June 19, 2024

Vita Nectar

Health is the main investment in life

Is the gut our second brain? How the belly and mind are linked

19 min read

The Gut-Brain Axis is the hottest area of science as researchers find evidence bacteria in the gut helps the brain think and grow

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It wasn’t the most newsworthy event of February 2020. But when 50 or so Canadian babies filled their diapers during those last days before the pandemic lockdown fell over North America, it was a collective effort of major scientific significance.

That is because all these babies from Ontario and British Columbia had received a package in the mail that included, basically, a little tube of preservative solution and a little spatula.

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Then, one day in late February 2020, when the hour was upon them, each emptied their bowels in the normal manner, after which their parents used the spatula to scrape a sample into the tube, which they then shook vigorously before sending it by courier in a prepaid envelope to the University of British Columbia, where it was frozen solid at -70C and eventually sent for a complete genetic sequencing in a laboratory at Dalhousie University in Halifax.

“Who’s there?” the scientists wanted to know. Which species of bacteria were living in these tiny newborn guts, already teeming with microbial life?

But the scientists were not studying bacteria, exactly. They were studying the babies’ brains, and their quickly developing cognitive powers, which have been shaped by millions of years of evolution in a world that is covered in bacteria. According to a developing theory about the role these bacteria play in cognition, their poo offered an exciting new perspective on their minds.

Thus did these babies, now about four years old, become a special cohort of a few dozen boys and girls at the leading edge of what may be the hottest new area in science, the Gut-Brain Axis.

The experiment their parents signed up for was a pilot study for this idea that is revolutionizing neurobiology, even challenging old ideas about what consciousness is and where it comes from. These babies were early guinea pigs in the investigation of how closely the human mind, with all its wondrous powers of thought and feeling and unconscious control of bodily functions, depends on the human gut, with all its millions of resident bacteria.

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Researchers are studying babies to find connections between gut bacteria and brain development.

Several months previously, a group of Canadian scientists — including a neuroscientist of music perception, a psychologist of infant learning, and Canada’s leading researcher on the human “microbiome” (the collection of microbes that inhabit the body) — got to talking at an event for the Canadian Institute for Advanced Research, which runs and funds multidisciplinary science.

It was an odd grouping.

“Normally we wouldn’t meet,” said, Laurel Trainor, a neuroscientist focused on auditory perception at McMaster University and director of the school’s Institute for Music and the Mind.

Scientists are studying the link between bacteria and brain development.

But each brought a potential contribution. Between them, Trainor and Janet Werker, a psychologist of language development at the University of British Columbia, could test infants precisely on three key developmental cognitive measures: their abilities to discern rhythm, to discern sounds that are language from sounds that are not language, and to follow someone else’s attention with their eyes. Brett Finlay, a UBC microbiologist, could compare those developmental measurements to each infant’s gut bacterial population. If they found a strong correlation with any particular microbe, or combination of them, it might point somewhere interesting. It might help explain why the brain, a bundle of neurons in the skull, seems to be so deeply affected by bacterial activity in the gut, a machine for digestion far away down in the belly.

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So, they imagined an experiment. It would be nothing definitive, more like a survey of normal healthy infants, looking at the development of their brains alongside the bacterial contents of their bowels.

They wanted to see just how closely the gut is linked to the brain, not just through nerves, but through the behaviour and chemical byproducts of bacteria. Known as the Gut-Brain Axis, this concept arose out of insights that some conditions with psychological aspects, such as autism or depression, are correlated with digestive disorders, such as irritable bowel syndrome. Parkinson’s, for example, is a disease of the nerves that typically presents as a neurological brain disorder, but may actually begin decades earlier in the gut.

It remains a field of vast promise but sparse certainty. Finlay, who runs a lab at the University of British Columbia that studies the interactions of microbes and their hosts, in health and disease, calls it the hottest area in science.

Scientists are studying the link between bacteria and brain development.

Never mind malnutrition or asthma or immunology or the many other human medical issues that are related to bacteria in the gut. The Gut-Brain Axis is the next frontier in studies of the human microbiome, and all his young researchers are clamouring to pursue it, Finlay says. The future of brain science is the belly, and vice versa.

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Thanks to genetic sequencing technology that allows for easy cataloguing of bacteria, this field is starting to give up its secrets, and raising plenty of tantalizing new questions.

If bacteria are involved in the emergence of mental disorders, perhaps they are the key to cures. If bacteria are crucial to normal brain function itself, maybe they can be harnessed, guided, controlled, influenced. Maybe treating the brain means treating the gut, both in the everyday and the medical sense. Maybe disease can be averted, and health improved. There are early clues all of this is the case.

So, if these scientists could compare their inventory of each baby’s gut bacteria with measures of their cognitive development, they might find important correlations.

It is a nascent theory in search of evidence to refine it into practical knowledge. Finlay said he was struck with a sense of anxious fear about what he might find. He was worried they were about to find a bacterium that would be correlated with better cognitive development. Parents would demand it, raising all kinds of ethical questions.

“I woke up in a cold sweat one night,” he said. Dread filled his mind at the prospect of any strong positive results. “‘We’re going to find IQ bugs.’”

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People already get pretty excited about bacteria when they hear fermented foods such as yogurt and kimchee, or probiotic supplements can make their tummies feel better as their digestion goes more smoothly. Wait until they hear which ones make you think better, too.

Scientists are studying the link between bacteria and brain development.

Research on the Gut-Brain Axis hints at a whole new view of brain health and disease, Finlay said, even a whole new view of neurobiology itself. The current trouble is that the field is young, and the depth of these connections is only really starting to show itself.

“Luckily, we didn’t find any one microbe that made these kids smarter,” Finlay said. They did not find a single “IQ bug.” But what he and the half dozen other researchers on the project did find was that the Gut-Brain Axis may be more diversely wondrous than most people realize.

They found a couple of correlations between gut microbiota and infant cognitive ability that hint at future discoveries and will inspire future research. Finlay tried to be cautious as he explained them. He spoke of clues and hints, pushes in this direction or that. But he acknowledged the research had validated the interest and effort.

This paper, “Babies, bugs and brains: How the early microbiome associates with infant brain and behavior development,” published in August, is one of the first indications that there are certain species of bacteria that are important to cognition.

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“It really points the way,” Finlay said.

Scientists are studying the link between bacteria and brain development.

‘Good’ bacteria

Bacteria have traditionally had a negative reputation as regards human health. They are the cause of untold trouble, from plague and sepsis to food poisoning and all kinds of nasty infections.

It was not until relatively recently in scientific history that their benefits started to show themselves.

Now, it is well established that digestion depends on gut bacteria. These are the so-called “good” bacteria or probiotics. A whole field of consumer marketing is devoted to packaging bacteria as the key to healthy tummies, delivered through food products that boast about their bacterial content, from fermented sauerkraut to yogurt and even soda water.

Scientists are studying the link between bacteria and brain development.

Industry is cashing in. The U.S. probiotics market is said to have almost tripled in the last seven years, from around US$500 million in 2017 to a forecasted US$1.5 billion by 2027. Globally, the market is estimated to be more than US$70 billion.

In Canada, a quick glimpse through the probiotic offerings at the average grocery story reveals everything from Sesame Street Probiotic Mixed Berry vegan gummies, boasting a full billion “active cells,” to apricot-scented age-defying “probiotic” cleansing milk.

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There are probiotic drops for babies, all sorts of pills for women, and Garden of Life Probiotics Prostate capsules for the fellas, guaranteeing 15 strains and 50 billion individual microbes. There are kosher probiotic ground chia seeds, and halal probiotic yogurt. And, of course, there is probiotic dog and cat food. All of these marketing pitches are premised on the idea that ingesting good bacteria keeps things orderly in the intestines.

But cognition? Thinking? Emotional feeling? Consciousness itself? That’s a newer idea. We know bacteria help us digest. We could not do it without them. It would be astounding if the same were true of thinking. But the idea has a lot going for it, in new and exciting experimental results, long-established medical science and even in ancient intuitions about human nature.

In a sense, gut already means brain. To trust your gut means to trust the instincts that nature has endowed in your mind, silently guiding behaviour based on evolutionary lessons. A gut feeling is inexplicable but powerful. To feel something intensely is to feel it viscerally, literally in the intestines.

The idea that the Gut-Brain Axis is a two-way street had some cultural momentum before science caught on.

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It is an axis with many connections, including the endocrine system of hormones, and the immune system that fights disease. There is, for example, the vagus nerve that connects the brain to the nerves that line the gut, known as the enteric nervous system, through which information flows both ways. These nerves are so extensive, and control so many body functions, that they are sometimes nicknamed the “second brain.”

Scientists are studying the link between bacteria and brain development.

The Gut-Brain Axis also operates through the chemicals produced by gut bacteria. Some gut bacteria, for example, produce amino acids, the building blocks of proteins. Some produce neurotransmitter chemicals such as serotonin, which is important to the brain’s regulation of mood, almost all of which is produced in the intestine.

These chemicals in turn affect the brain’s operation, not just in healthy maturity, but at crucial steps along the developmental path from infancy. Without gut bacteria, our brains could not become what they are, or work as they do.

Bacteria arrive in babies’ guts early in their development, before key parts of the brain are matured. They arrive first from mother, through the experience of birth itself, and later through interaction with a world that is teeming with microbes. By the time a baby is trying solid foods, its gut microbiome is rich, diverse and complex.

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It has always been this way. Bacteria are among the oldest organisms and there are more species of them than any other life form. If some types of bacteria are key to the development of normal human brain function, then maybe bugs and brains evolved together, not separately, and maybe these early interactions along the Gut-Brain Axis evolved to promote higher-level cognitive functions and behaviour.

This may be the case all across the animal kingdom, that bacteria are key to brain function. For example, a key early result in this field came from laboratory mice, known as “germ free” because they are raised in special incubators that block all micro-organisms from colonizing the mice’s guts, which drastically impairs many aspects of their development, from immune response to brain growth.

As the “Babies, bugs and brain” paper describes it: “The microbiota gut-brain axis is an intricate communication network between the gut microbiome, the gastrointestinal tract, and the nervous system. The microbiota has been shown to influence and predict brain health in adulthood, and its absence in germ-free mice results in the development of abnormal brain functions … Research is beginning to show how the microbiome can influence neurodevelopment during infancy, an important and dynamic period of brain growth whose characteristics can predict risk or resilience to neuropsychiatric disorders, either in childhood or later adulthood.”

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Scientists are studying the link between bacteria and brain development.

Co-author Finlay said in an interview, “We know the brain controls the gut. What’s moderately new is that there’s feedback up into the brain.”

He expects, for example, to see data soon that bacteria are involved in craving. There is interest, but as yet no good data, on how they might be involved in emotions, as in the promise of psychobiotics or probiotics that improve mood. It’s a young and evolving field, and the microbiome is highly complex, but there is evidence that the gut microbiome is somehow involved in mood regulation, cognitive function and sleep, for example.

Evolution is famously blind, proceeding by random mutations and the vagaries of chance. For a microbe, maybe it’s better in the long run to, for example, cause constipation, and therefore hang around longer in the gut. Maybe it’s also somehow helpful to the bacteria to promote better cognition in the host.

One important question is what’s in it for the bugs, Finlay said. Is their role in human development an accidental byproduct of some other evolutionary pressures or could it be something more finely tuned?

Maybe there have been particular events in evolutionary history that were especially relevant to cognition, like a novel bacterium producing a novel chemical or a new way of eating or hunting or storing or preparing food, which promoted some kind of interdependence of brain and gut bacteria.

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Maybe.

However it happened, the healthy development of the human brain seems to depend on the presence of bacteria in the gut, which suggests the microbiome and brain evolved together.

It has made scientists wonder. Is the brain controlling not just the gut muscles, but somehow also the bacteria in it? Is there really two-way control all the way along the Gut-Brain Axis?

“I believe there probably is,” said Emma Allen-Vercoe, Canada Research Chair in Human Gut Microbiome Function and Host Interactions, and professor of molecular biology at the University of Guelph.

Scientists are studying the link between bacteria and brain development.

‘A moving target’

One of the odder things about the human gut microbiome is how different each person’s is.

Everyone’s microbiome includes different types of bacteria; curiously, they all seem to do more or less the same thing, in both sickness and in health. It is one of the foundational mysteries of human biology, how the complex behaviour of millions of gut bacteria, vastly different person to person, can create such similar results in the end, such as in the production of short-chain fatty acids or amino acids.

“People are realizing it’s not necessarily about who’s there. It’s about what they’re doing,” Allen-Vercoe said in an interview. “It’s a moving target.”

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Some microbes are more specialist than others, carrying out a smaller amount of biochemical production than the more common varieties, but doing it especially well or for an especially important purpose. These offer some of the most intriguing promise for connections to the brain. For some people, their gut bacteria might be making a set of molecules, or failing to make them, in such a way that their brain is affected for good or ill.

Consider depression and anxiety. Maybe, for example, people who suffer from these conditions have been colonized by a microbe or group of microbes that relate to that. On the other hand, maybe they have something missing.

“I’m leaning toward there being something missing,” said Allen-Vercoe, who was not involved in the baby experiment.

Scientists are studying the link between bacteria and brain development.

Her suspicion is there are microbes that have gone extinct, either personally via illness or antibiotics, or more broadly through changes in the population. As a result, some people may lack microbes that are critical to the regulation of mood.

Much of her work at Guelph involves experiments on a device she calls The RoboGut, which is just like it sounds, a mechanical model of the colon. Her team can feed it, remove waste, get it to a sort of digestive equilibrium as in a living human gut. And then comes the fun part — add something, and see what happens.

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The RoboGut does not have a brain, but it can be monitored and controlled in a highly precise way. Allen-Vercoe can, for example, add a whole lot of epinephrine stress hormones and see what the bacteria do in response.

This is a “bottom up” approach, as she calls it, and it is a little bit easier than trying to map the Gut-Brain Axis by starting at the brain.

“The trouble that I have is more an embarrassment of riches,” she said.

Allen-Vercoe also takes a wider evolutionary view. Looking at people through the bacterial content of their feces has a long history.

So long, in fact, that some of the work takes place in museums where, for whatever reason, ancient feces have been somehow preserved such that it can yield DNA, and therefore clues to ancient gut microbiota. Caves have been a good source of human waste that has given up such secrets.

What you find, Allen-Vercoe said, is that ancient human gut microbiomes were more diverse than modern ones.

Even more curiously, when you study isolated human populations, such as the Hadza in Tanzania or the Yanomami in the Amazon, you find that they have extremely diverse gut microbiomes. And not just that — they are remarkably similar to each other. They both have microbes the rest of the world does not have.

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Scientists are studying the link between bacteria and brain development.

The working theory is not that these tribes have coincidentally picked up the same bacteria over time, Allen-Vercoe said. Rather, it is that these microbes that once populated the human gut in the ancient world are missing from people in the modern developed world.

“The point is that these missing microbes seem to really be missing,” Allen-Vercoe said.

We don’t know exactly how fast that happens, but it has accelerated in the last century, Allen-Vercoe said. There are many plausible contributing reasons, from antibiotics and dietary changes to the much cleaner environments people tend to live in. None offers the full picture, though. We don’t really know why our gut microbiomes seem to have missing microbes or what might happen if they reappeared.

“That’s exactly what I’m trying to figure out now,” Allen-Vercoe said.

Scientists are studying the link between bacteria and brain development.

Babies & bugs

Back in the lab, the babies, having provided their feces, were put through a series of cognitive tests to see how they perceive rhythm, language and other people’s attention. It was early March 2020. Laboratory science was about to be put on hold. These would be the last results for a while.

The human microbiome changes dramatically in first months after birth as new bacteria colonize the gut. A key hypothesis is that those changes in the microbiome might be important for brain development, so bacterial differences between babies might be reflected in different cognitive abilities.

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One problem is that babies are tricky subjects. They can’t talk, and they don’t follow instruction very well. They cry and sleep and wriggle. This took some clever experimenting.

As Trainor describes it, a healthy child is capable of following another person’s attention by about six months old. It is a social skill that predicts future language and cognitive development. So, testing the attention skills of a five-month-old, as most of these babies were, is testing right when that window starts opening.

Scientists are studying the link between bacteria and brain development.

Seated at a table across from the baby, with four rolling toys between them, an experimenter began by getting the baby’s attention. The experimenter then drew attention to one of the toys by slowly rolling it to the side. Then the experimenter captured the baby’s attention again with a smile or a wave and saying their name. When they made eye contact, the experimenter then silently pointed and gazed at one of the toys for seven seconds. Then the experimenter lowered their head and held it there for five seconds, and looked back up at the baby, indicating the test was over. They did this five times.

If the baby’s first glance or point was at the correct toy, they succeeded. If it was at the wrong toy, they failed. If they did not pay attention, it was marked invalid.

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As the research paper reports, this simple test led to a striking discovery when compared to the babies’ inventories of gut bacteria.

“Infants who succeeded at the Point and Gaze test tended to have increased Actinobacteria and reduced Firmicutes at the phylum level; and an increase in Bifidobacterium and Eggerthella along with a reduction in Hungatella and Streptococcus at the genus level,” the paper reads.

In other words, the more Bifidobacterium a baby had in their gut, the better they were able to follow someone else’s attention. It’s not quite an IQ bug, but it is an interesting correlation, and it stands to reason, because members of the Bifidobacterium genus are well-known probiotics.

“The increase of Bifidobacterium is relevant for brain development as members from this genus are known probiotics that have strong associations with host immunity and connections to the Brain-Gut axis. Recent studies have shown the importance of Bifidobacterium species colonization during postnatal development as they can promote the formation of synapses and microglial function,” the paper reads. “Not only was the Bifidobacterium genus more abundant in infants who succeed on at least one of the point and gaze subtests, but it was also among the top five bacteria that contributed to the variance between the samples.”

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Scientists are studying the link between bacteria and brain development.

“Why is it prevalent?” Trainor asked. “Maybe because it has a role to play.”

Trainor studies rhythm, which you might think is even harder to test in babies than attention. But with a technique called electroencephalography, or EEG, she can measure the electrical activity of the babies’ brains as they listen to a rhythmic stimulus.

It seems esoteric, Trainor said, but rhythm is a fundamental organizing principle of the brain. “If I asked you to tap, you would tap equally spaced, every quarter note, say,” Trainor said. “This actually turns out not to be a trivial thing to do. We feel the beat even when there’s no sound event. The brain is processing it as if there is this underlying beat, even without an actual stimulus.”

Babies, of course, don’t know the musical difference between a double-beat march and a triple-beat waltz. But their brains instinctively look for regularity in what they hear and, in some cases, even try to impose it, influenced by past experience of what to expect. As with joint attention, this is a skill that develops early.

So, when the babies heard an ambiguous six-beat rhythm — which you could hear as either a waltz or a march, but not both at the same time — the EEG could tell which way they were hearing it, as double-beat or triple-beat.

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The experimenters could then prime the babies to hear the ambiguous beat this way or that by making some of the rhythmic beats a little louder than the others. Making every second note louder primes listeners to hear a march. Making every third note louder primes them to hear a waltz.

This ability to differentiate rhythm did not correlate significantly with any measure of the gut bacteria. What did correlate with the abundance of certain bacteria, Trainor said, was the infants’ ability to track the basic beat itself.

Scientists are studying the link between bacteria and brain development.

Another experiment came up with no significant findings. This one used functional near-infrared spectroscopy, a brain-imaging technique that harmlessly shines light into the brain to measure how oxygenated blood is, a proxy for what the brain is doing.

The babies’ brains were imaged this way as they heard a recording of their maternal language played two ways: once normally, which a healthy infant will process as language; and once played backwards, which a healthy infant will not process as language but rather as some weird undifferentiated noise.

“For some reason, we didn’t find correlation with gut microbiome,” Trainor said. But because of the other significant results, she has added a microbiome component to a forthcoming experiment on the cognitive development of premature babies.

“Although the tests were underpowered due to the small pilot sample sizes, potential associations were identified between the microbiome and measurements of early cognitive development that are worth exploring further,” the paper reads.

“There’s all these triggers microbes seem to be pulling,” Finlay said. The Gut-Brain Axis is coming into view. “There’s all these smoking guns. “All that said, we know very little about how it works right now.”

Illustrations by Brice Hall / National Post

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