Bacteriophages' role in the gut with Bryan Hsu

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Travis

Currently your body is full of bacteriophages. If this is the first time you've learned this, I apologize that it had to be in this setting. But I have good news for you. Bryan Shue is an expert in this very topic and was kind enough to join me on the podcast to explain what these things are and how they might actually be beneficial to our health.

Bryan is an assistant professor in the Department of Biological Sciences and an affiliate of the Freeland Life Science Institute. His research broadly focuses on using an interdisciplinary approach towards understanding and remodeling gut microbiota, with a special focus on discovering new phages and genetically engineering them to do good things for us. So Brian and I talked a little bit just about what phages are, how long we've known about them, and we got into what they do and don't do inside our guts. We also talked about what we're talking about when we're even saying the word guts because frankly, I wasn't really sure. explained to me some of the positive uses that he thinks phages might be able to do specifically related to antibiotic resistant bacteria and also the delivery of drugs in our guts. He shared a little of how he got into this field, why it gives him hope for the future and not to spoil anything, but we wound down the conversation talking about the importance of poop in this whole process. Be sure to follow, rate and or subscribe to the podcast.

I'm Travis Williams and this is Virginia Tech's Curious Conversations.

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Travis

I know you've done a lot of work around this topic of bacterial phages. So I think that's just a great place to start. What are bacterial phages?

Bryan

Yeah, bacteriophages, sometimes people call them phages, which I'll do now because it's just shorter and easier. These are viruses that only affect bacteria. So they're all over the place. Everywhere where there's bacteria, there's probably a bacteriophage. Most people will know about phages because of phage therapy. So there is this interest in using phages to kill bacteria as an antimicrobial especially for bacteria that are maybe antibiotic resistant. But because we can find them everywhere, they're kind of ecologically entrenched with bacteria. you you say, people say that your gut microbiome, sometimes you're more bacteria, bacterial cells and human cells. There are just as many phages in the gut as bacteria. And so what we're trying to figure out is what is the significance of these phages? to bacteria and to kind of the host environment that they're in. For example, us, if they're in the gut microbiome. And that's an area that's not super well understood. That's an area that people are trying to get into and trying to understand. And there could be some cool things, but we just don't know them yet.

Travis

So do I have phages in my gut right now?

 

Bryan

Yeah, you're full of them.

Travis

And I hear people ask this all the time and my son who's six asked me this question the other day. He said, what is my gut? So what are we talking about when we say the gut? I know that's a simple word. use it a lot of times, but I'm curious. Is it my stomach? Is it my intestines? What is it?

Bryan

It's all of those things. mean, it's the whole gastrointestinal tract and there as you like, you're basically a big meat tube, right? The inside of you is where the digestion happens, right? So, so then you eat food and it starts degrading your mouth, breaks it down, stomach breaks it down even further, your small intestine starts absorbing the little pieces of the things that you broke down. And then eventually that massive food that you ate turns into poop, right? And so along this tube that you have, you have a microbiome bacterial components, viruses that change for the whole duration of that tube, because you have different things available. And you as the body, your body itself has different things that can be provided to those things in your in your intestinal tract. So when people talk about a gut, it's usually just this short term, this a quick way of saying your whole GI tract, but most of the microbiome stuff that you might be thinking of probably happens in your lower GI tract.

Travis

Well, how long have we known about phages?

Bryan

long time, like more than 100 years. So we knew about bacteria before that obviously. But when we first learned about phages, people knew that they killed bacteria and they thought of them as antimicrobial. They thought they were exciting because this would be a new way of killing bacteria. And they came around a little bit before, but right around the same time as antibiotics. But because, you know, antibiotics took off, phages became less exciting as antimicrobial. But people, scientists at least, have been studying phages for a long time and they, there were means for understanding genetic transfer. So how genes can transfer between species or between cells. And so they had been of, you know, a lot of scientific interest for a while.

Travis

How are we able to leverage these to help maybe fight against bacteria? Because if they fight bacteria and I have them, it seems like obviously that's a bad question.

Bryan

you're asking a good great question because people always wonder about the anti the the bacterial killing effect right for phage therapy there that's the primary thing people are interested in is can we find or engineer phage to be a better killer of their targeted bacteria right phages are pretty specific and that they like certain species so that's one of the reasons why people are interested in phages now is that you can potentially kill a pathogen without affecting the rest of your gut microbiome, for example. So one way doing engineering or isolating from wastewater and things like that, people will try to see which phage can we isolate from the environment or generate has the best killing properties. And, you know, using these phages in phage therapy, that's a whole nother challenge. Because if you look at the role of phages, in the ecological environments that end up coexisting with bacteria. So it's optimal to not necessarily kill all of their bacterial hosts. I always like to think of things in more of like a macroscopic environment, right? If you think of lions, right? Trying to kill gazelle or something like that. I don't know if they're actually in the same environment. The ecology of my department will kill me. But a predator killing a prey, is it to the predator's benefit to kill all the prey? And right in the way you could if you deploy lions as anti gazelle therapy, I mean, what you probably is going to end up what's probably going to end up happening is that you have this predator prey kind of coexistence that happens. So with bacteria and bacterial phages, there's also this coexistence that occurs where phages propagate on their bacterial hosts. But then sometimes they deplete whatever bacteria are available to them. And then those other bacteria that are able to hide really well will survive. And then the phages kind of disappear a little bit until those bacteria reveal themselves again. And so they end up having this back and forth between each other. And there's also genetic elements that allow bacteria to be resistant to the phages and phages can counteract that resistance and so on. So there's multiple levels of this coexistence that occurs.

Travis

Yeah, is there any way to know which, is there certain types of bacteria that they target versus they just kind of live in peace with?

Bryan

Yeah, well, it's hard actually. We don't, have a general idea from, you know, doing, doing sequencing of the bacteria phages that are in the environment. You can do some host assignments, but usually it's not to this level of specificity that's needed to really precisely know which bacteria get infected by the phage. But there are different kinds of phages. There are phages that are virulent or follow a lytic life cycle. That's where every successful infection leads to bacterial cell death and the release of new phages. So that's like a lytic life cycle. There's also this lysogenic life cycle where a phase can affect the bacteria and then also integrate its genome into the bacterial genome and kind of hang out for a while until they feel the time is right. then they jump into the lytic life cycle where they make progeny, phage, lysate, bacteria that release those phage.

Travis

That was actually my next question was like, what about on the phage side of things? Can we figure that part out a little bit better? And it sounds like that maybe we have.

Bryan

Yeah, we're learning a lot about how phages interact with the bacteria in our life cycle and what are phages doing. But there's still so much more to learn. Every time we learn a little bit of something that opens a door for several new things to try to figure out.

Travis

Yeah. Do we know some of these phages that are more active and are more proactive against certain bacteria? Do we know how to use these to help make us feel better in general yet?

Bryan

We're trying. We know that phages have specific effect on their bacterial hosts. Now, bacteria don't live alone. They live in communities, sometimes with hundreds of other different kinds of bacterial species, especially in the gut. So if you introduce a phase that targets one bacteria, how does that affect the entire community? And that is not well understood. You can think that you have a way of altering the bacterial community if you provide enough phages. But to predict that is a little tough because everyone has, you know, different gut microbiome. They have different bacterial communities in their gut. They also will have different phage communities there as well. So if you introduce new phages, how does that affect that community? How does that reshape your gut microbiome? Well, we can try to predict things, but it's not always going to be totally predictive. So there's other ways of, there's, think we, you connected with me to talk about that mouse model that we developed, right? But there's also that we published something earlier, which was using a lytic phage or a virulent phage and engineering it to produce proteins, therapeutic proteins. The idea being with this coexistence, where a phage won't affect a bacteria and lyse that bacteria it can, we can reprogram that phage to produce a therapeutic protein so that it can get released with the progeny phage. and being in directly in the gut microbiome, that's a way of delivering, you know, therapeutic proteins. So we've been able to, produce a few different kinds of proteins, ones like a marker protein. So you can just see where it is. And the other things are things that inhibit, proteases that are associated with IBD or a protein that when it's broken down mimics a satiety hormone. And so when we give mice a high fat diet, when we have this engineered phase, gain way less weight than a mouse that has the non-engineered phase or no phase at all. So there are some ways to leverage through genetic engineering, know, leverage the natural relationship that bacteriophages have with their bacteria for therapeutic function. But then there's also other ways of trying to modulate the gut microbiome as a whole, that we're still learning about what are the consequences of that. Because what I mentioned of the community living in coexistence, everyone having a different gut microbiome. So the predictive ability there is going to be a little bit more difficult.

Travis

I'm curious, what would you use a therapeutic protein for?

Bryan

Well, if you watch TV and you see all these pharmaceutical advertisements for things to treat whatever diseases, those are usually protein therapeutics. You know, like monoclonal antibody for targeting something or you have peptides, you know, like GLP-1 agonists, have Wigovia and all this kind of stuff. Those are protein or peptide based. So, The thing about oral, like when you go to the supermarket or you go to CVS or something and you have a headache and you go get Advil or Tylenol or something like that. You can take it and swallow it and then it works that way, right? Because it's a small molecule, it doesn't get degraded in your stomach and then it gets released in your intestines and the small molecule can be absorbed really easily. then so that's an easy way to take things, things that are proteins are really tough to administer orally because your body is built to break down biological materials, right? Because you eat food, you eat proteins, you eat these kinds of things, your body's built to digest that stuff. And so the likelihood of those things that you eat or the biologics you take orally passing through your stomach is really low because it's probably gonna get degraded. that has generally been a challenge. And so if we use phages and then replicate on your gut bacteria to produce those proteins that normally wouldn't be orally available.

Travis

I'm curious what the potential is for phages, especially related to this kind of rise in antibiotic resistant bacteria, because I see that a lot being publicized. I see it a lot in the news. It's a major concern of a lot of people. It's the reason why my wife is like, make sure you finish all your antibiotics all the time now. Do you think the phages may provide some answers to maybe that problem now or in the future?

Bryan

It's tough because bacteria like to not be killed by any means, So whether by antibiotic or any other means. for antibiotics, know, antibiotics work usually by specific mechanisms where they will target some feature of a bacteria that the bacteria needs, right? And then bacteria replicate so rapidly that they can, like a large fraction will die, but some others will have had this adaptation through mutation to where they're not susceptible anymore to that particular antibiotic. And then you can choose another antibiotic or another one. And then so when we run out of antibiotics, so what's the choice now? Well, know, phages might be that choice. They have a way of killing bacteria that is different than antibiotics, and they can replicate on the bacteria. But just like bacteria developing resistance to antibiotics, bacteria can develop resistance to phages. So there's think as an alternative, if you were the one that is dying and you need a way to get rid of this bacterial infection, antibiotics don't work. Phages are fantastic thing to look into. But they are not. Well, I shouldn't say this because you're going to post it, but they they may not be the ultimate solution because bacteria on a whole can develop resistance to phages as well. Right. So they don't, I don't think that they're going to be replacing antibiotics, but for the individual or individuals that are in desperate need of some kind of therapeutic, you have to look at all options, including phages.

Travis

So maybe not the end-all be-all solution to get rid of all illness, but maybe this is another tool that we put in the tool belt to fight against some of these tricky bacteria. Are there good and bad phages or is most of their work resulting like a positive thing? Yeah.

Bryan

Well, okay, so the positive thing we don't know about that's actually stuff that we're my lab is trying to study. There, you can say that they're doing neutral stuff, maybe. It's just not really, really well known, right? I think they're doing positive stuff. I don't, we're building evidence to show that they're doing positive stuff. So I can't tell you definitively yet, but I think we have some good preliminary evidence that they are. We do know that they're doing negative stuff, though, some of them. So things like pathogenic E. coli sometimes can have these temperate phages that have integrated into their genome. And they're dormant usually. But then every once in a while, they'll decide, oh, I want to go through the lytic life cycle. they excise or pull their phage genomes out of the bacterial genome, replicate, make new phages. lyse the cell and release these progeny phages that can go and infect new bacteria. So that sucks for the bacteria. So it doesn't affect us. But those prophages or those phages that are integrated into the bacterial genome also have these genes that produce toxins. So they only release these toxins when they go through the lytic life cycle. So things like sugar toxin, cholera toxin, these kind of toxins are produced and released when those phages lyse those bacteria. And that's why in some cases when you have an enteric infection with E. coli, the doctors say don't take antibiotics. It's because certain types of antibiotics can induce these phages to pop out and produce toxins. So actually it will make your infection worse.

Travis

So it sounds like we just really need to understand more about these things.

Bryan

I think so too. Yeah, yeah,

Travis

How did you get into this line of work and did you want to study bacteria and the things that happen in our body and our guts?

Bryan

I think it's weird because sometimes it's like a circumstance of your situation. So I was a chemical engineer and a material scientist as an undergrad. So I had engineering degrees. And then I did research in a chemistry lab, something like physical chemistry, studying catalysis. The thing that your car does, your catalytic converter, you have all these beads of precious metals. And then the reason they're there is because they convert the output gas of your engine car engine into like water and stuff and CO2. So I used to study how those reactions happen on the surfaces. And then I realized that when I went to grad school, that I kind of wanted to do something more biologically related. And then so I was technically a chemist in in my PhD. program. And then I was making thin films that release drugs, things that will kill bacteria, for example, on implants, right to prevent implant related infections. And then when I finished my PhD, I realized, you know, I know nothing about bacteria, the things that I'm trying to target. So then I did a postdoc in systems or synthetic biology with the gut microbiome and there happened to be a position open in the gut microbiome area. And then I wanted to work in something different that not everyone will be working on because I knew that I knew nothing about whatever I was starting to do. So I wanted like a longer runway to catch up. So I started working on phages because they weren't too hot in terms of research-wise. We're getting more exciting. Things are picking up. People are getting more interested. So yeah, during my postdoc, I was working on that and then I applied for broccoli jobs, came to Virginia Tech and then started my lab, mostly working on bacteriophages. But then we have another part of my lab that's working on biomaterials for women's health. So I still keep a little bit of my engineering in my research.

Travis

That's awesome. sounds like you kind of went from maybe studying how don't know, it sounded like engines and cars work to studying how the engines that we are.

Bryan

Yeah, everywhere needs, everything needs more investigation, I think, to advance in society.

Travis

guess I'm curious, in this space, what gives you hope?

Bryan

Well, there's a hope of opportunity, you know, hope in the unknown, because we're learning so much about what is there, but we don't know how the things are happening or what the consequences are of those things for health, for example. So learning about these inner mechanisms of things you probably would never have thought of, right? most people never think about bacteriophages, right? Opens a door for new opportunities of understanding how to benefit health. You know, maybe these phases are doing something exciting that we didn't know and then we can use this therapeutically. It also opens opportunities for other people to do innovative things, which is, you know, once these ideas become available, other more creative people or intelligent people can devise something that is exciting, know, therapeutically, commercially, environmentally, all kinds of reasons. increasing this knowledge out there, I feel like opens a larger door for new opportunities for people to get excited in.

Travis

Well, I think that does sound very helpful, especially seeing how you're studying things that are just like running all through me. So I would look for you to better understand that to help you.

Bryan

Yeah, the best thing about studying the gum microbiome is so easy to study. You just collect poop and you're just non-invasive,

Travis

I hope so.

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Travis

And thanks to Brian for helping us better understand phages and the work that he and his colleagues are doing to help unlock the potential they may have to benefit our health. If you or someone you know would make for a great curious conversation, email me at Traviskw at bt.edu. I'm Travis Williams and this is Virginia Techs. Curious Conversations.

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