THE MICROBIOME SUMMIT : Impacts of Sanitizing Our World
Is Autism a Gut Disease?
Dr. Emma Allen-Vercoe, PhD
Autism has generally been approached as a brain disease. But Dr. Emma Allen-Vercoe, the lab director of the “Robogut” – a simulated gut that allows researchers to study microbes and their metabolites – is challenging the current understanding of autism with a different question – what if autism is a gut disease? Dr. Allen-Vercoe is engaging research in this important field by furthering the work of the renowned microbiologist Dr. Sydney Finegold who originally asked this question. In this interview, you will learn about how metabolites produced in the gut can influence the brain.
- Tracey:
- We’re here at the University of Guelph with Dr. Emma Allen-Vercoe, a Microbiologist and the Lab Director of the Robogut. Thank you for inviting us here today.
- Emma:
- Thank you for having me on board.
- Tracey:
- So, we’re going to discuss today some of the research that you’ve been doing in the area of autism, which is a passion project of yours.
- Emma:
- Yes, it is. It’s a little bit far away from what I’ve done in the past. I mean, my original projects were on inflammatory bowel disease. So, you’re probably wondering how did I get from inflammatory bowel disease to autism? And actually, it was through a mentoring good friend of mine, Dr. Sydney Finegold, who is at UCLA. Who I had lunch with him one time, which was a transformative lunch and one of those moments when you feel like, oh, well maybe I need to start looking at this. And I was aware of his research in autism at the time but I didn’t realize how far he’d come. And really, what the idea was is that autism is actually a gut disease, and not a brain disease. And that was quite a different way about thinking about things. And so, I was intrigued because you know that Sydney Finegold is one of our leading micro- Microbiologists in the world and very well renowned. And if he says that and perhaps we should sit up and listen. So, I did listen to him and he told me about his studies, and he had actually done a study back in the late the 1990s. When he took a very small group of autistic children. This is a severe form of autism now. Remember autism is a spectrum of disorders. So, what he was interested in was the regressive type of autism, which is the type of autism, that tends to develop later in life. Ah, when I say later, a child will develop normally for the first year or so of life and then regress and usually in a very dramatic way. And it is also, unfortunately, the type of autism that it seems to be associated with vaccines. Although, that we know now that’s the wrong assumption.
- Tracey:
- Yes.
- Emma:
- And so Dr. Finegold was was interested in this and found a small group of children and reasoned with the help of a parent of one of the children Ellen Bolte, who is actually an amazing woman who made the connection in the first place. Now perhaps there was something wrong with the gut and if that was true, and it was the microbes in the gut, and if he was to give some antibiotics, and in particular, an antibiotic called Vancomycin, orally to these children. The Vancomycin is a very large compound so it doesn’t get absorbed by the body as it transitions to the gut. And if that’s the case, then if it was given as an oral antibiotic, then it should only have an effect on the microbes present in the gut. And this study was quite transformative because in all eight children – I think it was eight children, eight or nine – there were significant gains made in behavioural and the symptoms of the autism that these children were suffering during that time period. And of course, unfortunately, it wasn’t to cure and it was never meant to be. It was meant to be a principle, to the share principle that there was something wrong with the gut.
- Tracey:
- Now that’s the parent who made the connection that something happened after a course of the antibiotics?
- Emma:
- Yes. So, Ellen Bolte was the parent of the child who was the index case in that series, and her child was Andy Bolte. He was her fourth child and so you think that she would know what she was doing as a parent by that point, and so, she realized that her son was developing fairly normally. He actually had like 15 courses of antibiotics in the course of about nine months. For what was thought to be an ear infection, which actually wasn’t an ear infection. It was some kind of an intolerance that was causing an inflammation of the inner ear. But the pediatrician at the time just kept giving antibiotic after antibiotic. Because the time that was the knowledge.
- Tracey:
- The standard of care.
- Emma:
- Right.
- Emma:
- And about halfway through those courses of antibiotics the child crashed in a big way and went from being a very placid, normal child to being a very aggressive and very upset, screaming typical behaviour for this sort of regressive autism.
- Tracey:
- Right. Now that was just the sort of the question raising – “Well, is there a connection between the gut and the brain?”
- Emma:
- Yes. And so now I had heard about this study and Sydney Finegold was sort of “you know, I started to look at the microbes now that are in the guts of these autistic children.” And a few people have started to do that as well with the tools of just coming online, which was the sequencing tools. And they had started to see the differences in the gut microbiome of these children. Unfortunately, it’s very difficult to tell because what was going on, they were using sort of the earlier tools and varied health studies to do you kind of needed because everyone is different remember. So, everyone has a different microbiota so it’s very difficult to tell what’s normal and what’s not. And so, there’s a lot of those early studies weren’t powered to adequately tell one way or another. And in my lab, we are beginning to think that perhaps we shouldn’t be looking for the specific microbes that are causing the problem. But instead we should be looking for the specific outputs of the microbiomes of these children. Thinking or reasoning that the metabolites that are being produced might be out of whack. Because the ecosystem is abnormal in some way. And again, it’s not about why bugs are there it’s what they’re doing. There’s a few clues that make us think that we might be on the right track, and I think for the biggest clue is that if you speak to parents, they’ll tell you that their child does improve, their behavioural symptoms does improve when they change the child’s diet. And so, when they change the diet of a child, what you’re doing is not changing the microbes per say, but you’re changing the way the microbes are metabolizing that food. So, you’re changing the metabolites that are being produced. So, our working hypothesis is that there are microbiomes that are associated with these children and which have the potential to produce metabolites that may not be beneficial, and may in fact, even interfere with brain developmental processes. And so, kind of explains why you change the diet um and for some lucky parents that’s seems to do the trick and they can manage their child’s symptoms. For some children it doesn’t work so well, because this again, it’s not a one-size-fits-all diet that we can do here. It has to be apparent and we don’t know really what’s wrong with the metabolism at this point. So, that’s what we’re trying to find out.
- Tracey:
- Right. What diets have been successful so far?
- Emma:
- Well, there’s a lot of talk online about casein-free, gluten-free and those kinds of things. And again, very difficult to know. In fact, we did a study in the Robogut where we tried to feed a an ecosystem that we had taken from a child with severe autism who had reported to have improved when they came off casein and gluten. And so we wanted to see what happens if we took that ecosystem and fed it casein and gluten, and we couldn’t really see any big difference. But I will stress maybe when we don’t have the capacity to go deep enough to see what’s going on. The method that we’re using to measure the metabolites is actually a very crude method and it’s a lot more expensive to go kind of deeper down. So, that’s something for the future and I also think that maybe it’s not the casein and the gluten itself, but the other things that go with those kind of food groups, that could be an issue. So, those we haven’t tested yet so it’s quite difficult to do.
- Tracey:
- Understandably. Because each of our ecosystems is so unique. So, we’re learning though that the diversity of the ecosystem is key. So, can you explain a bit about that?
- Emma:
- So, diversity is important because in any ecosystem in nature if you have diversity then you have the capacity for the ecosystem to adapt to whatever is thrown at it. Because there’s always something in there that can cope with the stress and can sort of support the other microbes that are present in the ecosystem or the other things that are present in the ecosystem to kind of live through whatever the perturbational stress there is. But when you remove that diversity then the ecosystem can collapse. And I think with the best analogy for that is a rainforest. If you think of a rainforest, there’s many many different types of species that live in a rainforest. It’s a very diverse ecosystem. Naturally. And you probably wouldn’t notice if one of the species in that ecosystem went extinct. Unless you were specifically studying that organism and the reason for that is the whole organism will adapt to that extinction event. Now if you take a naturally less diversity ecosystem, and a good example is the Kananaskis Forest outside of Calgary in Alberta. There’s a situation there, which is natural situation, which means that the ecosystem is a lot less diverse and that is at a higher elevation. There’s high UV and there’s extreme of temperature is extremely dry, and so naturally there aren’t that many species that live there, and actually what happened in Kananaskis Natural Forest is where you can see all the pine trees dying and the whole ecosystem is kind of failing. Is because the beetle was able to come across the Rocky Mountains from British Columbia to actually infect the pine trees there and the pine trees kind of form the basis of that food web and you take the pine trees away and the whole ecosystem collapses. So, it’s at the macroscale and microscale, the rules on diversity and how the affect ecosystems are very similar. And so, if you have a less diverse ecosystem it doesn’t necessarily mean in a fit itself you’re sick. But it means that you have the less of a capacity to remain well if you’re hit by some kind of stressful event.
- Tracey:
- Right. Now do we think that children with autism, the regressive type that you’re studying do they have less diversity?
- Emma:
- See, its very difficult to manage or to look at that and to study that because we don’t know what normal is right now. And that’s the key point to take away. The studies that have been done seem to indicate that there are differences. How big those differences are and how big they need to be before we see them affecting an ecosystem. No one knows that right now for sure. And it may be that were looking at species diversity, when in fact, we should be looking at metabolic diversity. And I think that’s the key. So, and we really started looking at the second thing, and it’s a lot harder for us to do that for us to look at the species.
- Tracey:
- What have we learned about the metabolic diversity?
- Emma:
- Well, there’s a few groups. So, Dr. Finegold’s group found that there’s deficits in sulphate pathways. So, the sulphate reduction pathways and the ability to metabolize sulphur. We don’t know what that means. It’s a small study again. It’s difficult to repeat these things in different centres, because different tools are used and different analysis are used. In my own group we found changes or differences in short chain fatty acids and the level of short chain fatty acids in the guts of autistic children versus unrelated match controls. But again, it’s very difficult. I mean that was a very small study. It was powered just as a small preliminary study pilot study. If we wanted to carry on with our study and in a better way and hundreds of children, and hundreds of match controls and it becomes very expensive and a very difficult study. So, at the moment, we prefer to wait and see what we can do with the Robogut kinds of studies because they’re much more easily controlled. Ah, but it maybe that we don’t see anything in the Robogut because there is a host effect that we are missing. Because when we’re looking in the Robogut, of course, we’re just looking at the microbes. And maybe there’s a two-pronged thing and if we are only looking at half of the equation we’re only seeing half of the effects and so we kind of need to look at that. So, the way that we’re trying to examine that in a bit more detail is to use an animal model. But not a mouse or anything. We’re actually using it a screening model, which is a zebra fish. And many people say we’re making autistic zebra fish and not at all. What we’re trying to do is to understand going on the hypothesis that an abnormal metabolism in the gut may lead to production of abnormal metabolites that may enter the bloodstream and have effects on the brain, and bearing in mind as well that we see this type of regressive autism forming at a time when there is an awful lot of work going on developmentally in the brain. Again when a system is in flux that’s when it’s more vulnerable. So, if that’s the case and now were hitting it with metabolites that it wouldn’t normally see is that somehow affecting the developmental pathway. So, we’re trying to look to see, whether we can see changes in developmental pathways when they’re exposed to metabolites that will come from ecosystems that have come from autistic children. So, it’s a very kind of crude in toxicological almost just to see – do we see a change? We’ve seen a little bit of the change and we’ve been able to repeat really the findings of another group at the University of Western Ontario led by Derrick MacFabe where they’re looking at rats who have been injected with propionate. Propionate being a short chain fatty acid and propionate profoundly affects the – if you puff it into the brain ventricles of these rats, then it profoundly affects the behaviour of the rats. And in a way that resembles autism, but we can’t call it autism. So, again, we’re not trying to make autistic zebra fish but when we treat zebra fish with propionate we do see behavioural changes in the zebra fish. And because the zebra fish are very small and we’re looking at the embryos and so that we can actually watch the brain developmental pathways, you can see there something not quite right. So, the next step is to trying to see, well, what is it? Is it just propionate or is it propionate with a bunch of other metabolites. You know all of those things is actually it’s tricky to do. But I think we’re simplifying the model and we’re trying to screen it. Just to sort of show potential at this point.
- Tracey:
- How close do you think we are to understanding this? Are we five years away? Ten years away?
- Emma:
- I would say it depends on the effort that we put into it. And you know a great deal of effort right now it’s put into proving that vaccines can cause autism. It a shame we can divert that funding into something into something more worthwhile where we’re likely to find something. I think that more and more we’re seeing the opportunity now arising granting agencies who are beginning to see that we might be onto something here so funding is becoming available. But it’s very difficult to do the studies – the studies without money. Honestly, and I think that’s true for any research. And so, but I think it’s just momentum. I think there are enough researchers now who are coming around. It’s not just me who’s thinking these things and coming up with these theories. I think there’s a growing number of us realizing that there might be this gut-brain connection. And gut-brain connection is now well understood, but whether or not this is true in autism as well we’re starting to see that it might be and there’s groups now around the world particularly in Cork, in Ireland, who do some fantastic work in that area. So, potentially I would say within five to ten years we’ll start to see some very good evidence in one way or another as to whether we are on the right track for sure.
- Tracey:
- Interesting. You know, there may be some clinicians watching, some parents out there. What kind of information would you want them to understand about maybe the diet influence on these metabolites?
- Emma:
- Right. Well, I think what is clear to me, and again, I’m not a specialist in autism but what’s clear to me speaking to lots of parents of autistic children is the number of them who will tell me that their children improve when they change their diets. The problem is that they’ll look to the internet or they’ll look to a book written by a celebrity or something. Oh, they have to change the diet doing X, Y, Z. But there is no prescribed diet and its very imperative and we have to figure this out per child because every child has a different microbiota. And so, it’s going to be very different and what you see of benefits in one child maybe actually detrimental in another. So, it’s not like we can treat this type of autism as if it’s one disease. It’s a spectrum of diseases. And I think it’s to do with metabolism but because we don’t know and we don’t have any biomarkers and we don’t have any way of looking closely at what metabolites might be important or we’re trying to find out which ones are but we don’t know what they are yet. So, it’s a little bit like the blind leading the blind right now, but I think parents know their children and I think that they will know when the children are doing better, and if they keep very very close tabs and it is very difficult to do, and I know that. But if they can do some kinds of elimination diets to try and figure out what might be beneficial for their child, I think that’s the first step. And then they can kind of build on that keeping very careful notes on behaviour. I’m involved in a group called the N of One Autism Foundation based out of Dallas and Texas and it’s run by a dad of an autistic child who did exactly what I’ve just said. He went through and figured out the dietary triggers and actually created an app. So, that you can actually look and use the app to track your child’s behavioural, dietary, bowel habits. All of these things, which we think might be involved. To help to understand.
- Tracey:
- That’s really helpful.
- Emma:
- Exactly. So I think that kind of thing is what we need and it can’t be a prescribed diets and I think we have to move away from I think physicians – I think physicians know that. I think physicians understand that a lot of time they can give advice but it’s very difficult to tailor that unless they’ve got more information. And they don’t see the child every day. So, the parents need to be doing that.
- Tracey:
- But maybe we have enough information to say that you should be more of a plant based diet; could we say that?
- Emma:
- Well? It’s difficult because we don’t know exactly what the metabolites are that are causing the problem and so we don’t know where they come from and it could be that a plant that we feed to one autistic child has a benefit and to another has a detrimental effect. So, I don’t think it’s like a swathe of metabolism I mean we know that we eat too much protein in the western world just in general. Protein when it’s broken down in the gut, and fermented in the gut, is to form not so great metabolites. But we shouldn’t restrict protein because it’s also a very rich source of energy. So it’s finding the balance, and I think that if proteins come from mostly from meat and they also come from certain beans and pulses and things like that. So, the type of protein is also important, and so, again, it’s about eating a diverse diet and trying not to be a sort of fixated on one type of protein. It’s very difficult because with autistic children in particular they tend to fixate in their diet so that they won’t eat anything except for a very narrow group of foods. I wish I knew. I’m not a parent of an autistic child. I don’t know how to overcome that. But I think that is the key and that was the way of doing that to kind of monitor how to diet progresses. How the diet changes behaviour would be a very good thing to do.
- Tracey:
- This is amazing information. Thank you for sharing all your knowledge with us.
- Emma:
- You’re welcome.
