says, “Why are you in such a foul mood?” I can say, “Oh, it's my gut, so leave me alone.” 

Ulland: There you go. (Laughs)

Chin: All right. Barb, do people with dementia have notable differences in their gut microbiome? If that's true, why do you think that is?

Bendlin: Yes, they do. We published a study in 2017 where we compared people with and without Alzheimer's disease dementia, and we found that people with dementia had differences in their gut microbiome. One of those differences that there was less diversity—so there was less different kinds of bugs in the gut. There was some that were increased in Alzheimer's disease, but most of the gut microbes we looked at were decreased in dementia. Another interesting thing we found was that even among people without symptoms, there was a relationship between the gut microbiome and what we looked at in the brain in terms of Alzheimer's disease pathology. There seems to be a really early relationship between what we see in the gut and what we see in the brain. Why that is, we don't know for sure. There’s a lot of things that can affect the gut—what people are eating, medications, even where you live can affect your gut microbiome composition. The question is now, what affects the gut? How does that loss of diversity influence the health of the gut? Then, how does that eventually affect the brain? Those are the kinds of things we're studying in our research program.

Chin: Clearly, diversity is important in the gut.

Bendlin: Yes. If you look at really any kind of health condition, loss of diversity is not specific to dementia. You actually see it in a lot of other kinds of conditions like type 2 diabetes, obesity, and also diseases that affect the gut. Loss of diversity is usually what you see in disease condition, and unfortunately, it's also what you see with aging. There seems to be this idea that keeping diversity high could be good. If you think about a healthy ecosystem, you want to see lots of different kinds of plants and animals and not just a monoculture. Generally speaking, diversity is good.

Chin: Of course, I want to ask you questions about food and diversity, but I’ll wait for later in the show for that. Until we get to that, Tyler, you mentioned this in your first response. You mentioned some symptoms, and you also mentioned what germ-free mice are experiencing. How does somebody know if they have a poor gut or poor gut health?

Ulland: Well, I think first off, if somebody is concerned that they have truly poor gut health, they should go talk to their physician and chat with them about it. Poor gut health is often associated, first off, with just digestive symptoms. We're thinking about frequent diarrhea, we're thinking about constipation, we're thinking about heartburn. We're thinking about bloating and gas and things like that. That can be some of the first signs that somebody might have issues with their gut and their gut microbiome. As we talked about before, it can really impact all sorts of aspects of life. It can affect your sleep, your mood. You can also think about it within the context of illnesses—certain parts of the microbiome can be really impactful on how the immune system interacts with various different organisms. If you have some issues with the gut, you might have a higher frequency of getting sick or those sicknesses could be perhaps more severe. There are a lot of ways in which gut health—and poor gut health in particular—could really impact somebody’s life.

Chin: Well, Barb, hearing that then, how did you assess the gut microbiome and then incorporate it into a study that's looking at some of these things like thinking ability, but also Alzheimer's biomarkers? 

Bendlin: Yeah, so the way that we first of all determine what the gut microbiome composition looks like is to collect stool samples from participants because whatever's in the gut will come out in the stool. If we want to know, for example, what kind of gut bugs people have, we'll take the stool and we do a genetic analysis. We're not looking for human genes, but we're looking for the genes of the bugs in the gut. Using that kind of analysis, we can find out what is there, how much is there and also what are those bugs doing? What is their function? The other thing that we can actually look at all kinds of things in the stool and in a recent study what we did was to look at a protein called calprotectin and that's a marker of intestinal inflammation. That's kind of a slightly different measurement but we were wondering if intestinal inflammation is potentially linked with brain disease. We actually looked at levels of calprotectin to measure inflammation, and then we used some tools to look at what's going on in the brain, including brain imaging and also analysis of cerebrospinal fluid, which bathes the brain.

Chin: Tyler, why did you choose calprotectin as the marker for intestinal inflammation?

Ulland: This, I think, actually grew out of a conversation that I had with Federico Rey, our other co-leader for this study. We had been interested in gut permeability and gut inflammation for a long time. Barb and Federico have led some absolutely wonderful studies in the past looking at the gut microbiome. This really came from kind of going into the literature and looking at really good markers for gut inflammation. Calprotectin is a protein that is both expressed and secreted by this cell called the neutrophil, which is extremely abundant. Neutrophils are in your blood and they have access to pretty much every place in your body. When they get some sort of signal that says that, “Hey, there's inflammation here, we have to do something about what's going on here,” they can go through this process called degranulation. That's basically when they dump a bunch of the proteins that are inside the cell to outside of the cell in order to talk to the various cells around them and in order to attack whatever is in front of them. Calprotectin is one of these proteins. We also knew from the literature that calprotectin is extremely stable. At room temperature, calprotectin is stable for days, even more than a week. It was a really attractive target to be able to say it should still be in stool if it was in stool to begin with. Sort of regardless of how the samples ended up being treated from when they came from a donor to when they got to the lab. It was a really attractive target. That is one of the reasons that we picked it. Both it was attractive and it was easy to assay for. We thought it was going to be really abundant in the gut of somebody who had a lot of inflammation going on there. 

Chin: No, I can appreciate that. I also think for our listeners that are not in the scientific field or in the medical field, this is a good opportunity to explain that we are as good as our tools, and our tools are imperfect. Right now, we have certain tests in the blood or the spinal fluid that may be okay at detecting inflammation, but hopefully, you know, in the next year, five years, or 10 years, we'll have even better tests. Then we can go back and look at this relationship. I always have to caution people. No, that doesn't mean it doesn't exist. It just means we haven't found it with the current tools that we have, but it's exciting to see that relationship. Barb, did you have any issues getting participants' stool samples? Were people uncomfortable with the idea of sharing their stool?

Bendlin: For the most part, we've had such good response in terms of stool sample collection. Our research participants in Wisconsin are super engaged. They're already doing everything they can to help us learn more about Alzheimer's disease. Most people were really enthusiastic about this kind of research. People have also collected stool samples before for different kinds of tests. I think it wasn't that unusual to do this part of the study. We've had a really great response.

Chin: I will say that I've had a patient who has attended one of your presentations and came into my clinic and asked me if I would be collecting their stool. I said, no, that's not what we're doing in clinic. You can go see Dr. Bendlin for that, for research. I'm glad to hear that there's such energy.

Bendlin: Go ahead and collect it and send it our way. Send it to Tyler, not to me.

Chin & Ulland: (Laughs) 

Chin: Tyler, Barb did a nice job of leading up to how you guys studied some of this. I wish I could ask more questions about the actual analysis of stool from our wonderful participants, but I'll skip that. Can you tell us, what did your study actually find then?

Ulland: Our study had several major findings. The first was that calprotectin, this protein that Barb had mentioned, which is associated with higher levels of inflammation, was actually increased in the stool samples from individuals with AD dementia. It looks like there's more inflammation going on in the guts of those individuals. Actually, when we took a look at individuals with the highest levels of amyloid burden—one of the proteins associated with AD—we found that those higher burdens of amyloid were associated with higher levels of calprotectin. Barb also mentioned that we took a look at CSF, or cerebrospinal fluid, and we found that high calprotectin levels were also associated with an increase in some of these cerebrospinal fluid markers of AD, or some of the proteins that we can find in the CSF. I think, really intriguing—sort of an additional finding that we had that we weren't really looking for, but was one of those things that we saw as we analyzed the data—was that higher levels of calprotectin were also associated with age. This is consistent with the idea of inflammaging, or inflammation associated with aging. We found that as individuals got older, the older the individual was, the higher the levels of calprotectin in their gut, regardless of whether or not they had AD.

Chin: So you see that as people get older, one, there's a decrease in diversity of microbes in the gut, but then two, there's this increase in inflammation as well.

Ulland: Right. Yep.

Chin: If there's inflammation in the gut, is there a way for you to then see if there's extra or increased inflammation in the rest of the body? Like, I'm thinking about blood tests or even in that spinal fluid. Were you able to look at any of that?

Ulland: In our initial analysis, we did try to look for some of those biomarkers in serum, and we weren't really able to detect much of a difference there. I think Barb can speak more towards what we found in the CSF though.

Bendlin: Just a couple of additional comments. That increased intestinal inflammation—when we saw that among people who already had dementia—we actually saw more amyloid in their brain. That was mostly done using a type of brain imaging technique that's sensitive to amyloid in the brain. That was pretty surprising actually, that with more inflammation, you would see more amyloid in the brain. But Nate, these are very early studies and they need to be replicated. We need to see if this holds for other groups of participants. We're also doing some more mechanistic studies to try to figure out exactly why it would be that if you have gut inflammation, you might end up having brain changes. One of our hypotheses is that when you have gut inflammation, it could lead to a condition called leaky gut—or intestinal permeability is the more scientific term—but that perhaps things that should be staying in the gut are getting out, and that could cause more systemic inflammation in the body. Then that could also exacerbate inflammation in the brain and potentially even the spreading of pathology. That's the hypothesis, but we need to do a lot more studies to see if that's the case.

ADRC Announcement by Alexia Spevacek: We interrupt today’s episode with a word from the Wisconsin Alzheimer’s Disease Research Center. We talk a lot about medical research and the science behind Alzheimer’s disease, but what impact do social connections have on brain health? Join the Wisconsin Alzheimer’s Disease Research Center for the annual Fall Community Conversation happening Tuesday, September 10, 2024 from 4:30 p.m. to 7:30 p.m. CT at the Middleton Performing Arts Center in Middleton, WI, and live streaming on our YouTube page. This year’s Fall Community Conversation is focused on providing information to help people stay connected, improve brain health, support memory, and live healthier, happier lives. The event will feature a health and wellness resource fair, talks lead by University of Wisconsin faculty, and a Q&A with evening’s presenters. To learn more about the Fall Community Conversation and how to attend go to adrc.wisc.edu/fcc2024 or find the link in the episode description. Thanks, and we hope to see you at the 2024 Fall Community Conversation

Chin: Barb, what do you think is a link between the gut inflammation and amyloid protein? Do you think it is this idea of the leaky gut or just whole-body inflammation? What kind of mechanism are you looking at?

Bendlin: Actually, Tyler's lab does really elegant studies in animal models showing how certain immune cells in the brain can actually seed amyloid pathology. Tyler, I don't know if you want to sort of break it down a little bit, but the general idea would be that inflammation in the body affects these cells in the brain, which then kind of promote more deposition of amyloid in the brain.

Ulland: Yep, that's exactly true. We have a cell type in the brain called a microglia, and folks may have heard of macrophages, right, which are sort of tissue-resident cells that are really important in cleaning up damage and responding to various different insults. Microglia are the cells in the brain that are really important. They're sort of the brain macrophage, even though they're slightly different. Our lab and others, particularly Michael Heneka’s lab, have found really good evidence that as you activate microglia in a particular way, they create a complex of various different proteins kind of stuck together. As that cell dies, that complex of proteins is left over. The microglia either ejects it or dies around it and, actually, that can create a point at which a lot of amyloid can stick to it, and you can generate a new plaque that way. Now it's not to say that all plaques are seeded by this protein complex from microglia, but we certainly have good evidence that at least some of them are.

Chin: Oh, that's fascinating. I had not heard that before, Tyler. It's like leaving trash after a party and then all of the wild animals come and congregate.

Ulland: It is exactly that. Unfortunately when you have microglia dying, those are the cells that are supposed to be the trash collector. They don't come in and clean up after themselves nearly as well as they need to. That is actually associated with a lot of different neurodegenerative diseases, particularly with MS where microglia are really important in cleaning up all that debris from dying oligodendrocytes. If you don't have microglia properly functioning, then you get a lot more damage, and the damage is sustained because you just don't collect all that debris.

Chin: For our listeners, oligodendrocytes are another type of these helper glial cells that kind of help wrap a sheath around part of the brain cell itself to help with communication. That's fascinating. I do want to pivot a little bit, Tyler, because you also had some interesting findings when it came to just cognitively healthy individuals, those without dementia. What kind of relationships did you see in your study?

Ulland: Right, so I think we mentioned the two biggest factors so far already in that we found that in individuals that were aging, so in older individuals, they had higher levels of calprotectin, which is what we think is associated with this increase in gut inflammation. When we took a look at the levels of calprotectin in healthy individuals, the levels of calprotectin were associated with lower verbal memory scores on the various different tests that we did. As we look at that inflammation in the gut, it is associated with these lower verbal memory scores and that is a potential connection, which we haven't entirely worked out yet, but it's something I think that is really interesting for future work.

Chin: The gut doesn't necessarily have to be affecting us through amyloid proteins or other proteins. It could actually affect our cognition through other mechanisms, which is what you guys will be investigating.

Ulland: Absolutely, yep.

Chin: Then, Barb, why do you think older people have higher levels of gut inflammation?

Bendlin: I think there could be a lot of different reasons. I mean, aging itself is associated with changes in the gut microbiome, which could affect the composition and maybe create an environment where there's more inflammation. Also, as people age, they're likely to have more comorbidities, take more medications. They've probably taken more antibiotics over time, non-steroidal anti-inflammatory drugs, proton pump inhibitors—any number of exposures. It can also be the case that as people age, they could have decreased—I was gonna say gastrointestinal motility, but basically slower digestion. That by itself could also be pro-inflammatory, so there's really just a lot of different things that could happen as we age that could promote inflammation.

Chin: You mentioned PPIs, or proton pump inhibitors, and medications and medical conditions. Tyler, were you able to account for any of these things? Did you have any findings that would relate to medications or chronic medical conditions?

Ulland: Yeah, so because of the cohort being so well characterized—all the patients that we have, we have a lot of data on what they look like, what they eat, and things like that, sort of the diseases that they have, the medications they're on, and all of that. We took a look at things like inflammatory bowel disease, irritable bowel syndrome, probiotic usage, and things like proton pump inhibitor usage as well. Really, the only thing that we found out of that group of various diseases was that when we took a look at PPIs, these proton pump inhibitors, we found that PPI usage was higher or more frequent in individuals with higher levels of calprotectin. I think that of the individuals we were looking at, approximately four in ten of those individuals reported some use of these PPIs.

Chin: You didn't see a relationship with irritable bowel syndrome?

Ulland: We didn't actually, at least in the data, but I think the numbers there—we were probably underpowered to be able to make any really conclusive statements about IBS or IBD.

Chin: Barb, do you think the gut microbiome and gut health in general have a role in early detection or eventually an intervention when it comes to brain conditions like Alzheimer's disease?

Bendlin: I think that there has been some interest in potentially using what we see in stool as a way for early detection. I'm a little skeptical because I don't think that what we see in the stool right now is really specific to Alzheimer's. There's much better biomarkers for Alzheimer's, either through brain imaging, cerebral spinal fluid analysis, or even blood tests. I think those make more sense as early detection tools. If we notice shifts in the stool, it's possible that we could potentially identify perhaps new mechanisms by which the gut influences the brain. I think that's how we're thinking about it—if there's a relationship between the gut and the brain, it's telling us more about why those brain changes are happening, and those could potentially be targets for interventions. We even think that there might be bugs in your gut that are beneficial, and we want to have more of them. Potentially, if we find those bugs, then we could use those to help people have healthy brain aging.

Chin: Barb what bacteria do people actually want then in their gut? Now I get to ask you, what role does food play in our gut health?

Bendlin: Kind of circling back around to what we discussed at the beginning of this conversation, diversity tends to be good. You want a lot of different kinds of microbiota in your gut. Probably one of the better ways to promote that diversity is to eat a lot of different kinds of foods. A plant-based diet tends to be associated with high diversity and eating generally foods that are high in fiber, vegetables are always good, fruits are good, legumes. One thing we haven't talked about too much, but I did want to mention for your listeners, is that when we feed our microbes and they grow, essentially we get, they become more abundant, we get more of them. They also produce small molecules that can be good for, say, reducing inflammation or reducing leaky gut. The idea is you have microbes in your gut. You eat lots of different kinds of healthy foods. That promotes the growth of more healthy bacteria, and those in turn help you maintain your health. That's kind of the long and short of it.

Chin: Well, that helps me with the way I want to end our conversation today. I have two personal questions for the two of you as gut microbiome researchers. I don't need you to justify your answer, but feel free to if you feel compelled. Tyler, I'll start with you. Do you take probiotics? That's question one. Question two, what foods do you eat in particular, hoping to improve or maintain your gut health? 

Ulland: I personally don't take a probiotic. Although I do, I try to eat things like live culture yogurts and a lot of fruits and veggies. A lot of things with a lot of fiber, a lot of things that really help promote good gut health. 

Bendlin: It's honestly the same answer for me. I also do not take a probiotic, although honestly that's where this research is going. We want to find out what are the good bugs and then hopefully have them in capsules so that people can take them to promote healthy brain aging. I also think that right now, perhaps diet is the best way to think about it. If you think about your own gut microbiome, say, as a garden, you want to tend to your garden, you want to give it a lot of good water and nourish it every day and avoid dumping things on your gut that kill the plants. Avoiding processed foods, high sugar, antibiotics if possible, although we know antibiotics are also important in certain situations, pesticides, et cetera. Try to reduce those things that would disturb your gut microbiome diversity and take things in that promote the diversity.

Chin: I appreciate both answers from some gut microbiome experts, I will tell you that I agree with everything you say. I also recognize that I do not have a perfect diet. I will periodically take a probiotic in hopes that I am countering some of my ultra-processed food consumption or restaurants that I do enjoy. With that, I'd like to thank you both for being on Dementia Matters, and I certainly hope to have you back again when we have more results.

Ulland: Wonderful, thank you.

Bendlin: Thanks, Nate. 

Outro: Thank you for listening to Dementia Matters. Follow us on Apple Podcasts, Spotify, or wherever you listen or tell your smart speaker to play the Dementia Matters podcast. Please rate us on your favorite podcast app – it helps other people find our show and lets us know how we are doing. If you enjoy our show and want to support our work, consider making a gift to the Dementia Matters Fund through the UW Initiative To End Alzheimer’s. All donations go towards outreach and production. Donate at the link in the description. Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center at the University of Wisconsin–Madison. It receives funding from private, university, state, and national sources, including a grant from the National Institutes on Aging for Alzheimer's Disease Research Centers. This episode of Dementia Matters was produced by Amy Lambright Murphy and Caoilfhinn Rauwerdink and edited by Eli Gadbury. Our musical jingle is "Cases to Rest" by Blue Dot Sessions. To learn more about the Wisconsin Alzheimer's Disease Research Center, check out our website at adrc.wisc.edu, and follow us on Facebook and Twitter. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.