Autism and the Gut - with Dr. Derrick MacFabe | The Empowering Neurologist EP. 1

Hello, I'm Dr. David Perlmutter. Today I have the distinct pleasure of interviewing Dr. Derek McPhabe. Dr. McPhabe is assistant professor at the School of Medicine and Dentistry, Western University, London, Ontario in Canada, where he heads up the Kylie Patchell Evans Autism Research Group. They've put out a lot of terrific scientific papers correlating the relationship of autism to gut issues, specifically to changes in the gut bacteria. His work has been characterized as being one of the top 50 scientific discoveries in Canada, and he played a pivotal role in the movie The Autism Enigma. If you'd like to learn more about Dr. MacPhabe, just Google his last name, MacPhabe, M-A-C, F as in Frank, A-B-E. and the word autism. So let's go ahead with our interview. So it's a great honor, as mentioned, to have Dr. McFabe with us today. Dr. McFabe, welcome, and I'd like to start right in, if you could, by giving us just a brief overview as to what was it about autism per se that was so attractive for you and really got you started in this whole area of exploration.

Well, it was a series of accidents, both before I went into medical school working with special needs kids and then going on through my residencies in internal medicine and neurology. But before, I was so surprised by these children that seemed to be in there and indeed had some aspects of giftedness in memory or music or whatever, but in addition seemed to be trapped in a world with this repetitive antisocial behavior, self-injury, And of all things, bizarre food cravings and gastrointestinal disturbances. Saw that before I went into medicine, and then a lot of my work was in internal medicine with people that had gastrointestinal problems and also some behavioral effects. You would think of them as having a nervous gut, but be very intelligent. And then, in addition, patients with severe epilepsy and autism associated with self-injury. So the constellation of that work, as well as basic science work looking at things to try to protect the brain, At the very same time, these Clostridium difficile outbreaks were happening in the hospitals with these superbugs with overuse of antibiotics. I was working on compounds to try to protect the brain or affect brain metabolism. I was using this compound called propionic acid, really obscure. When I went to order it from the internet when it was developed, I found, hey, this bacteria was also— this compound was also produced by bacteria that cause C. diff and antibiotic— other antibiotic-resistant infections. Then there's this brilliant infectious disease gentleman, Sidney Feingold, who has found unique gut bacteria in patients with autism. These compound bacteria are also Clostridia, and they almost also make propionic acid. It was kind of very serendipitous that a compound that I was using was produced by bacteria that could wreck your gut. And then also are produced by autism-associated bacteria. And then further on, I found by accident that it's also found in the foods, the refined carbohydrates that patients with autism crave. So you're either feeding the bacteria a compound to make propionic acid, or you're actually eating it yourself, and autism-associated bacteria make propionic acid. So it was like— 7 degrees of Kevin Bacon that this strange molecule started showing up.

Well, let me just take a step back. We've all known about the— that there's a strong correlation in autism with gastrointestinal issues. Then the work revealed that there were changes in the gut bacteria that were typifying the autistic patient. Then what you've discovered then is that these changes in the array and the diversity of bacteria and overgrowth of certain bacterial species led to the overproduction of a certain chemical called propionic acid. Once you had that information in hand, what did you do next in terms of any kind of animal research, or where did it lead you?

What we found in other studies were that patients with autism had peculiar brain inflammation, strange lipid changes, abnormalities in their mitochondria. We said, okay, if this compound has anything to do with autism, we should administer it to animals. Uh-huh. Either as adults or through development and see if the brain and behavior changes looked anything like autism. We were actually shocked when we did this initial work at the University of Western Ontario. Taking this gut metabolite, propionic acid, immediately these animals became hyperactive, antisocial, had tics, preferred objects, learned like crazy but couldn't unlearn, very peculiar behavioral effects identical to autism. Then the brain changes, when we examined the brains, the brains had the same brain inflammatory changes, abnormal lipids, low omega-3s, and a compound called carnitine being low. Then the same mitochondrial effects. The compound was affecting the energy of the brain identical to autism. Then we also found that the propionic acid could turn on and off autism-related genes. It was a serendipitous thing, but at least at At an animal model level, this compound could turn the brain on, so to speak, to cause all the brain and behavioral effects consistent with autism.

So suddenly you increase the propionic acid level in the experimental animal and you observe that these animals become socially withdrawn, become hyperactive, similar characteristics as we would see in autism, and that even at the molecular level That there are changes happening within the brains of these animals that mimic what is seen in autism in terms of compromised mitochondrial function and even inflammatory markers being elevated. What did that tell you, and what did you do then?

It was a serendipitous link. Initially, we put it in an adult animal's brain. To take a step back, people thought children with autism were behaving funny because their tummy was upset. Right. You can tell that these behaviors wouldn't be just an upset stomach. The fact we gave a small amount to the brain and we could elicit these effects, it was a central brain effect. Then we've given it in development. Early on in development, we get more profound effects. Then working with my collaborator, Richard Fry, we found— delved further into the microbiology and the chemical changes of these animals, and we even found tests Right.— to examine patients with autism. We found that patients with autism had similar abnormalities in energy and fat and mitochondrial function. Not only the model looked like the autism patients, we could delve further into the model and predict changes in patients. This pointed toward the patients with autism having an acquired mitochondrial disorder, not a genetic condition because we looked for it, but it was the idea that gut microbes can tinker around with your brain and behavior and even modulate your mitochondria, which are, you know, their long-lost relatives.

Let me take a step back just for a moment. What you just said is that gut mitochondria— gut bacteria can tinker with your brain. And if I may, I mean, we kind of talk about that with facility these days, but that's a bit of a leap from where we would have been 5 to 10 years ago. That you, looking at a so-called brain disorder, autism, are now really focused on changes in the gut bacteria as, may I say, playing a pivotal role in that disorder. I mean, how do you feel about this paradigm shift?

Well, I think it's very encouraging because it allows a lot of people at the table to offer potential preventions and therapies. As you've mentioned in your book, all the microbiome research around the world is showing these Early alterations in gut bacteria, mostly from birth, but not exclusively, can change the trajectory of the developing gut bacteria and lead to a lot of chronic illnesses— autoimmune, obesity. That was the first one. Also, in a lot of these other illnesses, there are behavioral consequences, as well as with autism. In addition, there's a grab bag of symptoms that— and risk factors of autism that didn't seem to make sense. As I said, early antibiotic exposure, a C-section, some hospitalization, whether they were in the hospital for whatever reason, but all these different conditions, as well as some acquired ones, metabolic ones, would actually lead to either more bacteria that make propionic acid or less bacteria that keep these bacteria down. This little molecule hopefully may bring together all the disparate views of autism. Is it genetic? Is it environmental? What's the gut problem? What are the immune problems? Again, even with the genetics, which is, as you know, can't explain a huge increase, although genetics has a risk, you can't go from 1 in 10,000 to 1 in 68,000 in 50 years and not have these increases. We're also finding that these gut bacteria compounds, these fatty acids, can turn on and off genes. So it goes full circle, hopefully having a kumbaya moment, bringing the disparate views of autism, but also great work being done in the microbiome showing the bacteria that produce it are being increased, showing that there's increased propionic acid in the stools of patients with autism. A lot of the treatments that people are trying to do Cutting the carbohydrates out or giving compounds like carnitine or omega-3s to patients with autism all actually work to, at a global level, lower the levels of this fatty acid. It starts making sense of a lot of empirical treatments, but also the risk factors associated with autism and autistic regression.

Now, probably based upon— well, obviously based upon this idea that one of the core issues in terms of causality for Right. —for autism may be this changes in the gut bacteria as you've described. The University of Arizona, as you are well aware, has now recruited autistic children for a procedure intervention called fecal microbial transplant. In other words, giving healthy gut bacteria from fecal material of a healthy individual to the autistic patient in hopes of seeing some clinical improvement. I wonder if you could comment on that.

Well, it seems like an exciting future for a number of conditions, and it's exciting, but the good news is a study like this is being done in a proper clinical trial. We actually met as a group with other people working on whole body issues and microbiome and autism, led by my collaborator Richard Fry, to sort of set a standard that if we're going to do something like this, What is the proper way to do it? The answer is, is that, as a step back, you're putting healthy bacteria in to try to keep down the bad bacteria. This has been used in severe illnesses like Clostridium difficile, where you have an adult that knows what the cause of the illness, and it's had remarkable efficacy in very old and actually sick patients with no risks. The question lies into changing the microbiome, restoring it, if you will, to its proper complexity with a lot of other diseases. The autism picture is encouraging, but also we have to caution with the ethics because here's a disease that the microbiome is playing a role in. It is in evolution. We have to know the long-term effects of it if we're treating a child. It's a child without informed consent. Having said that, if there are a large team of people, which we hope, that understand bacteria, Metabolize— metabolism, blood markers, clinical improvement. And more importantly, what is the donor? The donor has to be free of illness, has to be free of viruses and other antibiotic resistance. The choice of the proper donor is absolutely central in any disease where we're trying to restabilize the microbiome. Other groups, like in Scandinavia, Tor Medved has had another approach of taking the bacteria from a mother of 30 years ago who now has She's healthy, and her children are healthy. That bacteria near birth has been extensively studied and screened for any infections. That, along with probiotics, along with even in certain cases some antibiotics, which it's a double-edged sword, can eradicate these bacteria. These all look like the future done in a proper setup as Dr. Adams is setting

up. I'm fully planning to call you up again 5 years from now and see just exactly where we've gone. But it seems to me that you and I are having a conversation right now at the very nascent primordial stage of our understanding of this role of this 3-pound organ within the human body, which we call the microbiome, and the powerful effects that changes in the gut bacteria have on a wide array of human physiologic parameters and metabolic activity. Yeah. I'd like to, if I could, have you just tell us what your experience was in the role that you played in the film, The Autism Enigma, that was on Canadian Public Television.

Yes, about 5 years ago, they approached us regarding, at that time, just the beginning of understanding gut-related issues in autism and starting to center on our understanding of the microbiome. It was a large group of us that were working on this from different views, but it was mostly centered on some of our work, but also this peculiar story of Somali refugees. So again, they would come from East Africa to either Canada, the United States, or Scandinavia, and remarkable studies have shown, particularly a good epidemiological study in Sweden, that they could be a very small portion of the population, 5%, and be up to 35% of the autism. What's remarkable is all these people that had children with autism, the patients were conceived and born usually within 1 to 2 years after moving to the Western group. These are an interesting group to study at a broad level. They also had exposure to a lot of antibiotics, and they originally adapted over from a more archaic Western— African diet to a high carbohydrate food. Right. It's a complex group of studying why, but it shows how, at a broad level, either we have got— they came here and got our bacteria, or their bacteria was suited to a different diet, and they've got our foods. They could be missing particular foods back in Africa because they eat a lot of— they're a cattle-based culture, a lot of yogurts, things that would conceivably reduce these bacteria.

A lot of prebiotic-rich fiber as well.

Absolutely. It's a very good point because the African studies have shown that the bacteria that actually make fatty acids, mostly the good ones, in Africa, African folks have more of it when they're born in Africa. We could be overfeeding that bacteria where they normally got their calories from eating, as you said, higher fiber-based foods. These are very unique populations, and in addition, the converse is true. I've gone to the Middle East and Southeast Asia, and then in the future now in China, finding these groups that have switched over to the Western food and early anti— and high antibiotic usage, well-meaningly trying to treat early childhood diseases. In your own country, Dennis Lang, who did some remarkable work with the Gates Foundation, the MALAD studies showed that these populations that are exposed to our high carbohydrate, high antibiotic use, end up having high chronic diseases later on, obesity, autoimmune, and a large amount of cognitive problems. This is a worldwide problem. As we are moving around and our bugs are moving around the world, at least in the West, both our countries, we have tight controls on the use of antibiotics. In those areas, there may be more indiscriminate use, which is a real problem.

What do you think then, if there is this relationship that is so well developed, between changes in the microbiome and risk for not only autism but other inflammatory neurological conditions. What are the biggest things that we are involved with, do you feel, that are challenging our microbiome? I know you mentioned a couple, but I wonder if you could elaborate.

Well, again, at a broad population level, as you— we get most of our bacteria, maybe early, but most from the normal birthing process. So we get initially from the vaginal wall and fecal material. If you've delivered a baby, the baby corkscrews and the face points toward the anus. Researchers are showing this is the main inoculum that goes into the bacteria, and then later on breastfeeding. These things tend to have a normal progression of microbiome. C-sections and reduction of breastfeeding may change the alteration of the microbiome, promoting other bacteria, either from the skin of the mother. If the child's in the hospital, they might pick up some opportunistic bacteria. But one has to be clear, it's a risk-benefit ratio on why C-sections are needed or not needed, and if the child can't get enough food from— just solely from breastfeeding. But that's a big risk. The other risks are the antibiotics that are used for, you know, sometimes necessary, but maybe sometimes not so necessary. treatment of early childhood infections. As you know, clinically, the majority of ear infections are viral, and just treating patients on spec with antibiotics not only is going to treat or not treat an ear infection, but its biggest effect is it's going to change the microbiome. This post-antibiotic diarrhea, it seems like nothing but an early developing brain— gut Alterations of that bacteria are changing the priming of immune function and fat metabolism and brain development. So this plethora of symptoms that are associated with autism, C-section, a kid at risk that may spend more time in the hospital, overuse of antibiotics, at a broad level does convey a potential for risk. Let me be clear, it's a relative risk when you look at large populations. Right. It's not as simple as a C-section is going to destine someone to an illness, but it is part of the picture.

I agree. You know, that— you made a very good point. On the other hand, I think that we are at a place in terms of the literature right now to indicate that studies are clearly showing an association between number of exposures to antibiotics, being born by cesarean section, and increased risk Absolutely. For a disease, autism, for which there exists no treatment. I think one of our missions as physicians— missions as physicians, I like that— is to really do our very best to get this kind of information out, at least to the public, as a form of empowerment and let people do then what they may. I mean, you mentioned cesarean section, which is clearly a life-saving procedure. A fantastic procedure for saving the lives of mother and/or baby during times of complication. But I think when, at least here in America, when you recognize that a third of all births happen now by C-section, it's kind of difficult to imagine that that is a requirement in 33% of births, that there's that degree of complication, especially through the lens of what you just presented, indicating that— C-section birth, depriving that baby of his or her first inoculation of the microbiome, may have some long-term risk in terms of autoimmune conditions, metabolic issues, and as you have so well described to us, even autism.

You're absolutely right. It's— I think the paradox occurred that obstetricians were so good at doing C-sections That the bar for doing them just kept getting lowered. A meeting that I saw in Scandinavia following patients showed that you have this blip of producing a lot of them. Again, in the future when we understand restoring the microbiome or even using— these are ongoing studies in your country and Puerto Rico, ideas of C-section babies, if they absolutely need them, being able to get— Yeah. the flora transferred from the healthy mother, provided the screening shows no disease, is an interesting future. There are a lot more benefits that we're finding with the normal birthing process, priming the brain, catecholamine, the stress response for the child being able to develop. Again, it's the same with antibiotics. We need to have our clinical skills and also educate and empower families saying, We're watching this, this kid with a runny nose. They don't have a high fever. Everything's running. This doesn't look bacterial, but you can always come back in the future. We're not only going to help this child, because don't forget, as you well know, it's a child that doesn't get antibiotics, but also if they're in large groups of daycare where everyone else is getting antibiotics, these bugs are going to jump. So again, it's not a cause for absolute alarm, but when— you're absolutely right. When you look at these large populations, you see a very huge risk. And it can also be not just the C-section, it's the child or the mom hanging around for a longer period of time in a hospital, which although it's lifesaving and a question of judgment, they're going to be picking up different kinds of flora.

Well, in terms of antibiotics, I think we as physicians have all been trained in the notion of risk-benefit ratio. What is the benefit of using any particular intervention, be it surgical or pharmacologic? Pharmaceutical versus what is the risk, what are the downsides. And I think you've added a very important layer to our understanding of risk as it applies to the changes in the microbiome, the importance of a healthy microbiome in terms of inflammation, immunity, and actually, as you would agree, keeping this propionic acid level in check because that turns out to be a fairly significant brain toxin in terms of affecting the mitochondria, the energy producers of brain cells. We have been honored to have you agree to speak at our International Symposium on the Microbiome, Integrative Healthcare Symposium— Yes. In October of this year, and really looking forward to you, you know, being able to take us to the very cutting edge of what you're going to be talking about. So I want to just thank you for participating in today's interview and also for agreeing to share your expertise with us in this upcoming seminar. In closing, I wonder if you can just give us a sneak preview of what you think the next 5 years, 10 years may hold based upon the groundwork that you have provided to us.

Oh, you're too kind because again, it's a large group of a lot of people around the world including yourself in educating the population. But if I can be bold to what's occurring, these longitudinal studies all around the world in developed and undeveloping and changing nations, following bacteria from mothers from birth right on up to young adulthood, and seeing the trajectories of these bacteria or their metabolites predict later disease, is going to have huge capacity that we can prevent something. Yeah. The idea that major obesity may start early in development, or autism, or behavioral effects, all these chronic diseases of Western society, may be circumvented by just kind of keeping that little baby microbiome stable for the first 18 months is going to go a long way to the future. Even later, the idea that we thought these bacteria can't change, and you can't change things later, a leopard can't change his spots. Isn't being true. The bacteria may be harder to change, but you can change what they make in a day or so. Diet may be more of a factor in people that may already have some of these changes. That may explain obesity or behavioral effects, and even autism, the yo-yos of behavior. The idea that it's coming into— as I mentioned before, the old ways of looking at autism and most conditions, Alzheimer's, other major illnesses, cancers, are largely genetic, and that you have a broken gene, which is important in a small group. The concept that these fatty acids are called epigenetic programmers, they're switches that can turn on and off genes, and these genes need not be permanently altered, is really encouraging. The biggest thing is the first pregnancy and 18 months of a kid's life, keeping mom's bugs happy and the kid's bugs happy. Don't derange it, and it will play a huge role, is important. Mixing it with all the other effects of medicine, that we can— when we understand that these conditions, as you've said in your book, the dementias, cognitive behavioral effects, seem to be immune and metabolic, these point toward potentials for reversibility. It does add the idea of— we always talked about we are what you eat. But we saw some people that would eat and have huge effects, and others won't. The microbiome is going to be the main thing interfacing between diet and environment and our health. Because there's 10 times more of them than us, they're part of us, but there's tremendous capacities for them to recover and restabilize. There's techniques now in the last 10 years since we started to actually understand The big data. A lot of diseases that we thought were— our background in neurology, we just sort of thought it was maintenance and prevention of further effects. The idea to improve and prevent is very gratifying. But not to be negative, the understanding is still important. This is a feeling in evolution, but it is starting to answer a lot of questions between the different views of looking at chronic disease. Yeah.

Well, I find it very, very exciting because finally the door has been opened for us as brain specialists in a new playing field, a new arena where we may have powerful tools that we can leverage not only from a diagnostic perspective, but as you so eloquently just described, from a preemptive perspective, recognizing that we can identify those individuals who, based upon these parameters, That are measurable would be at risk, and those parameters are actually manifestations of dysbiosis or changes in the gut bacteria. So that sure sounds exciting. Well, again, let me thank you for your time. I know you've got to get back to your research. Very, very exciting, and I look forward to seeing you soon.

I'm really looking forward to the great meeting you've set up. And once again, you can go to our webpage, the Keely Patch 11 Autism Research Group, Or do McFabe and Autism, and you can get a— we're a not-for-profit group, you can get their publications and downloads. And again, thank you very much for having me, and congratulations on your excellent book.

Thank you, Dr. McFabe. We'll talk soon.

My pleasure. Bye-bye.

That was an incredible interview, I think. Really amazing information that really challenges us to look well beyond the brain as it relates to things like autism. Dr. McFabe is doing some incredibly pioneering work in terms of relating things in the gut, specifically the gut bacteria, to things in another part of the body, in this case the brain. And I think what's so exciting about Dr. McFabe's work is that challenging us to think outside the box, outside the skull as it were, in this way is really, I believe, going to open up the possibility to do some to some really new and exciting novel treatments for this situation. You know, autism is a situation that has increased 7 to 8-fold in just the past 15 years, so we've really got to pay attention to researchers like Dr. McFabe who are finally getting some traction in terms of what may very well be the important underlying science. Thanks for joining us. I'm Dr. David Perlmutter.