Your intestines are a seething and growing colony of aliens.
There are trillions of them and they include thousands of different species.
Many of these microorganisms, including bacteria, archaea, and eukaryotes, have been around for much longer than humans, have evolved alongside us, and are now many times more numerous from our own cells.
And indeed, as John Cryan, professor of anatomy and neuroscience at University College Cork, quite eloquently defined in TED talk: "When you go to the toilet and get rid of some of these microbes, just think: I'm more human now."
Collectively, these legions of microbes are known as "gut flora" - and they have a clearly defined role in maintaining our physical health, from digestion to metabolism to immunity.
They also provide key compounds that the human body cannot produce on its own.
But what if they also have a direct telephone connection with our brain?
In our new book, Are you thinking clearly? 29 Reasons Why You Don't Think and What to Do About It explores dozens of internal and external factors that influence and manipulate the ways we think, from genetics to personality traits to technology, marketing, and language biases.
And it turns out that the microbes inhabiting our bodies can have a surprising amount of control over our brains.
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Over the past few decades, researchers have begun to uncover unusual, startling—and sometimes controversial—evidence that gut flora not only makes our brain work at its best by helping us extract nutrients from food for it, but that it may directly influence to our very thoughts and behavior.
Their findings could even potentially strengthen the way we understand and treat a whole range of mental health problems, from depression to anxiety to schizophrenia.
The picture is still far from complete, but after the covid-19 pandemic, which it had harmful influence on the mental health of people in many parts of the world, solving this mystery could be more important than ever.
One of the key origin stories of this field of research took place in the wilds of North America - and, be warned, reading this could really turn your stomach.
The year was 1822. and a young trader named Alexis St. Martin was crouching outside a trading post on what is now Mackinac Island, in what is now Michigan, when a musket accidentally fired next to him, hitting him in the groin from a distance of less than three feet.
His injuries were so severe that part of his lungs, part of his stomach, and a good portion of his breakfast from that day tried to escape through the wound on the left side of his groin.
Death seemed certain, but an army surgeon named William Beaumont came to the rescue and saved St. Martin's life, though it took nearly a year and several surgeries.
What Beaumont could never heal, however, was the hole in his patient's stomach.
That persistent fistula would remain a grim and permanent reminder of the misfortune, but Beaumont was not one to pass up a good opportunity when it presented itself - no matter how unpleasant.
Realizing that the hole represented a unique window into the human gut, he spent years and years researching the intricacies of St. Martin's digestion.
Exactly how willing a volunteer St. Matthien was remains a matter of debate, as Beaumont employed him as a servant while conducting research on him - a dubious arrangement almost certainly would not consider ethical today.
Among Beaumont's discoveries while studying St. Martin's intestines, however, is how they are affected their owner's emotions such as anger.
Through this discovery is Beaumont, who will become respected as "the father of the physiology of the digestive system" , got the idea of the "gut-brain connection" - that the gut and the brain are not completely independent in relation to each other, but instead interact, and one affects the other and vice versa.
And now we know that microorganisms in our intestines make this process even more complex and unique.
"A growing body of research suggests that gut flora can influence brain and behavior in many different animals," says Elaine Hsiao, associate professor of integrative biology and physiology at the University of California, Los Angeles (UCLA).
How exactly our gut flora affects our brain is a growing, pioneering and still relatively new field.
But in the last twenty years there has been progress, especially in the case of animals.
And the argument is slowly building that these microorganisms are not only a vital part of our physical beings, but also of our mental and emotional ones as well.
"In medicine, we have a custom of dividing the body into segments," says Krajan.
“So when we talk about brain problems, we usually think of the neck up. But we have to put things evolutionary.
"We mustn't forget that microbes were around before there were humans, so we co-evolved with these 'friends with benefits'."
There was no time when the brain did not receive signals coming from microbes.
"What if those signals are actually very important in determining how we feel, how we behave, and what we do? And can we modulate these microbes therapeutically to improve our thinking, behavior and brain health?"
Hsiao is one of the leading researchers in the field, and her lab at UCLA has explored the role these microorganisms may play in everything from fetal brain development to cognitive and neurological conditions such as epilepsy and depression.
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She also researched how these microbes could affect our brains and thinking.
"Certain gut microbes can modulate the immune system to affect the brain, as well as produce molecules that send signals directly to neurons to regulate their activity," she says.
"We found that microbes can regulate the early development of neurons in ways that lead to lasting consequences for brain circuitry and behavior.
"We also found that in shorter time frames, gut microbes can regulate the production of biochemicals such as serotonin, which actively stimulate neuronal activity."
And indeed, research suggests that our microbes can communicate with our brains through a number of channels, from immunity to biochemicals.
Another candidate is the vagus nerve, which functions as a superfast "internet connection" between our brain and internal organs, including the gut.
The bacterium Lactobacillus rhamnosus JB1, for example, improves mood in nervous and depressed mice.
This positive effect disappears, however, when the signals traveling through the vagus nerve are blocked, suggesting that the bacteria could use it as a communication channel.
Most research in this field is conducted on mice (and other small animals).
And mice, of course, are not people.
But given the fascinating complexities of establishing causality between microbial signals and changes in human thought and behavior, animal studies have provided some intriguing insights into the unusual interaction between bacteria and the brain.
Research, for example, shows that "germ-free" rats and mice (without any gut flora after being raised in a sterile environment) are more anxious and less social than those with intact gut flora.
The germ-free mice and those given antibiotics were also found to be more hyperactive, more prone to risky behavior and less able to learn or remember.
Antibiotics, which can reduce the intestinal flora in animals, also reduce the tendency of zebrafish to stay in schools, while probiotics encourage them.
Once again, the human brain is immeasurably more complex than the brain of rodents or fish, but they share some similarities and this can point us to certain phenomena.
It makes sense that bacteria, wherever they live, would benefit from helping the host to be friendlier and less nervous.
By interacting with other people, for example, we help spread our own bacteria.
And regardless of whether they actually pull our strings or not, it is in the evolutionary interest of our microbes to make their environment as receptive as possible to survival.
But are communicative microbes, friendly fish or good-natured mice essential?
Researchers hope they are.
Ultimately, a better understanding of these processes may lead to revolutionary new methods of treating a wide range of mental health problems.
"We coined the term 'psychobiotics' for interventions based on gut flora that have a positive effect on the human brain," says Krajan.
"And there will be more and more of these approaches with psychobiotics."
There are fences, of course.
Although some strains of bacteria appear to have a positive effect on the human brain, many others do not, and researchers have yet to definitively determine why - and how.
Humans are also unfathomably complex, and when it comes to thinking and mental health, countless other factors are at play, from genetics to character traits to our environment.
"We need many more large-scale human studies to take into account all these individual differences," says Krajan.
"And maybe not everyone will react to the same bacteria in the same way, because everyone has a different basic intestinal flora anyway."
These caveats aside, however, new research may also bring new hope.
"The good news is that you can change your own gut flora, while there's not much you can do to change your own genetics—except to blame your parents and their parents," Krajan adds.
"The fact that you can modify your own gut flora potentially gives you control over your health outcomes."
And indeed, probiotic and prebiotic supplements, simple dietary changes like eating more fermented foods and fiber—and maybe even meditation—can help you change your gut flora in ways that benefit your brain.
Philip Barnett, associate professor at Oxford University's Department of Psychiatry, points out that many mental health problems are linked to changes in gut flora.
This imbalance, or "dysbiosis," is often characterized by reduced amounts of certain bacteria, especially those that produce short-chain fatty acids (such as butyrate, which is widely thought to boost brain function) as they break down fiber in the gut.
And indeed, a 2019 study by Mireje Valles-Collomer, a microbiologist at the time at the University of Leuven in Belgium, and her colleagues found a correlation between the amount of these butyrate-making bacteria and health.
Specifically, the researchers noted in the study:
"Butyrate-making bacteria Faecalibacterium and Coprococcus are consistently associated with higher quality of life indicators. Along with Dialister, Coprococcus was also reduced in depression, even after accounting for the disruptive effects of antidepressants."
Human studies on the communication between gut, brain and intestinal flora are still relatively few.
And Barnett urges caution: "It is not known whether these altered levels of gut bacteria are causing bad mood or whether the number of microbes is changing because people who are depressed may be modifying their eating habits and eating less."
Still, he's researching how prebiotics (which promote bacterial growth) and probiotics (live bacteria) could one day be used as psychobiotics to expand the population of "good" bacteria—and treat a wide range of mental health conditions.
For example, a 2019 study by Barnett, Rita Baiao, a psychologist also from Oxford University, and their colleagues produced some particularly interesting results.
Although the study was funded by a company that makes probiotic bacteria, it used a randomized, double-blind, controlled trial -- considered the gold standard of study design during which neither the participants nor the researchers know whether or not they're getting the drug.
Scientists investigated the effect a multi-strain probiotic might have on emotional processing and cognitive abilities in people with mild to moderate depression.
But the study also tracked their mood before and after the experiment with the Patient Health Questionnaire 9 (PHQ-9), which measures the severity of depression.
Participants who were taking no other medication were given either a placebo or an over-the-counter probiotic - which contained 14 strains of bacteria, including Bacillus subtilis, Bifidobacterium bifidum, Bifidobacterium breve and Bifidobacterium - for four weeks.
The results were fascinating, mostly because the participants on the probiotic experienced a significant subjective improvement in mood in contrast to the placebo group, practically becoming less depressed according to the PHQ-9.
Changes in the participants' anxiety level, which was also measured, were not observed.
This was a short and small study (71 participants), and more research is needed to prove causality.
But it's an early indicator that "psychobiotics" could one day become a useful treatment method for those suffering from depression — especially those who don't want to seek medical help or take traditional antidepressants, Barnett says.
And indeed, psychobiotics will not replace existing drugs - but they could eventually serve as a useful adjunct.
"It's not going to make anyone happy," Barnett says, but probiotics may one day serve as adjuncts to established mental health treatments.
"Only time will tell if we get psychobiotics," he adds.
"But the field is really advancing rapidly... This area of research is dominated by animal studies, however, so we need to have more human studies with more participants."
But the potential of psychobiotics has captured the imagination of many.
"We've also gained a lot of public attention," Barnett adds.
"People are extremely interested in preserving health and well-being with natural supplements and supporting the cultivation of good bacteria as an aid to mental health has captured the imagination of the general public. Especially today, when people are more anxious and depressed after the pandemic".
With Amy Chia-Ching Kao and others, Barnett also investigated the role these microorganisms play in psychosis—and whether prebiotics (which promote the growth of bacteria in the gut) can help people with the condition think more clearly.
Many people are aware that psychosis can cause hallucinations, delusions and detachment from reality.
But people with psychosis often also experience difficulties with cognitive functions such as attention, memory and problem solving, which can affect their ability to maintain work and relationships.
And while drugs can be used to treat hallucinations and delusions, improving patients' cognitive problems has proven to be much more difficult.
A double-blind, placebo-controlled study by Barnett and Chia-Chong Kao, however, points to a possible way forward.
"We found that giving prebiotics to people with psychosis did improve their cognitive function by clinical measures," Barnett says.
At the start of the study, the participants were on medication and free of psychotic symptoms - but still experienced the cognitive deficits typical of psychosis.
During 12 weeks, they received a prebiotic or a placebo while their metabolism, immunity and degree of cognitive impairment were measured during that time.
At the end of 12 weeks, they were switched, so that both groups spent the same amount of time on the prebiotic and placebo.
And the effect was small, but significant.
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The prebiotic improved overall cognitive function, particularly attention and problem solving, leading the researchers to conclude that the improvement was enough to provide a boost to their social and mental well-being.
There was no evidence that the immunity or metabolism of the participants was altered, so it is not clear exactly how the prebiotic triggered this effect.
But it's another small step toward understanding the relationship between our gut flora and our mental health, and potentially developing new treatments for disorders that affect our thinking.
There are hints that gut flora can affect cognitive abilities more broadly.
It is well known that antibiotics disrupt the red flora, but do they also affect our cognitive functions?
A recent study, which looked at the health and well-being of 14.542 nurses over several years working for the NHS in Great Britain, found that those who took antibiotics for a longer period of time (more than two months) performed worse on cognitive tests such as are learning, working memory and attention tasks than those who did not take such drugs.
More importantly, the cognitive abilities of the women who took the antibiotics were slightly worse when they were tested again seven years later.
Although this is only a correlation, the researchers believe that it could be due to changes in the intestines caused by antibiotics.
Much more needs to be done, however, to properly understand this.
This is a fascinating but extremely complex field, and research requires funding.
The benefits of it all, however, could be extraordinary.
"So far, only a handful of specific microbes have been studied," says Hsiao.
"Not necessarily because they are the most important, but because we as scientists have a lot more to do to really understand the enormous diversity of microbes in the gut and how they function individually and in community."
"I'm most excited about the opportunity to uncover new mechanistic understanding of how we and our microbial symbionts can work together to improve health and prevent disease."
In the meantime, maybe we should all pay a little more attention to our gut flora.
A Mediterranean diet rich in fiber, especially vegetables, is probably a good start.
And fermented foods, such as kimchi and kefir, could be of great benefit.
In a small study of 45 participants, for example, Krajan and colleagues showed that those who were given a diet high in fiber, prebiotics, and fermented foods (such as onions, yogurt, kefir, and sauerkraut) reported feeling less stressed. than the control group on a different diet.
"What I like about fermented food is that it democratizes science," Krajan says.
"It doesn't cost much and you don't have to buy it in some fancy store. You can do it yourself. In this field, we want to provide mental health solutions to people from all socioeconomic backgrounds."
The relationship we have with our own intestinal flora is "a bit like a federation", adds Krajan.
"These microbes are our companions."
It would not be bad to remember that - for the sake of our physical and, most likely, mental health.
* Are you thinking clearly? 29 Reasons Why You Don't Think and What to Do About It by Miriam Frankel and Matt Warren is published by Hoder Studio.
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