The microbiome: From blood pressure to behavior

Christina Sumners: Welcome to Science Sound Off. I’m Christina Sumners.
Tim Schnettler: And I’m her cohost, Tim Schnettler.
Christina Sumners: And we’re here today with Dr. Robert Alaniz. He is from the Texas A&M College of Medicine. Welcome to the show.
Dr. Robert Alaniz:  Nice to be here.
Christina Sumners: So tell us a little bit about yourself. What do you do with the College of Medicine?
Dr. Robert Alaniz:  So I am a faculty member in the Department of Microbial Pathogenesis and Immunology. For all those listeners out there, I am an Aggie, graduated in ’91, and I’m a Texas native from San Antonio. And I’ve been in the department for about 10 years, a little bit more than that. And I do a little bit of everything, and I enjoy all aspects of that. I am an educator. I teach graduate students as well as medical students in their immunology curriculum and some advanced courses for the graduate students. And another large part of my time is involved in running a research laboratory which focuses on particular questions in biomedicine that I’m very interested in, and we can get into that more a little bit later.
In that role, I also train graduate students towards their PhD degree, which is heavily involved in different research projects for their dissertation. And on top of all that, I run a core facility for cell analysis, which uses some of the latest cutting edge technology for analyzing cells in different studies for different faculty members, and studies these cells in a single cell level in order to understand their behavior during health or disease.
Christina Sumners: You can find out about their behavior just from looking at a single cell, huh?
Dr. Robert Alaniz:  Yes. But we often don’t look at just one cell. We look at millions of cells, but we’re able to dissect the behavior of a single one of those millions of cells with very precise and high resolution. We take advantage of an instrument and a technology called flow cytometry, and it allows us to use antibodies that specifically mark cells for expression of surface proteins, which are indicative of their phenotype as well as their behavior. And then those antibodies bound to these markers are fluorescently labeled with different colors, if you will. And then we use fancy lasers in order to excite those fluorophores, and emit light in distinct spectrum, which allows us to deconvolute what that cell is amongst a number of other cells.
Christina Sumners: To see what’s going on?
Dr. Robert Alaniz:  Yes.
Tim Schnettler: So how’d you get involved in all of this? Was there something as a kid that drew you to this or was it later in life? How’d you get started with all of this?
Dr. Robert Alaniz:  I think I’m the traditional geek. I was always interested in science growing up, and a wide variety of science. But I think as I got into late junior high more high school, I became much more interested in medicine. And in fact, throughout high school, I thought I was headed towards medical school. And when I enrolled in college I was in the pre-medical program with a biology major. But the more I looked into it, I found that my questions that most interested me were more in understanding the mechanisms of disease in order to help treat disease rather than treating disease on the frontline with patients.
One thing that people are not very familiar with is that our current medicines that are in use today are often 10, 20, 50 years old. And unless new research is done to uncover new pathways and better pathways for treating disease, we just fall into the old traditional ways of treating disease. And that is good, but it can always be better.
Christina Sumners: Absolutely. So how is some of your research actually helping us potentially down the line create some better ways to treat disease?
Dr. Robert Alaniz:  So I think my research actually has a much shorter path towards reaching the clinic or reaching patients, than other basic type of research. Of course, we never really know. A lot of basic research has uncovered things that were unexpected and have dramatic clinical impact. You may have heard a lot about CRISPR CAS, where 15, 20 years ago, that was a very basic study about microbiology. And now it’s turning into one of the more promising areas of new therapeutics.
So similarly, the research I study involves, well, let me step back. I’m an immunologist, so I honed my research expertise to understand everything about our immune system. How it develops, how it helps us fight off infection, how it prevents us from getting cancer. And then understanding all the diseases that humans may unfortunately suffer when the immune system is dysregulated or goes awry. Autoimmune diseases, allergies, and things like that.
So anything that impacts the immune system, I’m very interested in. And I will say that beyond immunology, I was also very interested in microbiology. So I’ve tailored a lot of my training to balance both microbiology and immunology. And I first wanted to target that towards infectious diseases. I basically wanted to create better vaccines for many of the unfortunate infectious diseases worldwide that yet to have an effective vaccine.
But as I was doing this research, I became more familiar with a dynamic that exists within many humans and other mammals, and other organisms where we are colonized by a large population of microbes that symbiotically inhabit us and work beneficially with us in the symbiotic relationship, so that we help them by providing food and a safe environment. And they help us by digesting food, providing more energy, and actually influencing our health.
So this had been known for hundreds of years. We have microbes, they’re in our gut. Which is the largest population, but they’re also on our skin. So almost every distinct body site on a human has a unique community of microbes that facilitate health at those sites.
So I became very interested in the microbiome as it’s referred to, and particularly in the gut. Because at first, many pathogens I was studying were enteric pathogens that are naturally acquired by contaminated food and water. So they must go through the gut first. And what I began to learn when I was just finishing graduate school is that this community of microbes, the microbiome actually does a lot to prevent infection from these enteric pathogens. So we may not want to think about it, but many things that we ingest as clean as we think it is are, are likely going to be contaminated with some sort of microbe.
Now those microbes in few numbers. They come in, they’re unable to establish infection because the microbiome is using a number of mechanisms to prevent them from causing disease. But when we have heavily contaminated food, the numbers of the infectious microbes can overwhelm our natural protective mechanisms that are mediated by the microbiome. And overwhelm it and cause disease. And then we get things like foodborne illness, or things like dysentery, some more severe enteric diseases. And the same thing can be said on different body sites, but I was focusing on the gut.
But as I really began to delve deep into this, I became less interested in the infectious disease aspect of it, and more interested in what are the mechanisms that the microbiome uses to really influence our health? So this field has bloomed over the last 15 years. And I’m glad to say that I’ve been an early part of it. And what we now know is that the microbiome influences everything from obesity and diabetes, to neurologic disorders, to our allergies and asthma. In many, many ways such that when the microbiome is healthy, we’re healthy. But when we perturb or disrupt the microbiome, either through our diet or through the use of antibiotics or some other agents that might enter our system that will disrupt this community, it can have downstream consequences for our health. And we may become more susceptible to things such as obesity or allergies.
Oftentimes, I refer to it as we’ve become too clean in many instances and we’re not exposed to a wide variety of microbes that we have naturally evolved to be exposed to. And then you compound that with the introduction of antibiotics or antiseptics that we’re now exposed to because we think cleaner is better. It’s changing our microbiome, and not for the better. So I’m really interested in what are those changes, and what are the mechanisms the microbiome are actually using to influence our health, particularly influencing our health mediated by the immune system.
Tim Schnettler: That’s fascinating. I mean that’s just so wild. I mean it’s so neat and just, there’s so much to it and you don’t realize that. Like you said, we think cleaner’s better, but sometimes that’s not always the case.
Dr. Robert Alaniz:  That’s not always the case. So if you want to know a little bit more about the particular aspect of how I’m deciphering the mechanisms used. So we know that the microbiome and how the community is structured. If it’s abundant and it has a diverse array of microbes, that’s usually very good for us. And it can influence our health at sites that are very distant from the gut. The lungs, the brain, and even the skin. And even though those sites have their own microbiome, the gut being the largest mass of microbes in a human has the largest influence. And another thing about the gut is that it is considered the largest immune organ. Now it has different compartments and different architectures, small intestine, large, and things like that. But as a whole, it is the largest immune organ. And every cell in our body, even in different tissues at one point or another, traffics, migrates through the gut and then goes back to where it belongs, through circulation, etc.
So the gut influences a profound influence on the behavior of these immune cells. But we all know that the microbes in the gut stay in our gut. They’re in our intestines, we don’t want them coming across our intestinal wall. Because once they do that, then all other bad things happen. So the question is how do they influence immune cells that are on the other side of this intestinal wall and at distal sites, but they don’t actually cross over?
So what my colleague, my close colleague and collaborator here at Texas A&M in the Department of Chemical Engineering, Dr. Arul Jayaraman, we long ago realized that they must be producing some compounds or some chemicals that are able to cross over, influence immune cell behavior, and maybe even enter circulation and influence tissue and immune cell behavior at distal sites. So we really focus on the unique biochemicals that are only made by the microbiota and that these chemicals are what are likely mediating these beneficial and potentially detrimental effects at distal sites. So we’ve identified a novel class of these compounds and have been testing them rather aggressively.
And getting back to your original question, what we’ve been able to uncover is that these chemicals are very potent, and potent to the point that they have drug like activity. So they’re not just a simple regulatory signal. We’ve been able to demonstrate that they have drug like properties such that we can actually reintroduce them in a diseased animal model, and overcome the disease, and prevent it or treat it for therapeutic effect.
Christina Sumners: Just like a drug could.
Dr. Robert Alaniz:  Just like a drug. So we like to think of the gut as being a new repository of novel drugs that are just waiting to be discovered. Because if you think about it, these chemicals are already inside us. So they’re largely safe. And, they’ve been chosen for their functions over millennia by coming from microbes that symbiotically inhabit us. So their function has been selected for over time. So they’re going to be very functional and very safe. And if we can just figure out what these chemicals are, what they do. And once we know what they do, we can identify a disease that they would be useful for. So that’s the big part of our approach in our research.
Christina Sumners: So what are some of the compounds that you’ve discovered so far that might be beneficial?
Dr. Robert Alaniz:  So some of them we’ve published on, some of them we have not. So I won’t be discussing those publicly.
Christina Sumners: Not yet. We can bring you back on some time.
Dr. Robert Alaniz:  You can bring us back on. I mean, we’re trying to make headway on that. With the help of the university, we’ve been patenting a lot of our discoveries. And beyond patenting these chemicals and how they’re used, we’ve also formed a company with the university to try to take what we do in the academic discovery side and actually translate it and try to turn it into a bona fide drug.
But some of the chemicals that we’ve been identifying are very simple and straightforward. So one class of chemicals we’ve identified are derived from the amino acid tryptophan. So something that we all need to eat as mammals. It’s an essential amino acid. So we don’t make tryptophan, but we need tryptophan, and so we need to acquire it in our diet. So it’s something that can’t be ignored and it can’t be left out of our daily dietary needs. And it seems like a perfect substrate for why the microbes have identified tryptophan as a substrate that they can then metabolize, make new compounds out of. And those new compounds have some benefit to our immune system. Because tryptophan has to be there. So it would have been one of the first substrates that the microbes would have been utilizing for a benefit.
So we have a number of potential candidates that are all derived in some form or fashion off of tryptophan. And each of them are proceeding at different paces through the basic research and into the more translational side through the company.
Tim Schnettler: So is this something that, why is this not been studied or developed before? Or has it been studied before? Is this something that’s been a long time in coming or is it up and coming? Tell us a little bit about that.
Dr. Robert Alaniz:  That’s a really good question. So the last 15 years have seen this explosion in microbiome research, largely due to technological advances. So one thing that has been challenging, we’ve always known since the time of, who’s the father of medicine? Hippocrates. He has a saying that was over 2,000 years ago saying all disease begins in the gut. So even the ancients realized that if your gut is healthy, you’re healthy. If your gut is not healthy, you’re not. And we’ve all unfortunately suffered from gut disorder, debilitating gut conditions. I mean, it knocks you out. So it’s a central a crude measure of your health. But it’s long been recognized that the microbes in our gut are very helpful towards us. In ancient China, they were using soups made out of fecal material from healthy people to feed to unhealthy people. And that would in a crude way, but it was a kind of a traditional medicine in China. And maybe 50 years ago, and this has actually been done a lot in the veterinary medicine, is that you take healthy fecal material from an animal, a horse. And feed it to a horse that’s suffering let’s say from diarrhea. That horse will become better. And then we’ve all known and have pets that somehow eating … So there’s something to-
Tim Schnettler: They know what they’re doing.
Dr. Robert Alaniz:  Whether they know it or not, they know it is making them feel better, in a sense. So there’s all this kind of anecdotal data is suggesting that this is an important area to study. And knowing that we have this vast community of microbes, so each individual human has their own unique set. But between humans, there’s some commonalities. But an individual may have 1,000 to 1,500 different species of microbes living in their gut. And then each of the species has either high numbers or low numbers relative to each other. And we’ve known this. However, getting an accurate identification of these different microbes and an accurate counting has been difficult. Because many of the microbes that live in our gut live in such a unique environment and require living in a community rather than living in isolation.
Christina Sumners: In a Petri dish or something.
Dr. Robert Alaniz:  As microbiologists, we’ve been unable to culture them in a Petri dish. And that has dramatically limited our ability to understand who’s even there. But, 20, 30 years ago with the rapid advances in genomic sequencing, we’ve been able to overcome this. And now, you can take a sample. The human genome project took 10 years and billions of dollars to sequence one human genome. Well now we can do that in a matter of hours for less than $1,000. So what’s become even more powerful is now we can take the sample of the feces or the luminal contents, or any other site in the body. And we can sequence the entire genomes of all the microbes that are present and actually separate which ones are present. So this started happening in earnest 15, 20 years ago. And that now allowed us to say we could only grow 100 on a Petri dish. But when we do the sequencing, there’s 1,500 species there. So that really was the advent of a resurgence in microbiome research.
So then as people were sequencing the total community of microbiota in individuals, clever scientists were saying, “Well, here’s a sick individual. Here’s a healthy individual. They’re related. Twins, brother sister, mom and child.” And they’re” saying, “Is there a difference in the microbiome between the healthy and disease?” And they found that wow, the communities of microbes were vastly different between people who were healthy versus unhealthy. And then when they did this in larger groups, they found that people who are healthy have this very a mixed community of microbes. And that people who are unhealthy have a very distinct and more on a smaller diversity of microbes that is fairly unique to that type of disease. So then we understood that there’s clearly big differences. So technology really led the ability to go back and ask these fundamental questions.
And then in a more animal type of technological advance is the availability of animal models where these animals are basically entirely sterile. So now we can have animals that completely lack microbes in their body. And what we know about those is, and it’s very difficult to raise these animals. They have to be in a plastic bubble, everything they get is sterile, it’s very rigorous. But it’s become more available. And with the availability of these animal models that are germ-free as we refer to it, we’ve been able to ask really important questions about saying, now we’re going to test the real role of the microbiota in mediating health or disease. So what certain investigators did about 10 years ago is they took microbiota from healthy and diseased humans, and transferred one set to germ free animals that got healthy microbiota. One set to other germ free animals that got the unhealthy microbiota. Let them live for a number of weeks. And only those animals that received the microbiota from the unhealthy humans became unhealthy. And they manifested the exact disease that the donor had given. And this was a seminal set of studies that really established that the microbiota itself can transfer health or disease. So these types of technological advances have really helped move this field rapidly and something we just couldn’t have done earlier.
And then along the lines of the sequencing advances, now there are newer advances in what is referred to as metabolomics, which is the ability to use a mass spectrometer, an instrument that allows you to identify distinct chemicals within a mixture of chemicals. And it’s this metabolomics that allows us to take a snapshot in a healthy person or an unhealthy person and say, “What are the chemicals? What does this healthy person have that this unhealthy person does not have?” And once we understand that, then we can start making predictions about whether what’s missing and the unhealthy person if we give it back, does that make them healthy, or what’s elevated in an unhealthy person if we block that-
Christina Sumners: Take it away.
Dr. Robert Alaniz:  Take it away. So it’s a very simple approach that couldn’t be done without the advent of the sequencing and the metabolomics technologies.
Christina Sumners: Could you give us a real-world example of what you’re taking this research?
Dr. Robert Alaniz:  So one thing about me as a scientist is I find myself enjoying the research and learning much more through collaboration. Science today, as you may realize, is hard to perform in isolation. And many of the most challenging questions in science and in medicine particularly, require interdisciplinary efforts. So for example, I’m an immunologist. But I’m not a specialist in metabolomics. However, my close colleague, Dr. Jayaraman in chemical engineering is an expert in metabolomics. So the synergy between our distinct disciplines is something that we could not do individually, but we can only do together. So this is how I like to approach science.
And in doing so and in my basic research uncovering the potent functions of those unique biochemicals made by the microbiota. Once I uncover a mechanism of action for any one of these chemicals, it allows me to make a further hypothesis about how this may be useful in the context of disease.
So one of these chemicals I identified was regulating cells in a manner that I knew was important for hypertension. And I knew that if this was a compound that was limiting in humans and in animal models of hypertension, that it could potentially be a new and important drug for treating high blood pressure. But I’m not a cardiologist. I am not an expert in cardiovascular diseases. But luckily, my good friend Dr. Brett Mitchell in molecular physiology here at the College of Medicine, he’s an expert in this area. So I began to chat with him about our findings and what his disease model was revealing. And it turns out that the immune cells play an important role in regulating blood pressure as well. So the way immune cells need to be regulated seem to be the exact way this compound I had discovered was regulating the immune cells. So we just basically wanted to put two and two together.
So we wrote a grant capitalizing on our unique observations and our unique expertise, and putting them together. And we wrote a grant to the American Heart Association on trying to understand one, the role of the microbiota and hypertension. And two, trying to understand the changes in the chemicals made by the microbiota during hypertension. And weather, depending upon which one we identified, we can potentially use that as a novel antihypertensive drug.
So I think not so luckily, but I feel lucky. Dr. Mitchell and I were informed a couple of months ago that we received funding for what’s referred to as an innovative project through the American Heart Association. So something that they think needs a lot more study, but could potentially have huge impact.
So we’ve just received funding for this work and are getting it underway. It’s a two year grant. And at the end of this, we think that if our hypothesis proves correct and this compound from the microbiota proves to have a good role in regulating blood pressure, we’ll probably be very eager to continue the basic research but also move on to more translational research, which could drive the use of this chemical compound into the clinic for patients.
Christina Sumners: For patients who have high blood pressure.
Dr. Robert Alaniz:  That’s exactly right.
Christina Sumners: Wow.
Dr. Robert Alaniz:  And many things can cause high blood pressure as you know. The job itself that we have. But Dr. Mitchell has really studied a couple of models of high blood pressure. But one common model that I think we all can respond to is the use of, overuse of salt in our diet. So he has a high salt model of hypertension where basically, animals are fed large amounts of salt over time, their blood pressure goes way up. And then the trick is how can we bring that down? And we all know, stop eating salt.
Christina Sumners: Yes. But that’s much easier said than done. Yeah.
Dr. Robert Alaniz:  But human behavior and diet modifications we all know are much harder than we think they should be. And oftentimes, a simple solution that doesn’t alter your lifestyle is sometimes the easiest way to go to change a patient’s health outcome.
Tim Schnettler: Right.
Christina Sumners: That’s really exciting. I think most people would never have even thought that the microbiome could affect blood pressure.
Dr. Robert Alaniz:  That’s true. And I think we’re learning more and more in the general field of microbiome research of just how important this community of microbes is in regulating our overall health.
Some of the things that I do not study, but I keep abreast of in the field is really how the microbiome actually affects behavior. So there’s a rapidly advancing area of microbiome research, studying how the microbes that are in our gut influence behavior such that there may be differences in microbiome for people who suffer from autism. And it turns out there may be a unique chemical made by the microbiome that actually can cause autism, or can cause autistic like behavior in animal models. And that this chemical is found elevated in people who suffer from autism. And that if this chemical is given by itself to an otherwise healthy animal, it will exhibit autistic like behavior. So the way to approach using this as a target to alleviate symptoms of autism is likely find out which microbe might be making it or which enzyme of the microbe is making this compound, and develop a drug to inhibit that enzyme, which would then cease this compound to be made, and hopefully alleviate the symptoms of autism. So behavior linked to the microbiome, it’s not very intuitive, but…
Tim Schnettler: It’s not something you think of. I never would have thought that something like that could affect behavior. That’s unreal.
Dr. Robert Alaniz:  And I actually think when I got into this, I probably wouldn’t have thought that either. And that’s just 10, 15 years ago.
Christina Sumners: Yeah. What are some other disease models that microbiome affects?
Dr. Robert Alaniz:  To me, what makes this area very interesting is that the microbiome is now being shown to have profound effects on dozens of different diseases. So another one that is highly studied is the role of high fat diets, which cause obesity, that change the composition of our microbiome for the worst. And this was another disease model where the microbiome from an obese individual versus a lean individual was also transferred into germ free animals, and the animals receiving the obese microbiota became obese. Even without eating a high fat diet.
Christina Sumners: Doesn’t seem fair, does it?
Dr. Robert Alaniz:  This has a lot of epidemiological ramifications. Because if you think about it, if you happen to grow up in a family that has been obese, your parents were obese. And maybe you’ve tried your best. But a lot of times we inherit our microbiome from those in the environment most close to us. So your family. Families share similar microbiomes compared to each other than to different families. So you basically inherit a good portion, or the quality of your microbiome from your family and your parents. So you are fighting an uphill battle from the day you’re born if you grow up in an obese family. And this is very unfortunate. And despite people’s best intentions, if I’m going to change my diet and this, sometimes it’s hard to overcome those initial changes that were imprinted in your microbiome when you were born.
So this is an extra challenge, but it also provides maybe another opportunity for intervention. So perhaps children who grow up in obese households, maybe they need an intervention early. Resupplying a healthy microbiome. These microbiome transfers are one clinical remedy that are being experimented with throughout. It’s fascinating. And like I said, it offers another opportunity for intervention.
But for my research and more related to obesity type models, I’ve been working with a couple of investigators where either through a high fat or a high fructose diet, so high sugar. We all know sugar is poison now. But this causes not only increased fat deposition in animal models, but they both cause symptoms of metabolic syndrome, which is basically diabetes like symptoms. We can’t regulate our glucose, we don’t respond to insulin.
And the excess fat or excess adiposity is not recommended. But it’s really these metabolic changes and the inability to control glucose that causes a lot of the detrimental physiologic conditions that people suffer from.
So we’ve found that in animals that are undergoing a high fat or a high fructose type diet, some of the metabolites of the microbiota we’re interested in decreased dramatically. Suggesting that they were either beneficial at the beginning and that their loss is exacerbating this particular diet. So our simple hypothesis is that, and knowing a little bit about the functions and properties of some of these metabolites that I’ve already mentioned. We would make a new hypothesis saying that well, we think that not only will this function in preventing inflammatory diseases and hypertension. But it may actually play a positive role in regulating metabolic syndrome. And we still have some work to do. But early data is suggesting that we may be even able to use these metabolites as drugs to prevent or therapeutically intervene in diseases such as diabetes and obesity.
So it seems as if the opportunities for new drug discovery coming from molecules that are already inside us is just tremendous. And what makes it even more tremendous from my perspective is that when we look at the number of microbes that inhabit us, the number of microbial cells outnumber our own human cells by a factor of about 10 to one. So there’s more microbes cells in us than our own cells. And if you think of the genomic content of those microbes, it outnumbers our own genome content by a factor of 200. So there’s 200 more. And as we count better, that number is going up. 200 times more genomic potential in the microbiome than our own genome.
Christina Sumners: Right.
Dr. Robert Alaniz:  And then if we go beyond that and that for every gene, there’s a potential for one gene, one product. Or multiple products because of different modifications the gene product may undergo. The potential for novel chemicals made by the microbiota is over 3 million novel chemicals. Whereas it’s thought our own genome, just human genome only makes 100 to 200,000 maybe chemicals. So there’s a vast order of magnitude, greater number of biochemicals made by the microbiome that are likely functioning in some way in our body. And the challenge for us is to identify what they are, identify their function, and see if we can manipulate them for our benefit.
Christina Sumners: See which ones are doing nothing, see which ones are helping us and try to—
Dr. Robert Alaniz:  That’s exactly right.
Christina Sumners: Yeah.
Dr. Robert Alaniz:  So we’re very excited. It’s work that’s going to go on long before I retire from science, but I hope to make a good impact in these early stages.
Christina Sumners: Very interesting. It definitely sounds like you are. And thank you so much for being with us today.
Dr. Robert Alaniz:  My pleasure.
Christina Sumners: It’s great to talk to you.
Dr. Robert Alaniz:  Yes.
Christina Sumners: And thank you all so much for listening, and we will see you next time.