Part 2 of a 3 part interview, with Emeran Mayer, MD, PhD on the mind-gut connection. Dr Mayer talks about irritable bowel syndrome (IBS) as an example of a known brain-gut disorder, focusing on the research on dysbiosis—alteration of the gut microbe from healthy individuals—and what it means for the 15% of world population suffering from IBS. He answers the question: is it all in patients' heads? He also discusses the development of the gut microbiome in infants and the influence of prenatal events, breastfeeding, and antibiotics on gut content.
David Carreon: This is the fascinating idea that neural hacking, that the bacteria are hacking into our nervous system to get what they want. That's such a cool idea and I’m certainly excited to see what the science shows as this field develops. Would you talk a little bit about maybe an area where the communication relationship is more well established. You mentioned IBS a little bit earlier. Could you explain what is IBS and what is the gut microbiome have to do with it?
Emeran Mayer: IBS is the acronym for Irritable Bowel Syndrome, a very common disorder, about 15% of the world population are affected. It's a syndrome defined by symptoms because we don't really have a biomarker for it. It's a combination of chronic, recurrent abdominal pain and discomfort and altered bowel habits. It seems like a very loose definition, but it's pretty accurate, with a pretty high sensitivity and specificity, if you can rule out other causes for these symptoms.
David Carreon: I think just to pause and emphasize there's something that I don't think everybody is aware of, but 15% of population and you put an endoscope in, do a colonoscopy and there's nothing there, there's nothing that you can see or take tissue. It's not something that you can diagnose with objective, at least thus far, signs. That's a huge burden. I think the emphasizing the importance of figuring out what it is, what's going on, trying to better characterize this thing that's rather common and underdiagnosed.
Emeran Mayer: What has happened this area, because it's recognized as a brain-gut disorder, so when the microbiome science started, immediately people jumped on it, including ourselves. There's a series of studies that they all can be criticized based on small sample size, mixing males and females, not controlling for diet. Then, not unexpected, several labs found different abnormalities. These abnormalities are called dysbiosis; that means an alteration of the gut microbial composition from a healthy control population. Most of the studies have found evidence for dysbiosis even though the type of dysbiosis, what taxa are altered, if there's increased or decreased diversity and abundance has varied from study to study. The latest evolving concept is that there are several subtypes of IBS based on their microbial signature, as many want to call it. One that's indistinguishable from healthy controls and one that has significant dysbiosis. Interestingly, these two do not correlate with the typical clinical parameters that we use, like bowel habits, subtype, or pain versus discomfort. Seems to have a different function.
You may ask yourself, if half of the patients have a normal microbial composition, the others have an abnormal, but they have the same symptoms, do these microbes really have a causative role, or is this something that's a consequence of something else? My personal feeling about this is that, and that's often forgotten now in this fascination that the microbes can talk to us, that our brain can really effect the microbes, both their environment in which they live, meaning the transit rate through the intestine and the stomach, which is regionally regulated, slow versus fast transit, the secretion.
Many things are being secreted, which the brain sort of modulates, like the defensins from Paneth cells, there are many endocrine cells, serotonin cells in the gut, enterochromaffin cells, which are under autonomic control, so that we now know that serotonin, as well as norepinephrine, can, under stress for example, increase in the lumen of the gut. Since these microbes have receptor or analogs for those substances, can influence their behavior. What I think, and I've had sort of this bias for a long time and seen a lot of those patients, that this is something that really starts at the brain level, possibly, most likely early in life. Could be stress, hyper-responsiveness, or increased emotionality, which sends chronic signals to the gut and its microbes and changes their development. The first three years of life, the microbes, the community is actually shaped, so if during that time there's an imbalance of the autonomic influence on these microbes, they will assemble in a different way. That may happen in some patients and not in others. That's why I personally think you now find a subgroup of IBS patients that have a normal gut microbiota. There's other people that disagree with that, but I think, we'll see.
IBS has been an interesting research area, interesting in quotation marks. So many hypothesis, just during my career, have been proposed to explain it, and most of them have come and gone. Right now it's the microbiome. We'll see if this is the final answer.
Jessi Gold: I've heard people say that IBS is all in people's heads and it's all anxiety and there's nothing else besides anxiety and the idea that it's a separate disease entity is wrong.
Emeran Mayer: That's the thing. When people say it's all in the head, this got a bad name and a very bad impression for patients because what the physicians meant, it's not a neurobiological process, but it's a neuroticism. I still am, in my early parts of my career I sort of taped these talks of the leaders in the field that would say it's a disease of neurotic housewives, middle-aged neurotic housewives. I think now, when we know so much more about the brain and how intricately it is connected and wired with the gut and back to the brain, I think this has a different connotation. I would never use that term to a patient, "It's all in your heard," but surprisingly, if you explain to them with the concept of the brain-gut axis, they all agree, they'll all tell you, "Oh, yeah, I've always known that it's connected to my emotional state or to the stress." It's very few patients, if you give them the right model, that would not accept that.
David Carreon: One of the things you said just a few minutes ago was that the gut microbiome is established around the ages of zero to three, which, as a psychiatrist, is very interesting. We talk about how critically important the first few years of life are for the psychological development, but you're saying that those years are especially important for the microbiological development as well.
Emeran Mayer: Yeah. The microbiome has added another dimension to the importance of developmental diseases. We also know that it predates delivery as well, so prenatal influences. Very interesting studies that, for example, nutrition of the mother, the pregnant mother, stress of the pregnant mother have an influence on the development of the microbial composition and abundance and diversity, and there's even an animal experiment that shows some very intriguing mechanism that stress of pregnant mother changes the microbial composition of the vaginal microbiome and when the baby goes through the birth canal, one initial seeding of the infant's gut microbiome comes from the vagina. In these animal experiments, it's been shown that stressed mother, different vaginal microbiome, the gut microbiome of the newborn is different because of that different priming. Again, in animals, that was associated with a change in brain development in the first few months of life. If that happens also in humans, it just illustrates the importance of prenatal events on the development and the architecture of the gut microbiome of the infant.
After three months, it seems to be fairly stable. It's also very important concept. Regardless what you do later, if you become a vegetarian or become gluten-free or whatever, your microbes will change and the metabolites that they produce will change, but if you go back to the default diet, you'll go back to that same architecture that you had after three years. You don't change that basic ... You can modify it in a certain bandwidth, but you can not really reverse it. There's very few exceptions.
Treatment with antibiotics could do that and also there's this one infection, this C. difficile colitis, which can basically knock out most of your microbes and lead to this overgrowth of the C. difficile organism. Antibiotics, I should mention that they also now have gotten a very new meaning because an extensive amount of antibiotics given to babies, the mother during pregnancy, treatment of the vaginal area with antiseptics, prophylactic antibiotics to the mother to prevent sepsis, this is a huge field. The amount, I forgot the number, that infants by the age of three have received an antibiotic dose is just phenomenal. That clearly interferes with that establishment of the gut microbiome.
Jessi Gold: You're saying that before age three, there's stress, there's antibiotics, there's whatever else the mother went through, there's just natural stress to the infant, how does then from three on can you regain that, are you just now at a disadvantage as a kid because you have this altered microbiome for life?
Emeran Mayer: As I said before, it doesn't stay exactly the same, but I think the current thinking, and you always have to realize that we're just at the very beginning of this microbiome science. This is like, let's say the first decade of neuroscience 150 years ago. I think a lot of things we're talking about today will be thrown out. Yes, pretty much the basic structure, it's like the operating system is established. You don't change during life the operating system of your gut microbiome. You can add new software to modulate it, but the operating system stays the same.
David Carreon: Interesting. That's an interesting analogy. What is the heritability of it? Where do the microbes that are in my gut, where do they come from? You mentioned the birth canal is one source.
Emeran Mayer: Yeah, there are a lot of influences. I should have also mentioned breast feeding during the first three years of life. One very interesting mechanism of how they're programmed. One is clearly the genetic make-up of the infant's GI tract that attracts certain parts of the gut, different communities of microbes. The microbes are not, the microbiomes are not a homogeneous population from the stomach to the end of the colon. In each of those areas, we have to assume there's different communities that are attracted to these regions by genetic influences of the person.
In addition, during programming, in the breast milk of the mother there are these so-called human milk oligosaccharides, or HMOs. These are large molecular substances that cannot be absorbed by the infant's GI tract, so they evolved to the evolution exclusively as food for the microbes of the infants. They play a major role in establishing this community early on. Does a large number of these HMOs that are contained in mother's milk, they're influenced by the genetics of the mother and they're also influenced by the diet of the mother. Two major genetic influences. One is through this early nutrition of the microbes comes exclusively from the mother, then the GI tract of the infant it comes only from genes of the father and mother. There are examples. Genetics don't dominate the population. They play an part. I think there is some mouse models, where genetics play a much bigger role, but in humans, I think influences other than genetics have a major influence, including early nutrition.