THE MICROBIOME SUMMIT : Love Your Microbiome

The RoboGut: A Tool For Studying the Microbiome

Dr. Emma Allen-Vercoe, PhD

University of Guelph

Overview
Transcript

Overview

Dr. Emma Allen-Vercoe has spent years fine-tuning the technology behind the “Robogut” at the University of Guelph. The Robogut is just as it sounds – it is a simulated gut that allows Dr. Allen-Vercoe and her team to study not only microbes in a community, but also the metabolites that they produce. Metabolites are small molecules produced by bacteria that are able to communicate with the cells in our bodies and can even influence chronic disease. In this interview, you’ll learn about this emerging area of study in microbiology – the behaviour and language of metabolites.

Transcript

Tracey:
We’re here at the University of Guelph with Dr. Emma Allen-Vercoe. She is a Microbiologist and heads up this lab that we’re sitting in, that houses the Robogut. Thank you for inviting us here Emma.
Emma:
You’re very welcome. Thank you for coming.
Tracey:
What can you tell us about your Robogut?
Emma:
Well, a Robogut is a very complicated piece of equipment. You can kind of see some of it behind you there. And really what it is a very complicated system to mimic what is actually going on in the human gut. What you can think of it as is a life support system for the microbes that live in the gut. So, it’s a little bit like a colon, but it’s an artificial colon. It doesn’t do all the jobs that a colon does for your body, but it does support the microbes that live in the colon.
Tracey:
So, in the jar is behind us are the microbes?
Emma:
Yes.
Tracey:
We can’t see them?
Emma:
No.
Tracey:
But they’re busy working?
Emma:
There are very busy working and you probably noticed the smell in the air.
Tracey:
Yes. I noticed the smell.
Emma:
The smell in here is actually a sign that the microbes are working because they’re making metabolites or small molecules, which are the ones that you actually can smell. Small volatile compounds you can smell are actually being made by the microbes all the time as a result of the work they’re doing to break down food.
Tracey:
Right. And these metabolites that they make they’re mimicking was happening in our colon every day?
Emma:
Yes. And that’s one of the reasons that we study them in this way because we can easily extract those molecules from the soup that’s in those jars behind you.
Tracey:
Can you explain a little bit about why these metabolites might be important for us to look at once the microbes make them for us?
Emma:
Well, sure. So, one of the things that we’re realizing about the human microbiome about the human gut microbiome in particular. It’s not about what microbes are there, it’s about what the microbes are doing. And the best way to see what the microbes are doing is to see what they’re producing. We in my lab, we tend to think of the microbes or the metabolites that are being produced as like the language that the microbes are using to speak. Because microbes use small molecules as a way to communicate with each other and you might think that bacteria and microbes don’t really communicate, but actually in recent years, we’ve realized that couldn’t be further from the truth. They are actually very actively communicating with themselves and each other all the time. And so, if we can look at the molecules that they’re making and decipher the kind of language that’s going on; we might also be able to decipher then what happens when things are wrong, and the metabolites are not optimal. And there is sort of a stress response as a result, and so, we’re kind of looking at how the metabolites change in the response to the food that we feed the microbes, in the response to things like antibiotics and those kinds of things.
Tracey:
Right. Now your Robogut is being fed specific types of food?
Emma:
Yes.
Tracey:
And you’ve completed some experiments?
Emma:
Yes.
Tracey:
Can you tell us about that?
Emma:
For sure. So the food that we feed the microbes is actually been designed by us over several years now as sort of a basal medium, and what I mean by that is it’s a sort of a standard medium that we can feed the microbes and under which conditions we know the microbes are going to behave in particular ways. And what we can do is add things to that medium, and so for example, we can add types of food- substrates like lentils or peas that have been broken down so that they exist in a soup like your colon would receive and we can see how those affect the metabolites so they’re being produced by the microbes that are present in that jar, and we can do the same with antibiotics. We can do the same with our food additives, pesticides and all those kinds of things.
Tracey:
Right. And have we drawn any conclusions yet?
Emma:
It’s early days because this work is actually very very difficult to do. I mean one of the most difficult things is the fact that we’re not looking at a handful of metabolites here and we’re looking here on average thousands of metabolites. And those are changing all the time and so we have to measure that dynamic range. We have to measure how things are changing? We don’t know which of those molecules are important versus which ones are not. There’s also certain different ways to measure different types of metabolites and we still have not kind of decided which is the best method to go. So, we tend to use an nuclear magnetic resonance just to take a look – it’s a very high level look. It’s a bit like the flying over top of the city. So, you can see the houses but you can’t necessarily see the people, but we can get a very kind of a broad look of what might be going on and then we can take a deeper dive in and see something that might be a little bit different using different techniques.
Tracey:
Right. Now this lab has only been in existence since 2008 so this is really new? New science?
Emma:
Yes. Yes. And it’s taken us a while to establish the right parameters, the right way in which to grow the microbes. So, the types of basal medium, I mentioned getting that sorted out took a long time. So, once we had that all sorted out and then everything comes into place. But as you can imagine there’s a hundred things or thousands of things that we can test in the system. Each of the experiments takes on average about three weeks to do. And each of the vessels that you see behind you houses one ecosystem and if we build onto that, the complexity that every single person has a different microbial ecosystem living inside their colon. We’re trying to understand how we can measure that in the most effective way. Otherwise, we’ll be here for decades and decades trying to figure this out.
Tracey:
Because my ecosystem is different from your ecosystem.
Emma:
That’s right. That’s right. And it’s also as well as the interpersonal differences. We’ve seen big differences between the western world and the less developed world. There’s differences in culture in general. There’s differences in childhood compared to adulthood. From adulthood to old age, and all of these things, you know, we have to try and muddle as best we can. We really are in the very early days of that.
Tracey:
So, what do you hope? What is your hope for the Robogut? What’s its future?
Emma:
Well, I see many different futures for them. I think probably the most important ones are trying to help people understand what sorts of foods might be beneficial or not so beneficial. There’s an idea that perhaps we might be able to use this kind of setup to understand how your particular microbiome that is unique to you might process foods in a particular way so that you could one day go to the supermarket and buy food, which is kind of tailored to your particular microbiome, which would actually not necessarily that any other food will be dangerous for you, but that the diet that you can then eat will be optimal for your microbes and you can get your optimal amount of metabolites health generating metabolites from it.
Tracey:
Right. Interesting. But people can experiment a little bit on their own to see which diet works for them
Emma:
Yes, they can. But it’s very hard to do and I think the vase of thought right now is that you need to go in the book shelf and you’ll see all these different diets to try. And I think that’s a general sort of era that we’ve made in thinking that there’s a one size diet that’s going to affect people and that’s not the case because everyone has a different microbiota, and so, you need to have a diet, which is optimized for a particular person. So, there is no one-size-fits-all diet and you do have to experiment with the types of food to see what makes you feel good versus not good. Because it’s very subjective and it’s very difficult to do. There is no way right now easily anyway outside of a research lab, and a lot of time and money to figure out how a particular microbiota can process foods in an optimal way for a particular person. But I know that work is underway and several researchers around the world are trying to determine how we can kind of look at certain parameters that might be important, which will make it a lot easier. We wouldn’t have to look at the whole thing. Just a few different markers that would be a lot easier to do. But we have to understand what those markers are first.
Tracey:
Absolutely. So, I’m just curious what have you fed your Robogut?
Emma:
So, right now we have an experiment going on with Agriculture Canada and we’re looking at different types of pulses. So, light beans and lentils, and we’re looking at different types of microbiota from healthy people, obese people, and people with ulcerative colitis. And we’re looking to see how those foods substrates actually affect the microbes in their situations. So, we’re measuring the beneficial metabolites. In this case, we’re measuring things like butyrate which are considered to be a good metabolite as an overall bio marker like I was just talking about.
Tracey:
Right. It’s one of the short chain fatty acids.
Emma:
That’s right.
Tracey:
So, where are you so far in your experiment?
Emma:
We are about halfway through running all of the different vessels. It’s about a three-year long experiment. So it’s a quite a while. The experiments themselves take three weeks’ to run and a week to set up and then a week to take down and cleanup and start again. It takes a while.
Tracey:
So we can expect to see this in?
Emma:
I think will expect to see the first results coming out within the year.
Tracey:
Wow.
Emma:
And so, we’re really hoping that’s a…we definitely have seen differences in – actually what we have seen in the vessels, but we’re working with Agriculture Canada to do the analysis so that’s going to take some time to come out.
Tracey:
Right. Interesting. Now the one that’s behind us right now, you explained to me a little bit about that. Its interesting what it’s doing? Can you?
Emma:
Yes. It’s a special type of ecosystem, this one. And this is one that we have developed to be a therapeutic ecosystem. Ah, so what do I mean by that? I’m sure you’ve heard of fecal transplants? And fecal transplants are being used quite successfully for treatment of C. Difficile infection for example. But the problem is that they’re icky and it’s very primitive using human waste as medicine.
Tracey:
It’s taking poop from a donor and…
Emma:
Exactly. And putting it into another patient.
Tracey:
And putting it into another patient. Yes.
Emma:
And so, that’s not without risk because there’s plenty of other things that you can pass on through a poop donation, and of course, we don’t want to make these poor people with C. Difficile even sicker than they already are. So, what we did is we isolated from a very healthy donor a subset of microbes that we put together into an artificial ecosystem. Artificial from the point of view that it’s a cleaned up microbial species that are in there. So, it’s a little bit like a super probiotic mixture if you think about it like that. And then we can grow that is an ecosystem and then we can actually give that to people as medicine instead of a fecal transplant to treat that C. Difficile infection.
Tracey:
Now this is different from a probiotic? And you’re calling it?
Emma:
It is different from a probiotic.
Tracey:
What do you call it?
Emma:
We actually call it “repoopulate.” But it has a another more generic name now, and we’re developing it as a biologic drug. So, there are differences. So, probiotic is actually overseen by the Food Directorate and in generally, Health Regulatory Agencies. But this is a different thing altogether.
Tracey:
And it can be one strain of the bacteria or multi-strains?
Emma:
So, a probiotic tends to be one or two or maybe seven or eight strains. And usually a bacteria, and usually bacteria from a very narrow range of phyla. So taxonomic groups. That doesn’t make an ecosystem. So, what we’ve done is we’ve taken the human gut and we’ve isolated the microbes that we think are the really beneficial microbes. They span a group of taxonomic range so they’re actually much more mimic what’s really going on in an ecosystem and then we’ve created from that a drug. It’s a mixture of purified probiotic and probiotic is the wrong word, but it’s a mixture of purified strains that we put together. And it behaves as an ecosystem.
Tracey:
Right. I think that’s really important – the behaving as an ecosystem. Because this is something that’s new for us to sort of think about. That we are a living, breathing ecosystem. We are our own gardens.
Emma:
That’s right. And I think that lots of people probably don’t realize that they’re really not human. We’re actually all super organisms of humans and microbes. So, the human side of us is what we see everyday because those microbes are too tiny to really see them without a microscope so we tend to forget about the microbes. But if you think about metabolism, and metabolism is really what we do in my lab. Humans are very poor at metabolizing. Human cells really have a very limited range of metabolic pathways that they can undertake. So, where does all the missing metabolism come from? It comes from the microbes. Because microbes are professionals at metabolism. They can metabolize a very broad range of compounds and they can do it very very effectively and they have been doing it for billions of years. So, I think that’s one of the keys or the takeaways here that that part of us is part of us and and it’s there a metabolic engine. And I’d like to think of it as the metabolic engine of the car, the car body of our bodies.
Tracey:
Right. Right.
Emma:
And so, if we want that engine to run effectively, we need to feed it the right fuel so that it runs effectively, and so when you’re thinking about diets and how that kind of interacts with the microbiome is probably the number one way to everyday modulate your microbiome. So, it’s a lot easier for people to think about eating healthy diets if they know that they’re actually helping they’re microbes.
Tracey:
They’re feeding theirs.
Emma:
They’re not just doing it because Health Canada tells them to right? Yeah. So, I think that’s important.
Tracey:
I do too. Feeding the microbes seems to be something that we need to think about every single day. And what food we feed those microbes from what you’re studying seems to be that it’s going to be individualized.
Emma:
I think yes. We’re going to definitely see – I mean personalized medicine is a buzzword. I think that is definitely already coming to fruition. I think personalized nutrition is another one, and I think that’s going to be important for everyday life. I think that we’re going to start to realize that there are certain foods, which are beneficial to an ecosystem or some foods which may be neutral. Or some foods which may actually be detrimental. In general we don’t think of food that way. In fact you just have to look at a food label and see how it’s broken down into nutrient components and caloric amounts – the amount of calories that are there. That’s going to vary actually between person to person because we can extract more calories out of our particular foods depending on the type of microbes that you have in your gut. So, some people might be a lot better at doing that and some people might be less able to do that. So, if you’re reading a food label like that it can be a little bit misleading into thinking that it has that calorie amounts and it’s going to be in the general ballpark but is going to be different from person to person.
Tracey:
Right. Interesting. So with your synthetic poop – can we call it that?
Emma:
You can call it that. Yes.
Tracey:
With your synthetic poop using it as a base to look at different disease states. How does that work?
Emma:
So, what we’ve done is we’ve taken healthy individuals and we call those our healthy communities. Ah, what we do there is we take poop from these healthy individuals – they’re very generous donor – and we isolate. What we’re really good at in my lab is anaerobic bacteriology. So, what do I mean by that? I mean the microbes, so anaerobe means or lack of oxygen. So…
Tracey:
Deep in the colon?
Emma:
Deep in the colon. People don’t really realize that the colon is actually very anaerobic no oxygen environment. There’s a very low oxygen type tension there. And that’s because a lot of the microbes that live there, the metabolisms that I told you about that were so important; it can only occur in the absence of oxygen. Oxygen is actually a very toxic molecule to a lot of microbes. It’s important for us but is very toxic for the microbes. So, they have set up a little environment for themselves there where they can exclude oxygen. And so, we’re really good at anaerobic microbiology and it’s not an easy type of microbiology. So, we have to special chambers we can grow the microbes in and it excludes the oxygen. But what it does allow us to do is what we can culture these microbes, and we’ve got very good at unculturable microbes. We can actually prove that they’re pure and then we can put them back together into what we call a defined ecosystem. So, now instead of it being poop it’s actually defined poop so we know exactly what’s in there. And the great benefit there is that we can now tailor and engineer ecosystems and we can take things out and add things in, and see what those particular microbes are doing to the overall ecosystem. And so, that’s kind of the key to how we’ve applied that to looking at diseases and health is we’ve made defined ecosystems that mimic health. And several different healthy individuals or what we would consider healthy. But we also have the same for obese communities that have come from obese people. Those are very interesting.We have some from ulcerative colitis communities so inflammatory bowel disease. And also from autism and a number of other diseases as well are sort of coming through. And what we’ve seen, I suppose that we’ve seen lots of things. But just to sort of get it in a nutshell. Something that has come out of that work that we already realized in the field is that sick ecosystems tend to have less biologic diversity and that just means that there are a fewer species in a general term. But what it really means is that there’s a fewer capacity for metabolic work. Or less about it.
Tracey:
Right. We’re learning about that. Diversity is very important.
Emma:
Diversity is key, but in a way that we’re not quite sure. It’s very difficult to define. But what I can tell you when we look at an ulcerative colitis community that’s come from someone who suffering from a flare of colitis. The diversity is very poor. Very poor. And also, that the taxonomic distributions of the types of microbes that are there is very narrow. And so, it’s been in some kind of an event and it’s like the rainforest has been cleared and what’s left is really not very good at producing what is needed to keep the body healthy.
Tracey:
So, in the future your synthetic poop might be a treatment option?
Emma:
That’s what we’re hoping. But we can’t just kind of throw poop at the problem and see what sticks and hope. We fix it and we have to be like mechanics in a car shop and we’re talking about an engine. It’s much better to be a mechanic that can look at an engine and see what’s wrong, rather than just say, well, there is something wrong with the engine let’s take the whole thing out. Replace it. It’s much better to sort of try and replace those faulty parts. So, we’re trying to understand the metabolic engine and how the microbes are contributing to the metabolic engine and how we can kind of fix it without having to drastically undo what nature has already done with the ecosystem that’s present. But instead, just augmenting the ecosystem.
Tracey:
Right. Now have you experimented at all with the Robogut with what specific things might be not so good for microbes?
Emma:
Ah, well, we have done a lot of work looking at antibiotics. And so, antibiotics is one of those areas that people say to me “Well I will never take antibiotics again” and I would say that’s a very bad idea. Because antibiotics they are very important drugs and they exist in medicine for a reason and they will always have a place for in medicine and they save lives.
Tracey:
Absolutely, they do. Yes.
Emma:
But I think that the difference is that now we’re beginning to realize that antibiotics when they’re taken orally or when they’re taken for treating some kind of infection, there’s collateral damage to the microbes on the body. Up until recently, we didn’t consider were really part of the body. So now we know that when you’ve taken an oral antibiotic, just about any antibiotic will have some collateral damage on the microbes in the gut. So, what we’ve been trying to do using the Robogut is to understand the extent of that damage.
Tracey:
And what have we learned?
Emma:
Ah well, what we learned is that if you have an ecosystem, which is diverse, that ecosystem is much less likely to undergo damage, which is going to be sort of terminal damage. So, for example if you’ve got a nice healthy ecosystem and you take what’s the equivalent of dose of a week of amoxicillin and then you let the ecosystem recover afterwards and then you’ll see recovery and sometimes it’s complete and sometimes it’s partially complete, but it’s on a trajectory and we can’t run these things forever. So, it’s difficult to see. But when we look at for example, a less diverse community and that’s been treated with antibiotics, we see that community really suffers and it really struggles to come back.So, what we think is going on just generally in the field and the idea is that you have a diverse ecosystem if it receives a hit, once in a blue moon from an antibiotic; probably, it will recover from that. If it’s a nice healthy ecosystem if you’re supporting it by eating the right kinds of foods. But if you take an antibiotic and then you, for whatever reason, take another antibiotic and may be a different class shortly afterwards. I can’t define shortly, because it’s going to be different for different people. And if that pattern continues and the damage compounds, then it’s actually very difficult for that ecosystem to adjust and recover.
Tracey:
So, when is our ecosystem fully developed, when does that happen?
Emma:
Well, it is debatable. So, we know that it develops very rapidly during early childhood and especially during the time of weaning there’s very rapid changes and very drastic changes that happen as a baby is introduced to new foods. We think we see that the majority of changes that have become stable and that everything has happened by the age of between 3 and 5. But it is going to depend on cultures and it’s going to depend on the maturity of the infants and all of those kinds of things.
Tracey:
Right. Whether they were breastfed or bottle-fed.
Emma:
Exactly. All of those things are going to play a role.
Tracey:
Do you think in the future we’ll take a five-year-old and be able to say, okay, you now have a very healthy microbiome you’re good to go?
Emma:
That’s right. Well, I actually think that this is going to be where this kind of work is eventually going to come into its own. When we start to understand what is healthy which we don’t yet know. But when we do, we can start to apply that knowledge to children and make sure that they’re developing normally, that the microbiota were developing normally, and for example, a lot of antibiotics are given during childhood because that tends to be the period of time that children are most vulnerable to infection. We can then see if they need an antibiotic we can maybe predict what might be happening to the microbiome as a result or we can measure what is happening to the microbiome as a result of the antibiotic, and then make sure it’s back on a trajectory to recover, and if it’s not, we might be able to intervene. And that’s something that isn’t done right now. We don’t really have the ability to do it properly in a various of ways right now, but I can see it in the future.
Tracey:
Where do you think the future is?
Emma:
I would say within ten years, there will be ways of measuring that in our lifetime.
Tracey:
So, our lifetime?
Emma:
I would say so. Yes.
Tracey:
Interesting stuff. Thank you so much.
Emma:
You’re very welcome.