Nick: We are back speaking to Nathan about FMT for autism. So, Nathan, why the interest or why the belief that FMT can help autism?
Nathan: Look, it’s a very interesting question because obviously most people consider autism to be a brain disorder, and I won’t go into what autism is. I assume the listeners have some basic understanding of the condition, but for quite a while there’s been some lines of evidence that autism does relate in some way to disorders within the gut.
Nathan: The first level of evidence really is that autistic children often, or nearly universally, have gut symptoms such as diarrhea, abdominal pain, bloating, constipation, et cetera, and at the severity of those gut symptoms seem to mirror the severity of the autism. That was sort of the first clue.
The second clue is that there is a fair bit of evidence that antibiotic therapy, what we call intestinal decontamination, does help some children with autism. And thereafter there have been some studies done specifically on FMT looking into whether it could help children with autism.
There also have been some studies looking at changes in natural bowel flora. Since we’ve had these very sophisticated DNA-based tests of bowel flora integrity, if you like, it’s fairly clear that children with autism have decreased bacterial diversity, meaning that the number of different kinds of bacteria reduce. That’s been pretty clear from most of the studies into bowel flora changes in autism.
Nick: Okay. So there’s a lack of a diversified gut flora in children with autism.
Nathan: Yes, that’s true.
Nick: And so what FMT offers is this flora they can’t produce or just don’t have in their gut and bowel.
Nathan: That’s right.
Nick: And so the theory being, if they’re supplied with that flora, it should help their gut function probably, which should then also help their behavior, their overall health and, I guess, their brain?
Nathan: Correct. Improve these symptoms of autism.
Nick: There’s something I came across in doing the research for this podcast, and that was the gut brain axis. So do you want to touch on what that means?
Nathan: It’s an impracticality. The kilo or so of bacteria within predominantly your colon, because they’re all supposed to live in your large bowel, these bacteria are metabolically active, so they’re metabolically active in many ways.
Firstly they do make things, so they turn your food residue, stuff that you don’t absorb, into substances, for example, hydrogen sulfide, methane, opiate type substances and a whole bunch of other things. Butyric acid, propionic acid. So some of these substances may be good for people, some of these substances might be not so good for people. So they’re metabolically active.
Secondarily they interact with the gut immune system, and their interaction with the gut immune system within what’s called the mucus layer, which is the very thin layer of slime, if you like, over the top of your bowel mucosa, it’s full of bacteria and it’s full of immune cells and there’s an interaction between the immune system and the gut flora, and that also causes changes in what’s called the gut barrier or mucosal barrier which can be breached and which can cause the entry of bacteria and bacterial products into the circulation.
So this is very interesting interaction, which still hasn’t been worked out to anywhere near the degree that we need to between the bowel flora and the integrity of the gut wall and the activity of the gut immune system. And that in turn, those bacterial products, that interaction with the immune system, the integrity of the gut lining, is thought to cause changes within the brain.
And there’s all sorts of diseases that have been looked at. Autoimmune disorders like multiple sclerosis, degenerative disorders like Alzheimer’s and Parkinson’s disease and other diseases like autism. Mental health issues like depression and anxiety. All of these are being studied in terms of what effect bowel flora changes might have on those disease. So that, if you like, is your gut brain axis.
Nick: I see. Okay. Now that you’ve mentioned studies, I think what I’ve read is, and what you sort of just mentioned, is that FMT seems to help children with autism and help obviously maybe their brain functioning and their behavior. But at this stage, the reasons why that’s happening haven’t come to light. So it’s working, but you sort of don’t know why.
Nathan: That’s true of most … I don’t want to say most. That’s true of a lot of things in medicine, Nick. We often put the therapy before the mechanism and that’s been the case for years. There’s a history of that in medicine that goes back centuries. We don’t know always why our medications work and we don’t really know why FMT works in autism.
As I’ve mentioned in previous podcasts, the whole thing with FMT and any condition, the proof for FMT has to come with every single individual condition. You can’t generalize. So with most conditions that have been linked to improvement in FMT, the evidence exists only in terms of a theoretical basis or from very small series of cases. I did 10 cases, I did five cases, I did one case, we do a case report, stick it in a journal, that’s not evidence that FMT works. It’s low level evidence, if you like.
So the search is always on in this space for better more robust evidence that this will work, and that evidence is being accumulated with FMT and a whole bunch of conditions. For example, we know FMT works for Clostridium Difficile Infection. We have class A evidence for that. It’s part of protocols. It’s approved by the FDA. It was published in the New England Journal of Medicine, and it’s well accepted if you have recurrent Clostridium Difficile Infection, you will get better with FMT. It is the gold standard treatment. There’s evidence in ulcerative colitis. It’s pretty overwhelming that it does help some patients with ulcerative colitis.
Nathan: So they’re two conditions where we have sort of class A evidence. Everything else up until recently has been either wishful thinking or has only a low level evidence for its use.
Nick: Okay. But obviously there’s been enough evidence for the FDA to fast-track status to the FMT, or Microbiota Transfer Therapy is what they call it.
Nathan: Yeah. Thank you for educating me on that. I hadn’t realized they had fast-tracked that, which is kind of extraordinary based on the history of FDA. They must be feeling a little bit guilty about restricting access to this treatment in the US when they come out so quickly and approve that because, as we’ll discuss in a minute, the evidence from the studies that have been done isn’t overwhelming. It’s not class A evidence. Nowhere near it. It’s highly criticizable research, to be honest. Not that I’m criticizing [inaudible 00:07:21] fast-track it because I think it’s incredibly safe therapies. I don’t have a problem with that. I just think the evidence is not particularly overwhelming. But I do think it works.
You’ve got to understand that the way the scientific brain thinks in medicine is even though you think something works, you have to still evaluate the evidence critically. You’ve got to be always scientific. You’ve got to have your scientific hat on.
I see. But in terms of this type of treatment, I guess it’s a safer treatment than giving child lots of medication to try and handle a condition that really people don’t know how to cure or manage.
Nathan: There’s no therapy for autism. It’s all supportive treatment. Don’t get me wrong, the supportive treatments have been transformative in autism. Before the supportive treatments, these kids had no hope. You know, probably put in a corner, told they were naughty, all the rest of it. But the treatments that we’ve had so far are in the end supportive.
So the most important part of treatment of autism really is the educational outcomes and trying to get the kids as functional as you can. So a lot of people have put a lot of time and effort and continue to in supporting families with autism. Not just supporting the child with special teachers and special education programs, but also supporting the family as well so that the family unit can continue to do well in the presence of an autistic child.
So, don’t get me wrong, those supportive approaches are absolutely vital and will continue to be vital even in the age of FMT. Likewise, sometimes, unfortunately medication does need to be used to modify behavior, although it really is only supportive. There is no medication known to treat autism. There are lots of things that have been looked at and suggested and there’s lots of stuff in the alternative medical field about autism, but there’s no proven therapy for autism.
Nick: Sure. Okay.
Nathan: So that’s right. So when you’re doing FMT for an autistic child, you’re not doing it and not giving them the right treatment, you’re just giving them a treatment, because there is no other treatment. All the others is supportive.
Nick: With the spectrum of autism going from mild to extreme, are the case studies being done on that spectrum?
Nathan: The published research is the Arizona Autism Group, which is in Phoenix, Arizona. Obviously they [inaudible 00:09:47] specialize in autism. My understanding, and to be honest with you, I haven’t recently read the whole trial, but my understanding is there was definitely a spectrum of cases. My understanding was the trial wasn’t double-blinded or sham-blinded, but the results were fairly robust in terms of the amount of response they saw, and they published follow-up data suggesting the response is robust and it does persist.
So even when you stop doing the FMT, they continue to have ongoing improvement just by the fact you’ve stopped, suggesting that the bowel flora is permanently changed. So it’s not something you have to keep doing all the time. And these children, the benefit is persistent.
Nick: With that in mind and perhaps now that it’s been approved or fast-tracked by the FDA, there’d be a lot of interest, especially with parents who are desperate to help their children. What could they expect from a treatment?
Nathan: I suspect like everything else, Nick, it’s going to depend on a whole range of factors, not just the FMT. So the FMT [inaudible 00:10:53] factors you can control. You can control is donor selection, you can control using multi-donor stool. We don’t know whether that’s important in autistic children or not because it hasn’t been studied. You can control pretreatment with antibiotics, you can control how long you do it for or how intensively you do it.
But there’s a whole bunch of factors you can’t control. I think one of the factors is how sick the child is. So it might well be that sicker children respond better, or milder children respond better. It might be that it’s best done earlier in life rather than later in life. We don’t know the facts around that. Hasn’t been studied.
This is one of the problems again with FMT is that not only have you got to work out whether it works, you’ve got to work out which group it works in best and how to do it best in a particular subgroup. So all of those questions have not been answered. It might work really well in mild disease but not really well in severe disease. It might be vice versa. It might be better if you start early, better if you start later. We just don’t know.
So therefore I think in an individual person sitting in front of me, I would suggest they have FMT and we see what happens. That’s as scientific as I would get with a patient in front of me. Let’s do it. See what happens.
Nick: Obviously we want to be honest about this. We’re offering hope and the possibility of improvement and it’s sort of a low risk treatment.
Nathan: What you’re doing is offering a still somewhat experimental but essentially safe, because there’s only been a couple of case reports recently of harm, but honestly I think the donors were poorly selected in that case and I think the patients were very, very sick.
So in general, there’s been hundreds of thousands probably of FMTs performed and there’s only one case report of harm occurring. So honestly I think it’s a very safe procedure. So you can offer a safe procedure that’s non-drug-based, which some patients like. I don’t have such a problem with drugs, but some people do. That is given for a condition that has no known treatment, or no proven treatment, that causes a significant loss of quality of life for both the child and also the family and which has some evidence for it. So it’s all winning all round. So it’s thumbs up for at least trying it.
What would be ideal, of course, is if a local program, a local autistic program would take this up, which is the appropriate setting in which it should be done. But unfortunately to get that ball rolling is very difficult for a large unit at a public hospital or children’s public hospital to say, well, we’re going to do a hundred and see what happens. That’s what needs to happen. They need to do their own program and their own research. That would be ideal. There’s enough there. There’s enough evidence accumulated to go right, some big public hospital should just do it and just offer it to a hundred kids and just do a pilot study and publish all the research. That would be ideal. But I haven’t heard any rumors that that’s being done, which is frustrating. [inaudible 00:13:55] with no known treatment, and it’s common.
Nick: What about yourself? Have you treated children with autism with FMT?
Nathan: I’ve done one adolescent child with autism. I have another one who’s in the wings who’s younger, who we’re just evaluating at the moment. But that particular patient has done extremely well. His educational attendance, his behavior has significantly improved with his Fecal Microbiota Transplant therapy. He continues to receive maintenance therapy, because in discussion with his parents we’ve decided that’s the right thing to do. But he’s now on three monthly. I think he has them once every three months, and he continues to improve.
Nathan: Now you can argue till you’re blue in the face why that is, but I do put it down to the FMT.
Nick: Okay, well that’s obviously a very positive outcome.
Nathan: It has been. He was my first. I agreed to try [inaudible 00:14:54] this patient because he was older, so I think he was 16 or 17 at the time we did it. So he was almost an adult. And for that reason, it made it sort of a lot easier in terms of the way our practice runs to be able to offer that to him. So that’s why I did him first, and I said, well if this works, I’d like to do another five to see what happens with the next five. I’m happy to extend that to younger children.
There are issues with an adult gastroenterologist doing FMC on younger children, but I think, as we’ve discussed previously, generally we do our first FMT via colonoscopy. I don’t think that’s necessarily necessary in autism. So doing barium enema with the parents involved in that therapy is pretty low-risk kind of thing to do.
Nick: All right. I know we have to wrap up soon, but I just want to go back to one more question regarding what the FDA has approved. So they’ve approved microbiota transfer therapy and full spectrum microbiota. So are they both FMT treatments?
Nathan: Yeah, so basically what you’re looking at is the whole lot, the whole box and dice, the whole house plus the people in it kind of therapy, which is what we do. There’s no processing of our FMT apart from mixing it up and sticking some saline in or some salty water in it. That’s all we do to it. But you can purify down. You can remove bits and pieces from the FMT and that would be your full spectrum.
Nathan: So your full spectrum would be the actual fecal matter removed from the FMT. It would be just the bacteria I presume is what they’re talking about.
Nathan: The full spectrum, so this is the whole point again of FMT versus probiotic therapy. People say why don’t you just take lactobacillus and do that? The problem is lactobacillus don’t do anything on their own. Even multi-strain probiotics haven’t shown any benefits. So we don’t understand.
Nathan: Everyone listening to the podcast has to understand we do not know why this works. You can presume all you like why it works, but we don’t know why it works. Therefore what we do know that works is just straight out FMT. Take some stool, mix it with some water, put it up there. That’s how we do it and that’s what works, so, therefore, that’s the way we do it.
Nathan: If you want to extrapolate that to other therapies based on that, then you can choose to do that, but it might not work.
Nick: I see. I do know you guys go to great lengths to screen your donors. You choose mostly vegan donors and you do a mix, don’t you?
Nathan: Yeah, so in some of the studies, I mean, for [inaudible 00:17:37] doesn’t matter. For colitis, it does appear that multi-donor is better, so we’re pretty keen on multi-donor. And we’re keen on vegans because they just tend to have better bowel flora. They tend to have more diverse bowel flora and more of the good kind of bacteria, I guess.
Nathan: Again, the evidence for that is not great. Certainly, you could get a whole bunch of people that eat McDonald’s every day and they could be very effective FMT donors, so we just don’t know. But we just think if you can be selective, you should try and select what you think is going to be the healthiest donor. And we would use at least three or four donors for every FMT, sometimes more.
Nathan: So I think there’s definitely some evidence in some conditions. That’s the case. And if you’re going to FMT someone, which is a pretty drastic thing to have done to you, I guess, you want to give it the best chance to work. So if it doesn’t work, it hasn’t failed because you’ve not done it properly. It’s failed because it’s just not going to work.
Nathan: And that’s what we want. We want you, you’re desperate, you’ve got no other treatment, you’ve got no other treatment options. We’ll do FMT, but let’s do the best possible FMT we can.
Nick: Right. Okay. So to wrap up, you believe it works, FMT for autism, and obviously you’re happy to help a family who is considering this treatment.
Nathan: Absolutely. If you look at the ethics around it, I think it’s unethical not to offer it, because there is evidence for its benefit and basically the condition has no other treatment.
If there was a proven therapy that worked and we’re doing it in exclusion of that, then that becomes ethically difficult because the evidence is not, as I said, it’s not class A overwhelming evidence, it’s just reasonably strong evidence. But that’s not the case in autism. There is no disease modifying therapy. There is all this supportive care, which again I will stress is absolutely vitally important and it’s vitally important that if you have FMT or if you don’t have FMT. And in no way am I at all advocating that that’s not going to be necessary or that that’s not still the gold standard treatment. What I’m saying is to modify the disease itself or to modify the underlying processes, there is no proven therapy. So yeah, I think in that situation, given the devastating impact it has, I think it’s unethical not to offer it should it be sought out.
Nick: I agree. I’ve got a few friends who have children, and it is hard to see how they have to handle it every day.
Nathan: Yeah. You see the children with autism, and everyone’s seen children with autism. There is a basic breakdown of the normal parental child relationship, which is heartbreaking. I find it heartbreaking to watch, I really do. And for that reason I really wish, I really do wish, and here’s a call to arms, if you like, or a bit of a poke. I really do hope that some children’s hospital somewhere in Australia gets together a program for doing FMT for autistic children, because it really should be done ideally in a multidisciplinary clinic with psychologists and researchers and microbiologists and all that kind of stuff that they can throw at it to try and work out how it works, why it works, what the best protocol is for the FMT, how to safely do it, how to less and how much you have to do, all those little details. It would be so fantastic to work out in such a rich vein of research for us to do. I really do hope they do it.
Nick: Yeah, so let’s hope that happens, and I know you’ve got to go, so thank you very much for your time today, Nathan.
Nathan: My pleasure, Nick. Thank you for asking me.
Nick: No worries.