#125: Derrick MacFabe, MD- Carbohydrates, Ketones, Gut Microbes and Brain Function

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About Derrick MacFabe M.D.

Dr. MacFabe is the Director of the Kilee Patchell-Evans Autism Research Group, and Assistant Professor, Depts. of Psychology (Neuroscience) & Psychiatry (Division of Developmental Disabilities), at the Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. He is also a Core Member of the iTARGET Autism Initiative, University of British Columbia, Vancouver. He is investigating the role of gut-brain interactions on the identification and possible treatments of autism spectrum disorders. Dr. MacFabe’s research examining potential gastrointestinal and infective links in autism has been listed among the “Top 50 Scientific Discoveries in Canada” by the Natural Sciences and Engineering Research Council of Canada.

Learn more about his research

www.psychology.uwo.ca/autism

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Show Notes

Mike: Great to be with you. So, what I love about your research is you’re adding a lot of context and have a deeper meaning to this narrative about the gut microbiome. Maybe let’s talk about your research and the short chain fatty acids and these metabolites and how they affect whole body physiology.

Dr. MacFabe: Okay, as a backdrop, my background in neurology and basic science, we have sort of been at the stage seeing this extreme increase in autism, one in 10,000 in the ‘50s, when I started my residency it was like one in 170 and now in 150, so something is occurring and what we saw in the context of epilepsy and autism, all these children having these behaviors, but in addition, these strange whole body issues, largely with their gut. They’d have constipation, diarrhea, bizarre food cravings, mostly for sugars and for some reason, it seemed to make their behaviors and the digestive issues worse, but they liked it. And then there was all this evolving research going away from the hardwired genetics-only autism, which genetic loading is a part of it, but can’t really explain this, what we think is a real increase, that these children had whole body issues. Carlos Pardo found the brains of patients with autism were chalk full of microglia. They had inflammation and inflammatory factors. People like Dr. Deth had found that, and Jill James found that they had oxidative stress and problems with lipid metabolism and energy function, and then other groups had been finding abnormalities with general whole body immune function, autoimmunity, so you are getting these very strange pictures. And then one of the giants in microbiology, Dr. Sidney Feingold was finding, of all things, abnormal gut bacterial populations, a certain species of clostridia, it’s complicated because there are a lot of different kinds of bacteria, but finding more of these and found that if you eradicated those bacteria short-term, some of these kids started to improve for a short period of time. So you saw a cacophony of all these effects, children getting worse and better, also actually, of all things, being exposed to a lot of antibiotics, lifesaving, but as you know, there may be long term consequences, and then a good mentor of mine, Martha Herbert, was saying “Hey, is this not a hard-wired disease, it’s a whole body condition.” So we found these weird abnormal bacteria and immune system function, then it was “How could this happen?” and cause these whole body and behavioral effects. When these bacteria live in us, we are kind of like this spaceship. They outnumber us 10 to 1. They have 100 times more genetic material. We are 99% bacteria; in terms of we are more like a colony. When we eat, we don’t just feed ourselves, we feed these little guys in our gut, largely anaerobic. They ferment. They eat and depends what they eat. They eat these certain foods. We were interested in mostly these refined high sugar carbohydrates, some wheat-based carbs. You feed these bacteria. They ferment, kind of like giving carbs to yeast to make beer and alcohol, they make compounds very similar to alcohol called short chain fatty acids. Some of us know from personal experience, what small molecules like alcohol can do very complex things with your brain and your behavior, again, not all good and not all bad, but also very sensitive early in development. We had this idea, could these bacteria, which we did know these bacteria produced compounds called short chain fatty acids, kind of like alcohol, and could these compounds, have an effect on us similar to the intoxication of alcohol. When we went through the literature, it was mostly stuff from the gut. We found these compounds. We were particularly interested in a compound called propionic acid. It was interesting, because Sid Feingold’s bacteria that he found had also made more of this propionic acid.

 

Mike: The clostridia.

Propionic Acid

Dr. MacFabe: Yes, and some other bugs that he’s found and other groups have found as well seem to skew things more toward propionic acid. There were other fatty acids, butyrate and acetate and we were looking at all of them, but propionic acid, with the P, was kind of peculiar, because in addition it has some very weird properties. It could be sucked into the gut with transporters and it could actually get into the brain with these transporters. It had huge effects on gut motility, immune system function, mitochondrial function, lipids, mentioned later, gap junctions, gene expression, a whole cacophony of things for these little bacteria seem to be talking to us with their little small molecules metabolites. It was also interesting, might have been a red herring, but partly, as I said, if these kids eat these carbs we thought that they’d feed these bacteria to spew out propionic acid and dance with our metabolism, but also the compound, interestingly is a food preservative in refined wheat and dairy. That may be a red herring, but it is interesting that it was located and it has some beneficial effects too, but we wondered, “Hey, what could this compound, not necessarily the whole culprit of autism, but a way to look at how the microbiome or gut metabolites can talk to the whole body and the brain to induce behaviors that are similar to autism?” That was the million mile journey began with one step. On paper it seemed to make sense, but it had to be tested.

 

Testing Propionic Acid Theory

Mike: And you started testing that by injecting propionic acid, if I am not mistaken, into animals and noticing aberrant behavior, is that how?

 

Dr. MacFabe: We were actually shocked, so you can write a review paper and see all these linkages and also, as an aside, there were a lot of people that had problems, either not only making more propionic acid from their gut bugs, but also problems getting rid of it, but you are absolutely right, the best study ideas have to be tested to say “Well, take some of this propionic acid, give it in small amounts to lab animals, either into the brain, the fluid of the brain or the diet or in food, and if that has some link. Are there behavioral, electrical and the meat of it, the biochemical changes look anything like autism.” We were shocked. You would take an adult animal and give a small puff of this. We have a number of papers with control compounds and different doses. You have to do good science. The first study, we were shocked. Immediately when we put this compound in, the animals became hyperactive, did things over and over again, developed tics, fixated on objects, preferred objects to interactions, and had favorite objects, could learn things like crazy, like learning a maze, but when the maze was changed, it was my way or the highway, did the same thing. So you have all these repetitive antisocial object fixation, rigid behaviors looking like autism and in addition certain kind of seizures that are associated with autism. The brain became sensitized. The weird thing is, because it’s a little fatty acid, it gets burned through the citric acid cycle, the TCA cycle, mitochondrial function partly. Once the compound was burned away, the animals reverted behaviorally back to normal. So you had this idea that if the brain was flooded with this, so the gut produced a lot of these fatty acids, you could get a behavior that could go away. We started with the behaviors. So we did this with my collaborators, Peter Cane, Peter Alisoncot, Martin Cavaliers here in Canada. Then we started to go in meat and say “What is it doing to brain chemistry and all these other functions that we happen to discuss?” but we were shocked that the behaviors looked like autism and a lot of the biochemical effects of it looked very much like autism.

 

Mike: Wow. That’s really fascinating stuff. Now, the question that comes in my mind, and I haven’t read the papers in much detail, but was that a supraphysiologic dose or a dose that maybe would be representative of someone eating maybe a sandwich or some of these refined carbohydrates that would cause a bacteria to ferment them and create propionic acid and then effect behavior.

 

Dr. MacFabe: Now, again this would be a longer answer for a short question, but the levels we gave were approximately the levels of patients that have a metabolic condition called propionic acidemia, where they really can’t get rid of propionic acid. It’s very interesting. They have a lot of cognitive effects, behaviors and they’ll also effect similar to autism. We were only giving a small puff into the brain around that level, but we’ve gone down about 20 time. Again, we only give it over a minute or two and the body is breaking it down extremely quickly. This is a really pesky molecule to measure because as soon as it’s made, it is sucked into the gut and then it is immediately changed into something else. So those levels were sufficient to cause all these brain and behavioral effects. And then we used some control compounds that were kind of like it, propanol. They didn’t have an effect. We’ve worked on acetate, butyrate, the other two fatty acids, but propionic acid, the P is peculiar in that it had most of the effects. What we wanted to prove first, people said “Well, why did you put it in the brain?” and we defend this because people thought “Well, these children are acting out because their stomachs are upset.” And I’m not saying that’s not a part of it, but we thought that this was a central effect. A lot of children have upset stomachs but don’t engage in these horrible self-injurious and repetitive behaviors. We wanted to show that this compound could directly work on the brain in very small amounts and it was reversible. The short answer is, it’s around a level with metabolic conditions. Now remember when people can’t break this down, they get a lot of a dose. We were just giving small amounts of this and we’ve gone even lower, in terms of the effects. Studies on a lot of biology, which we can get into with other, how it affects immunity and mitochondria, have all found these levels to be acceptable.

 

Mike: So Derrick, let’s talk about those effects. You mentioned mitochondria, immunity, behavior. There are aspects in gap junctions and neurotransmitters. Let’s kind of take a deep dive. This is an area that people are really not talking about. You specialize in this, so navigate us through this journey.

The Inflamed Brain

Dr. MacFabe: Okay, I’ll try to. The big picture of people looking at autism, it’s like the blind man and the elephant. People are really learned people working from their particular lens. The geneticists have their lens. The mitochondria people have their lens. The fat people, the inflammation people have their lens. It’s not either or. They are all producing very good data….and the microbe people. A good way to look at this is to say “Okay, let’s hit a base hit to each of these giants looking at autism.” So we’ve circumstantially linked the behaviors, because everyone diagnoses autism largely on behaviors, like I mentioned at the start, these bizarre repetitive antisocial tics and object fixation. The next stage was okay. People found patients with autism, the autopsy cases and now the recent brain imaging studies found that brains were full of, chalk full of immune cells called microglia and these immune cells come from the bone marrow or the yolk sac and infiltrate the brain and they are part of normal development, cortical pruning. In addition, in inflammatory conditions these microglia blossom. They become activate. They get angry, if you will, as well as the astrocytes, the glial cells that outnumber the neurons, ten to one and in layman’s terms, the astrocytes are important with keeping neurons happy and working fast. They control the potassium and glutamate relations and the extra cellular fluid. So you’ve got these astrocytes, microglia and glia and Carlos Pardo found patients with autism, whether they were a toddler or an adult, were chalked full of these innate inflammatory cells. He was an expert in HIV and he was using similar stuff and saying “Hey, the brain is inflamed” in layman’s terms. So this is a different thing as far as it’s just a wiring issue. That was interesting in its finding, and also more information since that happened were how these microglia and astrocytes are involved in making synapsis and developing a brain and having a synapse go away when it’s supposed to. So long story short, they found those changes in patients with autism. So we said “Hey, let’s look at the brains of these animals that were exposed to propionic acid and the other compounds.” Lo and behold we found the same kind of inflammatory response as the patients. The interesting thing was, the brain cells, the neurons were not overly effected. So you have inflammation without a lot of neuronal loss, which is similar to autism. This is not to our knowledge, a massively degenerative condition. It’s an acute inflammation, so we found that. Then we had people going “Okay, there are problems with oxidative stress.” Dick Deth’s amazing work as well, Jill James’ work found that there were problems with damage of lipids, lipoperoxidation and glutathione, the main cleaner-upper of broad xenobiotic detoxifier. Carina Rodregus Kapote, my grad student said “Hey, let’s get a base hit for these guys.” And look at the oxidative stress changes. Lo and behold, we found the same oxidative stress and decreased glutathione. That decreased glutathione isn’t trivial, because not only is it good because, you’re having a model that’s consistent with the redox of the oxidative stress theory of autism, you are also saying “Hey, if you have a lot of propionic acid and your glutathione is low, you might be on a slippery slope with other things that may damage glutathione.”

 

Mike: Environmental toxins….

 

Mitochondria

Dr. MacFabe: Tylenol, good in low doses, not in high, so think of that picture of giving well-meaning Tylenol to a child that’s having problems. That fit. Other research was Rich Frye, a brilliant guy in Arkansas. He was a real expert in mitochondria, in showing that these kids had mitochondrial problems that didn’t seem to be, some had genetic mitochondrial problems, but most of them had all the mitochondrial changes, problems with changed organic acids, pyruvate lactate ratios. There’s a lot of really high powered stuff showing how these mitochondria were kind of sick with patients with autism. You couldn’t find a genetic cause of it, except in a small group. So his view are environmental factors are mucking about the mitochondrial function of cells. Now think about that. All our mitochondria are affected, but mitochondria in your brain are really important, because it’s highly metabolic active. Your gut is extremely important because its surface area is as a tennis court, so you need all that energy to maintain barriers and an underappreciated one is your immune cells are chalk full of mitochondria. He was saying “Environmental factors are affecting mitochondria” and a lot of them are, but we said, hey, we know this propionic acid, I said it’s peculiar, it’s a short chain fatty acid and it puts a wrench in mitochondrial function. So we found the mitochondrial changes in the animals looked identical to Rich Frye’s, a subgroup of Rich Frye’s patient base. We found that the model could replicate a mitochondrial disorder. This is an evolution. We are doing more studies, so all the changes in fatty acid metabolism and lipids could be skewed. In the animal model the same as the patients with autism. It’s really interesting, but if you take a step back, where did mitochondria come from?

 

Mike: Bacteria.

 

Dr. MacFabe: The bacteria. The bacteria in your gut are having a discussion, if you will, with the long lost relatives. So what do mitochondria? They are energy, but they are also changed genes, gene function. Other work we’ve done with our collaborator Bistra Nankova, these short chain fatty acids are, it’s a mouthful. They are called histone deacetylase inhibitors. They turn on and off genes. In cell lines, we’ve shown what genes are they turning on and off. Lo and behold, they are the genes that are associated with autism or autism-related processes, learning, memory, synapse formation, inflammation. So now for the older guard, I might add extremely necessary, the geneticists have done extremely good work finding these small groups that have these mutations, but the vast majority didn’t, but they were tweaking on important metabolic effects. You can have a genetic disorder that’s a damaged gene or you can, these fatty acids can be thought of as kind of like turning on and off a light bulb, by analogy with genes. So we went through all those effects and we found that, not only were they looking like patients with autism for each of the camps, the redox, the oxidative stress things, the behavior, the microbe guys, but it was also starting to reach out across the table with the eminent geneticists who have done extremely hard work over 20 years and not have not found, as in most diseases, the smoking gun of a particular set of genes. They have found processes that are involved. How we are increasing this work is, again it’s a way to ethically do studies between animals and patients, because we have to understand things. We haven’t talked on the complexity of the microbiome, but it’s like it’s the history of medicine. We mean well, but sometimes if we oversimplify things, we get things wrong. There are so many interactions with these bacterial populations. Other issues that really interested us is migration, where people come from one part of the world to another. We work with Somali refugees, where they come here and they could be 5% of the population and 10 times the autism, and their autism is severe. They didn’t have illnesses like this. They had other illnesses, but all these children were conceived in the west. We are still seeing this recapitulated around the world, as antibiotic use, which, again to be clear, this is where we think the changes are occurring. Anything that seems to skew the microbiome development in the first 18 months is probably one of the major culprits. Antibiotic use, C-sections, now to be very clear, life-saving necessary, but there is an appreciation that these microbiome changes, because this microbiome is priming your immune system, your metabolism in the ways I just mentioned, probably through these fatty acids. This is the key causing the risks of these chronic autoimmune and metabolic and behavioral diseases. In our small part, we are doing this, but it’s enabling us now ethically to try to ask the big questions on how can we intervene therapeutically, both the help kids that are here, and also prevent some the risk factors.

 

Mike: That’s fascinating. So just to summarize, the propionic acid is affecting the microglia, the immune cells of the brain most…

 

Mitochondrial Metabolism and Gene Expression

Dr. MacFabe: That’s the one summary with immunity and the other one is it’s, which we are really excited in with Rich Frye, it is effecting the mitochondrial metabolism and it’s effecting gene expression. It’s talking, and as an aside, there are multiple receptors in the brain that are designed to handle gut microbes. So like anything else, these bacteria have co-evolved with us to produce behaviors. Now as I digress a little, we found these compounds are involved with learning and memory. Our animal models show this, but you have diseases where you can’t remember, dementias. You also have diseases where you can’t forget, obsessions, rigid behaviors and the biology of repetitive movements or seizures. These bugs are actually, what we think is happening biologically, and there is a lot of evidence for this. When the bacteria are being fed, we are their spaceship, they send signals to the immune and nervous system to remember and elicit behaviors that make the host want to crave the foods. This is why that you have this bizarre refined craving, sometimes extremely bizarre in some of these children that they will crave these foods, but the behaviors will get worse. It explains how in certain cases, which we are not advocating, but studies where broad spectrum antibiotics have been used that knock off all these bacteria, like vancomycin, they found that these children improved. So here is the fact that by reducing, these things that reduced the production of propionic acid, not eating the refined carbs, cases, not advocating, but cases where the antibiotics have eradicated those bugs, there were transient improvements. This is getting into the future of being able to understand restructuring the, first respect the microbiome, don’t cause the effects, using maneuvers in the future that are in their infancy, probiotics, microbiome repair, but also giving compounds that help you get rid of propionic acid or improve their effects, omega 3s, carnitine, which improve fatty acid metabolism and certain antioxidants, N-acetylcysteine. All these changes are seen in the animal model, as well as the patient. This gives us a framework so we can, in part, autism is being more of a metabolic disease. I am a fan, because I am from Canada. Our university here is where Banting developed insulin for diabetes. Think of diabetes, a metabolic condition before insulin. It was hopeless and the behaviors were pretty darn bizarre, but when we understood the metabolism, we devised ways to measure, this is going to be the key thing, in diabetes you are measuring sugar levels. What we are trying to do is measure these fatty acid levels as ways to tailor the treatments for these kids. We think we can improve a lot of kids that are here. We certainly think that we have ways of reducing the risk factors, not just for all these micro…autism, but other microbiome-related diseases, and also some metabolism that we think can, metabolic augmenters can prevent the crash, which I’ve mentioned a little bit how this compound effects mitochondrial function and carnitine and antibiotics, not only change the gut bacteria, to increase propionic acid, but some beta glucans, I’m sorry, beta lactams which are used for common ear infections. You know how they disrupt the gut. They are also poisoning carnitine metabolism. This is our version of regression of autism. You have a developing brain with impaired fat and energy and mitochondrial function caused by antibiotics and gut bacterial changes.

 

Mike: A lot of people are interested in the practical application here. You mentioned fatty acids and NAC and antioxidants and so forth. Do those work by what you said, by enhancing propionate degradation or are they effecting, or are they mitigating the effects of propionate has for, example on the mitochondria and the brain. How are they working or do we know?

 

Supplementation

Dr. MacFabe: Probably both. As Rich Frye’s and we do, it’s like there is what we call endo-phenotypes. Just like there is theme of diabetes, type 1s and type 2s and drugs, there is a theme of the metabolic degradation in autism. We are always proven wrong, but there are trials that have shown carnitine, which is low in patients with autism in the model and effects. Carnitine supplementation has improved some behavioral effects in some trials. N-acetylcysteine has been done with OCD and a few others, omega 3s in developmental conditions. These, we think, are fairly benign and evidence-based for certain cases of patients, before we get into the more detailed effects. Our review papers we’ve got on our website, they’re open access. We talked about multiple ways where you could have impairments or propionic acid metabolism, genetic, acquired, mitochondria, drugs, Tylenol, these bacterial dysbiosis. There are multiple themes that tend to, just like there are multiple themes that effect sugar metabolism, this is the mirror image of that. The short chain fatty acids, think of what sugar does to metabolism. This is the hidden player on whole other field of metabolism, these fatty acids.

 

Mike: But they are also found in food, right? That’s the other thing that you were…can you talk about that a little bit?

 

Microbiome Evolution

Dr. MacFabe: And again, I think our microbiome has evolved from the environment we live in and our foods were also what we have been desired to. We are not advocating specific things, but you can…what is known at one level, and again there are all these different people. Not everybody’s bugs are the same or their genetics, but what has been very interesting is, okay, I talked about certain bacteria-producing more propionate, but it depends what you feed them. Interestingly, in animal models as well, if you feed certain grains to these bacteria, they make more propionate and less butyrate. Think of butyrate as better, propionate as peculiar. Eating grains shifts things to propionate. Eating refined carbohydrates, hidden sugars that we always talk about, gives you more propionate, but switching your or reducing refined carbs, that makes sense. If you are eating the carbohydrates that are inulins….

 

Mike: Fiber based…

 

Dr. MacFabe: Yeah, fiber based, your squashes, your veggies, your….again, more non-refined foods, that shifts things to butyrate, which seems to be better in term of gut profiles. The other effects can be hidden. There are some subgroups. This is a thing in evolution about, are you truly sensitive to gluten, gluten intolerance. It’s complicated. There are some groups that are…subgroups that are interesting, so I am not knocking, I think we eat way more of these refined sugars. That’s our problem is the amounts and maybe earlier in life, I mentioned, early in brain development and stuff. But switching less refined carbs with more of the carbs that go toward inulin-based, your onions, your leaks, just go to the vegetable place and your omega 3s from fishes and that’s the problem with some of the omega 3 supplements. It depends who’s producing them, whether or not they’re affected. Your main lean fish, it’s like the basic diet we all should eat. The other side of it is that some of these overly refined foods, again the omega 3s are blasted. They are more refined sugars if they are gluten/casein free foods or they are gluten free or have a lot of sugars to make them taste better. You can see that’s problematic. Also, if they are more refined, they have more propionic acid in them to keep their shelf life. The old, I’m not a nutritionist, but the over-simplified version of shopping around the edge of the supermarket and I am more of a moderate thing. Some subgroups may be a complete reduction in grains, maybe only for a short period of time, but the other thing is a much more moderate. If I could make a carpet statement that I’m comfortable with, we are eating way too many refined sugars, high fructose, and a lot of them that are hidden, right, in these refined foods. We are eating way too many sugars. There is a big difference between eating old or ancient grain breads and something that can be on a shelf for 6 months. Our guts are not designed to eat these things. It’s very clear that they change the microf….that’s a whole other topic, but studies are showing that our western diet is skewing stuff toward propionic acid, rather than the better butyrate.

 

Mike: So, Derrick, let’s pose a hypothetical here. Our children, for example for medical reasons were both born via C-section. We were talking off line about this and so we obviously can’t really change that and we don’t want to skew medical decisions to put babies at risk for challenges with birthing, but what can parents do after the fact in terms of diet, so it sounds like the real food diet, is it possible to not only change your microbiome with real food, but also prevent the imbalances in these short chain fatty acid metabolites have you looked at that?

 

Long-Term Studies of Children Born of C-Section

Dr. MacFabe: So there is some evidence from it, partly following children over long periods of time and then also some animal studies. Every case is different and a lot of the misinformation on C-sections, we are knowing that changes in C-sections, because the baby passes through vaginal fluid and poop and it’s amazing how they rotate through and that’s the inoculation of the bacteria from the mother, genetic information onto the next group. It is true that if you have a C-section, you don’t tend to get the mom’s flora. If the mom’s flora isn’t great, maybe that’s not a bad thing. The big answer is it depends. It is true that the C-section babies are being, and again is it life-saving, it depends on what it’s for. If it’s for a life-saving thing, like failure to progress, you are going to lose both parents, but all those things being said, if the child has a C-section, the flora don’t tend to start up from the mother. They start starting from the hospital, which is interesting in itself. Hospital-acquired bacteria are resistant to different bugs, but what the research is showing is breast milk, again gives you the antibodies and the oligosaccharides that tend to help the growing gut flora. It’s remarkable that most of the sugars that breast milk produced, that was the big thing that freaked people out. We can’t digest it. It’s not food for us. It’s food for these bugs. The breast milk seems to change. The overall close flora of the mother changed. The dental care, the oral flora is becoming from my developmental dental friends that work with a lot of autism and it’s a lot easier to get flora. The oral flora from the dental hygiene of the mother plays a huge role. Not to sound very reductionist, but loving and kissing and smooching your kids is also part of the inoculation, provided the flora is good. It depends. These things effect, what people have found, and again, it’s a big leap before I can say what to do, but people have shown that a lot of these formula tend to make the bacteria produce more propionic acid too soon, as opposed to breastfeed. The other things the first foods of children in other cultures they may be starting earlier. The old view was, withhold for allergies, the other is starting it earlier, but my friends the inulins, these things that are the squashes, that are the onions and the roots, when you are giving these to children in first foods, it’s baby steps. They are gradual and if you are keeping away from all the refined things, having said that, I don’t want to waffle, but it depends. If the mother cannot produce enough breastmilk, a small amount is good for immunity. One has to deal with these other groups. It’s a huge thing of contention about the idea of probiotics. The concept of putting good flora in is the future. Let me be clear, but one has to say have these studies been done long term and looked at, but getting away from that, your normal response of getting your normal lactobacillus, as I said, is from you, your skin, and real yogurts. These are all real regular foods. The microbiome and you have evolved on dealing with foods. The foods are changing in ways that we don’t completely understand. There are risks and benefits and they be up to two generations away. To digress a bit, there’s some very fascinating work ongoing. The first studies have come out with C-section babies and initially done in Puerto Rico, in your own country, following kids that had C-sections or not, where they simply swabbed the vaginal flora of the mother as an inoculant, and they are following these children and they’re finding so far, there seems to be some evidence of improvement. The problem with that, with the no offense, do it yourself, is it depends, it depends on the flora of the mother. Would we really want to advocate in our small ways, trying to get all these people together to really look at….these bugs are the lock and the key of explaining all these chronic illnesses fighting. There will be a part of something. They won’t be everything. This is as I think I mentioned before, the answer to these questions will come with these remarkable longitudinal studies that have been done, largely in Scandinavia, but also all around the world now. Scandinavians, my collaborator, Tor Medved, he’s one of the pioneers of microbiology. Ten-fifteen years ago took children that were born, whether they were normal and C-section and every few months froze all the bacteria, followed these children, whether they had a C-section or not or antibiotics or not for necessary illnesses and predicted the future of microbial analysis, which is way more complicated and way richer than what we did stuff. They are finding that these kids that had those effects, these early bacterial changes could predict whether they had obesity, autoimmune disease and, yes, in our fields neurodevelopmental disease. These studies are going to give us information on predicting the upstream things that happen before the behavior. As an analogy with diabetes, when diabetic gets really sick, he didn’t get sick that day. Something has been brewing for months, same as metabolic syndrome, with a heart attack. These groups following everybody, Gates Foundation have set a beautiful thing that just for folks that are reading, these are the papers that are coming out. They are called the Maled Study. This is all around the world looking at where western societies well-meaning have been trying to intervene with antibiotics for early childhood diarrhea, it’s complicated because there is malnutrition and everything else, but they’ve been following these children and indeed finding out the same thing that the Scandinavian study, early antibiotic usage over broad populations is not without potential risks. It may reduce and acute illness, but it is skewing the immune system and the microbiome and behavior later on. The good news is, I’m an optimist because it seems like nothing is being done, but I would like people and clinicians as well as families to follow these studies showing the wealth of information that’s coming from this showing cause and effect of microbiome in long term health and disease. The facts that our work shows that it has the potential to be at least partially reversible is useful. I caution people taking a broad approach. We talked about things like fecal transplantation for clostridium difficile, a known disease. People are looking at this in a lot of illnesses, inflammatory bowel disease and also, I would add, autism. But this is something in evolution. We don’t know the long term consequences of it. What I would envisage in my perfect world in the future, I’m an optimist because I think things are already being done. There is already an understanding now that hey, antibiotics, they are life-saving, but if we keep using them all the time, they don’t work. Like I told you, these kids with autism historically have had a lot of antibiotic exposures, maybe necessary, maybe not, for ear infections. Antibiotics are going to be more careful and there will be abilities to determine it’s a virus. We don’t need it. The techniques are there. The importance of it is…we will know the importance of trying to respect the microbiome for healthy vaginal delivery and following. But please be very clear with the antibiotics and C-section. Listen to your educated doctor, which we are doing and also educating them. Listen to the obstetrician. Things change very fast in birth and people have to understand that there are potential risks for things, but there are things very imminent. We are so good. The developmental pediatricians in the west have done so much. Trust it for a guy who’s kind of been around the world, to reduce so many infant diseases. We don’t realize the potential implications of demanding. Having said that, we realize that all C-sections, because they are so good at it, the level has been lowered for doing it, but now we are realizing we have to be a bit careful. We will with these blood markers, just like I said measuring glucose and things that we do for diabetes, we are going to look at these neuropsychiatric diseases similarly. We are going to talk about how diet, again, in your background in nutrition, it was always like “Well, here’s this diet and here’s this person with obesity, which is the main one, and how come it worked for them and it didn’t work for me?” When you do a big study, nothing works because people have different microbiomes. The microbiome is going to be the thing where the geneticists and the nutritionists can shake hands with the parents. The information is coming out now faster than, frankly, I can read. It’s not that it isn’t being done. It’s being done and the data is spitting out. We look at these diseases as largely preventable, treatable and trying to go toward, not a fancy diet, like blueberries are good for you and they are antioxidants and they are part of this, but if you eat blueberries all day, you are going to be sick. Coffee is good for you, but if you eat 60 cups of coffee, your behavior will be different. Hippocrates was right, it’s in the dose and it’s in the timing. We have an appreciation for the need of normal birth, of foods that aren’t just calories, but they are useful. But we also have to balance that against huge world migration, starvation. What do we do acutely when we don’t have anything? We can’t throw away foods to be able to stop famines. The thing is, we are seeing an appreciation of this is going to be not just for autism, it’s going to be all long term chronic western diseases. I don’t think I am the only one sticking my neck out. It’s going to start honing on these little bugs tinkering around with our brain and our metabolism in the first 18 months of life, but probably throughout life. There are a lot of things with that biology that I think we can prevent and also treat.

 

Bacteria Assessments

Mike: Now let’s talk about assessment for that, because I know a lot of practitioners that tuned into these shows and patients and so forth do stool tests and various things. You mentioned like eating yogurt and getting lactobacillus and bifidobacterium and lactic acid producing bacteria. What sort of genre of bacteria should people look at? Is there a certain genre, like you talked about clostridia produces a lot of propionic acid.

 

Dr. MacFabe: Well, again, I can’t comment on individual labs and stuff because not all clostridia are created equal. That’s not a fault of the labs. This is a field that’s growing at a lightning pace. More or less clostridia may not be useful. It depends on the subtypes and the genre. Not to sound negative, the organic acid testing, its information, but what it means is problematic as I told you. The compounds are absorbed, but if you see Frank Organic Acids Juria, these metabolic things, sure they’re useful. I’m interested in, it’s my pet thing along with Richard’s work, it would be very interesting in the future to see carnitine levels and this gets complicated, but where does the carnitine go? Papers in translational psychiatry showed short and long chains going up and down. Carnitine and free inbound carnitine studies, I think, are an interesting thing that can be warranted and looked at in more detail. Certainly I would say at a simplified level, if you have a patient that has low carnitine and a relative carnitine deficiency, which has been seen in patients with autism, known. And carnitine has some efficacy, known. Our animal work supports all that and even predicts it. It probably would be not unethical to try carnitine. I’m not honing that this is the only thing, but this is where we would like to see. It’s not knocking the labs. The information is coming faster than the labs. The other thing with the labs is, it’s going to depend on what they are eating. That’s another thing. We’ve talked about this. You can have a glucose tolerance test and we are thinking of other ways of challenging the microbiome. Think of these things that most metabolic testing is normally fasting. What are you doing? You’re not feeding your bugs. We would like to and we welcome to work with people to explore these things. Our initial role is to; I think these short chain fatty acids provide the language between all these different groups. I think the future, back to bacteria, as we know more from these longitudinal studies that are showing with the animal…it’s not just correlation, you are predicting that these bug derangements affect illnesses. Those particular bacterial populations may be useful. I’m afraid to be responsible this time, it warrants doing major studies to support it.

 

Mike: So at this time there is not a great assessment modality.

 

Dr. MacFabe: I think the theme is there and in those broad metabolic testings, you are going to find specific, some kids, right, might have a frank missed organic acid juria. It’s not being negative toward them. The theme of what these labs are doing, and not to be negative, does make sense. There are going to have to be standardized in terms of what you ate affects you.

 

Ketogenic Diets

Mike: Very interesting. Great sound bite. Now let’s finish off here. Ketogenic diets have been talked about quite extensively and I know being a neurologist, you’ve worked with epilepsy and so forth and are pretty familiar with that. There is some overlap here with the transporter proteins and ketone bodies. Let’s dive into that.

 

Dr. MacFabe: Yeah, we were kind of surprised by this too, because one thing I thought, again, you get over-simplistic when you think. I think the reason ketogenic diets work is, you are not eating the carbs and, so less carbs, less propionic acid. And then lo and behold, some of the work we’ve dug out is saying the ketone transporters, that take the ketones into the brain, as you know they are neuroprotective and for epilepsy and even certain brain malignancies and glioblastomas, people have been looking at metabolism of that. But anyway, the transporter for the ketones is the same transporter as the propionic acid. One of the effects, we wondered, could it be, it’s partly the bacteria that are changing in a ketogenic diet and this is an evolution. These reports are an evolution in term of long term effects, but it is known ketogenic diets change the flora. What that means is going to be a debate, but on top of it, it would make sense that a ketogenic diet and testable in our work. Propionic acid may prevent the ketones from coming in and the converse is actually true.

 

Mike: So it’s yet to be determined which one effects the other is what you’re saying.

 

Dr. MacFabe: Actually, what is known, this is basic science, the transporter, you can block ketone uptake in the brain by high propionic acid and the converse is true.

 

Mike: But since propionic acid is made by fermenting carbs, theoretically, they both wouldn’t be….