TEDxUCLA 2015: Beyond the Box
The mysterious origins of gut feelings
Hello. Anybody who has watched Magnus Walker’s TED talk on gut feelings realizes that this is a hard act to follow. However, I do want to start with my presentation with a personal story that illustrates the power of gut feelings that all of you probably have experienced yourself.
Up to the age of 17, I worked in my parent’s confectionery store, and that business had been in the family for six generations. I made pastries and cakes for all joyous, all kinds of joyous occasions, but I particularly enjoyed making fancy chocolates of all tastes, shapes, and forms.
I started to associate the sweet aromas of chocolate and vanilla and other ingredients with the seasons and with major holidays, without realizing, without conscious awareness that I was laying the blueprints for my future career, studying the complex interactions between food, the mind, and the gut.
I’m sure that most of you have made many gut-based decisions in your own lives and that you’ve used the expression “gut feelings” casually in many social conversations. And you’re not alone. World leaders, military commanders, rock stars, Magnus Walker, and millions of other ordinary people have used the same mechanism to make fundamental decisions about their life.
When it was time to make a decision about college, I agonized over this, over the decision to become the seventh generation leading the family business or embark on a career in science or medicine. After spending months of creating long plus and minus lists and listening to friends and family members, I finally started listening to my gut feelings and, to the great disappointment of my father, decided against the family tradition.
Several years later, after finishing medical school, I made another gut, fundamental gut-based decision, which made me abandon a secure faculty position at a Munich university hospital for an open-ended future as a scientist, as a junior scientist in a famous research center at UCLA that at the time was a magnet attracting research from all around the world, studying the emerging signs of signaling molecules from the GI tract.
During the first few days when I arrived at my new job, I realized this was light years away. The activities I was doing — isolating, purifying, and testing molecules from vast amounts of pig intestines that we had to collect in the slaughterhouse in the morning — it was light years away from the charm of working in the chocolate business back home.
However, after a few months, I did realize that this was actually a very fascinating topic, because at the same time reports appeared in the literature that the identical molecules that we isolated from the gut were also found in the brain, as well as in many animals and plants, and yes, they were also used by microbes to communicate with each other.
At the time we didn’t really pay much attention to this last example. It was considered to be an oddity. I wouldn’t have imagined in my wildest dreams that I would stand up here 35 years later and talk to you about this revolutionary concept that the microbes now gut, using the gut brain communication system, is able to influence your emotions, influence the gut feelings, and may play a significant role even in your brain health.
A few years ago, up to a few years ago, if you had asked any scientist what he would, he or she would consider the most sophisticated example of how a microbe can influence mammalian behavior, they’ll probably use the example of Toxoplasma gondii, a parasite that, like most parasites, require two hosts for successful reproduction. The cat and the mouse, the cat’s intestine being essential because it’s the only place where this organism can reproduce.
Now here comes the remarkable intelligence, the reason I bring up this example, the remarkable intelligence of this organism. In order to optimize the chances for the Toxoplasma cysts getting to the cat’s intestine for reproduction, the organism is able to get into the brain of the mouse and change the inborn fear of cats into a fatal sexual attraction towards the cat. So even the mere smell of cat urine will attract the cat, greatly enhancing the chances that it ends up ultimately in the G.I. tract of the cat.
Now when NPR picks up a topic and airs it on the Morning Edition, you know it’s got to be something of significant importance and interest to a large public. This happened about two years ago when the story aired about the, when the first story aired on NPR about the wondrous interactions between the gut microbes, or normal gut microbes, not the parasites, that can influence our behavior and our emotions 24 hours a day from the day we were born to the time that we die.
Most of these experiments, unfortunately, we only performed in rats and mice. So at that time, there was really no evidence that this would have a counterpart in humans. This is particularly remarkable because we have 100 trillion of these microorganisms in our GI tract, ten times more than human cells in the entire body and 100 times more than brain cells you have in our brain.
So one of the questions that comes up immediately, I mean, how did these microbes living in a gut in this vast universe, internal universe, how did they communicate with the brain? Let me give you a couple of examples of how we think that this may be working and then get into the details of the mechanisms.
So some of these experiments that were reported several years ago, people would have considered the imaginations of a mad scientist. So let me get to the first example. So when stool samples were taken from a genetically timid introvert mouse and transplanted into the colon of an outgoing extrovert mouse strain, these mice became just as timid as the ones that where the stool sample came from. Obviously, the stool sample contains the gut microbes.
So a second example, equally remarkable and pretty close to home, is that a genetically altered mouse strain that is obese because it’s overconsuming food, when it was transplanted into lean mice without any of their own bacteria, so-called germ-free mice, these mice also started to gain weight all of a sudden. And the majority of that weight gain was due to the voracious appetite, suggesting that something the microbes, that somehow the microbes were able to get into the mouse appetite center, the hypothalamus, mess it up and shut off the control mechanisms that normally stop the food intake.
So coming back to the question, how can these microbes that live in the gut, this sort of ugly environment, how would they get to the super clean, to a clean supercomputer, the brain, and make these phenomenal changes?
So you probably, most of you probably think about the gastrointestinal tract as this old-fashioned factory, a model from the early industrial age that would process many processed food and is and being concerned about calories and nutrients getting into your system.
You probably have not heard about the change in the conceptualization that we have of the GI tract as probably the most sophisticated information-gathering organ, paling really the NSA, that collects information at the gut level and sends it to the brain 24 hours a day, every millisecond, even when you sleep.
Now, just let me explain to a few examples that illustrates how the system does that. So our gut has its own nervous system, the second brain, 50 million neurons, the same size if you put them all together as your spinal cord, 20 different type of sensory cells and hundreds of receptors that are specific for specific kinds of molecules that either come from the microbes or from food components.
The gut also has the largest component of your entire immune system, and it’s basically acting there very closely adjacent to the lumina of the gut and influencing your entire immune response.
And finally, there is about 20 specific cells containing hormones, different kind of hormones or chemical messengers that play a role in a wide range of functions, from appetite control to craving and, as we’ll see, some other very intriguing functions as well.
So all these cells in the gut, what they have in common is they’re all connected to the brain. They’re signaling to the brain all the time. This vast amount of information is processed by the brain and influences many of our baseline functions such as background emotions and how we feel in the morning when we wake up.
Now here comes the interesting part of it, the most interesting part. There’s just a very thin layer, less than an entire cell, and sometimes that layer is even permeable if you have a leaky gut. So most of you have heard about this and heard the alarms go up. This tiny layer separates these trillions of bacteria humming around inside of you, and interacting with, via these various sensory mechanisms, with these cells that I just mentioned to you.
So it seems, so one of the questions is why do we have this complicated communication system between the gut and the brain? One plausible explanation is it’s there primarily for the reason to transmit this phenomenal wisdom that’s contained in our trillions of microbes back to the brain. And as we know, the brain is not just sitting there but the brain send signals back to the gut level as well, which I’ll show you in just a minute.
Now let me highlight this, these communication channels in one example. Serotonin, probably most of you have heard about serotonin, because it’s the target of antidepressant drugs. Serotonin reuptake inhibitors that most psychiatrists still today believe act primarily on the brain.
However, in reality, only 5 percent of the total body serotonin is actually at the brain level. 95 percent is stored in these endocrine cells within your gut, separated less than a millimeter from trillions of bacteria and food components that can influence both the production, but also the signaling of these molecules to the, to the brain.
It’s interesting that serotonin is not just contained in our body, but it’s one of those universal messenger molecules. It is in dark chocolate. It’s contained in the peels of a banana in very high concentration, and also the microbes have the ability to produce their own serotonin precursors that can be taken up by these cells.
So I mentioned a second ago that the brain just doesn’t sit there receiving this terabyte amount of information every millisecond. It can also respond and influence these cells, releasing serotonin or other stress mediators such as norepinephrine, into the gut lumen in response to a stimulus, to a stressor, to an emotional state.
Now, why would it do, what would these serotonin or the norepinephrine do inside the gut? Well, it interacts with receptors that these microbes have, very similar to our own receptors. And essentially the brain can stress out your gut bacteria. It’s also been speculated that an alteration in the serotonin system could lead to a negative influence on the emotions based on unhappy microbes that stimulate an abnormal amount of this messenger.
So one of the questions have been how did the microbes figure out how to communicate with us? This is an interesting question. Is it that the microbes learn these neurotransmitters from us, the design, or did we pick up this information from the microbes?
If you look at evolution, microbes have inhabited it, have inhabited planet Earth for close to four billion years. This was a lot of time to learn to communicate with each other. It primarily was a time for communication and the, the optimization of communication between multicellular organisms.
Only 500 million years ago, one of these guys started, came up with the idea it might actually be beneficial to live inside the GI tract of one of the most primitive marine mammals, the hydra. This turned out to be so successful, this symbiotic relationship, because the microbes in the gut got free rent, got free transport through the vastness of the ocean, and the hosts got substances that it by itself could not produce.
It was so successful that it was adopted over the next several hundred million years by all the animals, species in the world. About a million years ago, we as humans took on this communication system and the bacteria. And if you look around, from these two ants to cockroaches and any other animal, has the same system. So this is something universal, not really unique to us humans.
So until recently, and I mentioned this in the beginning, the only data that we had on this brain-gut, gut-microbiome-brain communication was really based on very spectacular animal experiments. And it was remarkable that not a single study had dealt with the question, is there a human counterpart to this communication?
So we decided to do a study, a very simple experiment where we took very fit, young healthy women, a probiotic cocktail containing yogurt for four weeks. And we looked at their brain responses to emotional stimuli. And to our amazement, the study showed that there was actually a decreased responsiveness to these stimuli in these healthy women.
Well, before you throw away your Valium or stop your early morning meditation, you have to realize these were completely healthy individuals and we did not see any effect on their emotional makeup, just the response at the brain level was decreased.
In a follow-up study, we ask another intriguing question, possibly more interesting, is the correlation between the organizational, like the signatures of these microbes in your gut, and the architecture of your brain, so the brain structure. And again, we found that there was a correlation of the white matter tracts that connect different parts of your brain with the pattern that these individuals had in their gut microbial composition.
So one plausible explanation could be that this is actually something that formed early on in life because we have our microbes from the day we’re born and possibly even before that in our intestines.
And there’s a few unique things about the early life phase. We get these microbes when we pass, when an infant passes through the vaginal canal during the natural delivery to first inoculation, but then there’s also later influences of early life in terms of diet and hygiene that would influence the composition.
The composition is unstable in the first few years of life, so anything that happens there is a fundamental effect on the later lifelong trajectory of this programing. The same thing is true about the brain. The brain is actually 15 years of development so both are a work in progress during the first three years.
Now I had a unique opportunity to look at an aspect of this early-life programming that only became relevant to the microbiome much later, actually just a couple of years ago, when a paper appeared that Native Americans living in the jungle of the Orinoco, the headwaters of the Orinoco, had a very unique composition of the microbes, the infants. So even before dietary differences between North America, infants in North America and infants living in the jungle, so all were nurtured by only breast milk.
So one unique thing about this, one of the most remarkable experiments for me during that time, was one night I left this village from the hammock that we were staying and went down into the jungle. It was a moonlit night. Quiet. And I saw this woman squatting over a banana leaf and deliver to her baby onto this banana leaf only surrounded by these invisible billions of microorganisms that inhabit this natural environment.
This is only a speculation, but I think we can assume that many of the programming, many of the trajectories that our microbiome takes and the influence it has on the brain starts very early, and it’s illustrated by these natives living a hunter-gatherer, prehistoric lifestyle, have very different microbiomes even later in life that something may be going on here.
So let me just close with, with one example, with one practical implication of this. So there have been a dramatic increase in diseases such as autism, multiple sclerosis, and Parkinson’s disease in the last 50 years. At the same time, we have noticed a dramatic change in our diet, particularly in the way food is produced and processed and in the use of antibiotics.
Is it possible that these influences, by influencing the gut microbiome, and all of these disorders have been identified recently to have a component of altered gut microbiota and altered brain-gut interactions, is it possible that these changes in our diet have actually led to this, this dramatic increase in, in these diseases in addition to many others like obesity?
So let me close with the thought, a better understanding. This obviously all has vast implications. A better understanding of the complex interactions and these universal, just universal connectedness of our gut microbiome with the world around us, with the food we eat, the way we are born, the way our food is processed.
Once you understand the science and the connectedness of this, I would predict it has major implications of how we see ourselves, the world around us, and how we see our health and what we have to do to optimize our health. Thank you very much.