Interview By Marion Gruner

Some of the other research you’re involved with is The Human Microbiome Project. What is that?

So, the human microbiome has really come to the fore as a very hot topic in research because we’re beginning to realize how the microbiome might interact with us to define who we are. And so therefore, around 2006 a project was started, the human microbiome project through the NIH, and there’s a European initiative as well called MetaHIT.

So, essentially what they’re trying to do is extend the Human Genome Project. Now, the Human Genome was finished in 2001 and everyone patted each other on the back and said great job everyone, now we know the human genome. And I think everyone was very surprised that actually we have very few genes in our body – that is, human genes associated with us – and they can’t possibly do all the things that humans can do in a biochemical sense, and so there was a missing link.

And really a microbiologist stepped up to the plate – a very eminent microbiologist at the University of British Columbia called Julian Davies wrote a great letter to the journal Science to say, great job, guys, you’ve sequenced the human genome. Now let’s look at the human microbiome because that’s the missing link here, that’s what you’ve not looked at and you can’t consider what a human being is without looking at the microbes that are associated with the human. And so, the Human Microbiome Project was set up to essentially be able to categorize and look in a little bit more detail at these microbial communities. We’re looking at several different areas, the gut is one of them. We’re also looking at the mouth, the skin, the vagina, the respiratory system and other parts of the body. And so more and more host associated communities are coming into focus.

We’re directly involved in looking at the GI part of the microbiota. And one of the things that we’re asking is, what are the microbes that live there? And that’s really not been touched on very much in the past because a lot of the microbes are very difficult to culture. We know very little about them. So, it’s estimated that around 80% of the microbes that live in our guts are only known from their DNA signatures; what we can sequence from them. We’ve never been able to grow them in the lab. That’s one of the focuses of my lab, to try to culture these unculturable organisms so we can understand their biology.

Does this area of research indicate a new way of looking at health and disease?

Yes. I think that this is the way of the future, because what we need to understand is that, for example, if I take an aspirin for a headache and you take an aspirin for a headache, that aspirin might be working on the headache in completely different ways; the aspirin might be broken down by our gut bugs in different ways because we have different gut bugs. That’s a very simple example. But it’s a very interesting question.

So, are we all going to have the same reaction to every drug? No, it will likely be dependent on our microbiota. And in fact, there are many drugs which we know work differently for different people. For example, some antidepressants only work on a very small number of people and it can be very difficult to find an antidepressant that works in a particular person if they seem to be recalcitrant to treatment. Maybe the microbiota has something to do with that. So, a microbiota does define who we are. Therefore, medicine should be more personalized and take that into account. The idea of personalized medicine is really developing right now. It makes things a magnitude more complicated than it already is, but it’s very important and we need to really be able to define this. And maybe in the future… if I could see into the future, I would predict that you would actually be able to take a stool sample to figure out what microbes live in your gut and from that be able to define what drugs might work better than others in a given situation.

How does the microbiome, and all of the microbiota, form?

The microbiota has just been really scrutinized in the last ten years or so. Things have really started to happen in this field. And one of the big questions has been, well, we have this incredibly diverse ecosystem living in our guts. Where did it come from? We have to remember that a lot of the microbes that live in our guts are extreme anaerobes, and that means that they will die even with a very minute contact with oxygen. And so, the mere fact that they get into our guts (which is in fact, a very anaerobic environment), it’s pretty incredible. We wonder where these bugs come from. And the answer is that we don’t really know, but a lot of groups are trying to look at this.

We do know that we’re born essentially sterile, and so a baby’s gut is colonized within hours of birth with what we call pioneer microbes, the ones that pave the way for the other organisms to come in and colonize. Where most of these organisms come from we’re not entirely clear on. They could come from diet. They probably come somehow from mother to child transfer. It’s not a focus of my lab but certainly other labs are trying to see whether there is, therefore, a problem when children are born by C-section, for example. How are they going to be colonized if the main source of colonization is the mother’s gut? I don’t think it’s any accident that the birth canal exit is situated right next to the anus, although I think a lot of people are grossed out by that. It doesn’t seem like a very evolutionary sensible thing to happen, but actually when you think about it, it is very clever. And so, when a baby is born by C-section, proper microbial transfer from the mother may not take place, and so what happens next?

We think that each species that is introduced might make its home based on the species that has colonized before it. And a baby, a newborn baby’s gut, the environment there is quite simple and the food of course is very simple. And so at first the ecosystem that lives there is also very simple. This microbe diversity in the gut of a newborn baby, is very low, and it remains so until the baby starts weaning and starts eating foods which a normal adult would eat. And then you see the gut environment changing a little bit more and you see other species coming in. We have no idea right now what actually controls what species ‘take’ in a particular individual, but that is a really interesting area of research because it can tell us a lot about how these ecosystems develop.

But what we do know that is becoming very clear is that the antibiotic use will change that colonization for us. So, if you live with an ecosystem that’s in a very fine balance and you take an antibiotic… I should point out, that antibiotics are life-saving drugs and one of the miracles of modern medicine but they’ve not been used particularly well in the last few decades. And only recently have we been seeing the bad side of antibiotics, and the health problems that they can cause. And so we’re now beginning to see how antibiotics can actually start to ruin the delicate ecosystem balance that exists in the gut. And some very good work that’s been published recently has shown that once an ecosystem is disturbed by antibiotics it doesn’t return completely to normal afterwards, particularly if the ecosystem gets multiple antibiotic ‘hits’.

And so the fear is that if you have a child who is just developing their ecosystem – and remember we don’t really understand how that happens yet – what’s going to happen when you throw antibiotics into the mix on top of that development? Is that going to disturb the natural order of things and is that going to disturb the ability for the ecosystem to build into a mature ecosystem which is going to be beneficial to its host?

How might regressive autism, in particular, be related to the development of the microbiome?

What really strikes me about regressive autism is that there usually is gut involvement. And that is one of the things that really attracted me to work in this field. I’m not a medical doctor, but I work with my medical colleagues closely. Many of them work in a particular specialty in medicine and they interact with their colleagues, of course they do, but they have a specialty. Necessarily so, because the field of medicine is immense. But what I see as an observer from the outside is that a lot of autistic children have gastrointestinal symptoms and they also have the autistic symptoms. But the two medical specialties that deal with each of those different problems are really very far from each other and it’s very difficult for any one of those specialists to see the child holistically. Medicine is usually a system of referral.

And so, I think that the gastrointestinal symptoms of regressive autism may not actually be that obvious to many of the doctors who routinely see autistic children. It sort of reflects this new idea that we have to look at a person as a collection of ecosystems. Healthy ecosystems in our bodies represent health, and so if you have a disturbance of an ecosystem in the gut it probably doesn’t just mean that you’ll have a gut problem. There could be connotations that go further than that, and essentially, in autism, these could be affecting brain and development.

A history of antibiotic use in children with autism seems to be a common story.

I do know from reading the literature that antibiotics have often been used in children with regressive autism, maybe a lot more often than would be in the general population. It’s not necessarily a one-hit thing. It seems to be that antibiotics are only really a problem to developing gut microbiota with repeated hits. And so repeated courses of antibiotics maybe for an ear infection that just won’t go away or a throat infection that just won’t go away, seem to be a problem. The work that’s being done now is showing that a microbiota will change in response to antibiotics, and it will try and recover afterwards. But if you keep hitting it, well it’s like the rainforest story where you keep stripping species out of the rainforest, eventually the ecosystem will collapse, and there’s not a lot to do to fix that unless you think about ways of replacing species.

And we think that that loss of species diversity in the gut might be one of the underlying reasons for the gut dybiosis is that we see, not only in autism, but in several other diseases as well.

After his work with Ellen Bolte that found clostridia bacteria in children with autism (and found that they improved on the powerful antibiotic, vancomycin), Dr. Sydney Finegold has continued his research on gut bacteria connected to autism. What is he focusing on now?

In his latest findings, he’s been very interested in a particular bug called Desulfovibrio. Now, Desulfovibrio is not related to Clostridium, in fact it is more related to E. coli than it is to Clostridium. But it is sensitive to vancomycin, and although it doesn’t form spores, it is a very hardy bug. I already mentioned that the anaerobes in the gut are very sensitive to oxygen. Desulfovibrio can also only grow in the absence of oxygen. But once it is out of the body and it’s maybe sitting around on a surface, it can survive. Not proliferate, but survive for a very long period of time. And so, it won’t die in the presence of oxygen, and it might therefore spread easily from person to person under the right circumstances.

And so this could also be an interesting bug from the point of view that it has some interesting biochemistry. It has some odd attributes that make it a promising candidate for a “bad bug” in autism. And some recent work in the field of inflammatory bowel disease, shows that in the guts of people with ulcerative colitis Desulfovibrio might also be over-represented. And so it’s feasible to me that this bug could be an emerging pathogen. The thing is I’m hesitant to say that this is THE bug, because I think we need to do a lot of work to prove any bug is involved, and there might be a whole group of bugs which are important in regressive autism, so we’re being very careful not to narrow our radar and just look at one or two bugs. We’re trying to look at the whole problem of gut dysbiosis as an ecological problem.

And so it’s very difficult for me to say that this one bug might be causing all of the autistic symptoms that we see in all of the patients, and I think that’s probably not true.
I think in a lot of cases you might have an organism or a group of organisms which cause a problem. But they work in concert with the microbial ecosystems. So, instead of thinking this is a problem with one bacterial species, a bit like you might think of cholera is a disease caused by the pathogen Vibrio cholerae, our autism hypothesis is more to do with an ecosystem dysbiosis. So the ecosystem in the gut is being disturbed. What is triggering that disturbance, we don’t know, but it could be the presence of a pathogenic organism of some kind. It could be Desulfovibrio, for example.

An unhealthy eco-system can be replaced using a fecal transplant. What is this?

Fecal transplants are kind of icky and nobody really likes to think about them, but the evidence is there that they work for gut dysbiosis correction. They’ve been used in medicine for a few decades now, and even more so just recently because there’s been a rising problem with Clostridium difficile associated disease, a gut disease caused by overgrowth of C.difficile, usually after antibiotic use. If you can’t cure that disease with more antibiotics, you’re really left with few options, and some of these patients have very serious disease. So in desperation, doctors have been trying fecal transplantation from a healthy donor, which essentially is ‘ecosystem therapeutics’ in a very crude way.

What is it? It’s taking a fecal sample from a healthy donor, who’s been prescreened for known pathogens to make sure that they are healthy as far as we can tell, and then taking the fresh stool, making it into a slurry and instilling it into the gut of a sick patient. And it works most of the time – it cures C.diff disease. And so, there’s obviously something in it as a therapy – but we can make it better. We can use it as a foundation for making more pure ecosystem therapeutics where we can manipulate things and have some control over the ecosystem. The problem with feces is that it contains hundreds of microbial species and it is undefined. And we could actually risk damaging a patient by unwittingly transferring a pathogen to them that we don’t yet know about from a donor. In a healthy donor that pathogen may not be doing anything, but in a sick person it may actually be a problem.

Do you see a future where we treat autism with fecal transplants?

Absolutely, I think that this could be a very interesting way to look at treating the problem. Autistic children often also have gut problems. And so we think that ‘ecosystem therapeutics’ might be something that we can apply, not only to C. difficile associated disease, but also to a number of other gut problems including ulcerative colitis, irritable bowel syndrome, and many others … but we have a lot of work to do before we can go this route. Safety is a number 1 priority.

But if you imagine that, if you understand that autism is a gut dysbiosis disease as well as a brain disease, a developmental disease, then we’re very curious to see whether an ecosystem replacement, which seems to be reasonably safe so far in C.diff patients, would have any benefits to autistics and to autistic children in particular, both for their gut problems and their neurological problems.

So, looking at autism in terms of a gut microbiota disease is actually quite a positive thing, because if there is an infectious component to autism, something in the gut that is allowing autistic symptoms to manifest themselves, we can target that. We can treat that. We just have to know how it happens.