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Looking after the multitudes of bacteria, fungi and other microorganisms
living in our guts could help us think better and even offer new ways of
treating mental health conditions.
Your gut is a bustling and thriving alien colony. They number in their
trillions and include thousands of different species. Many of these
microorganisms, including bacteria, archaea and eukarya, were here long
before humans, have evolved alongside us and now outnumber our own cells
many times over. Indeed, as John Cryan, a professor of anatomy and
neuroscience at University College Cork, rather strikingly put it in a
TEDx talk: "When you go to the bathroom and shed some of these microbes,
just think: you are becoming more human."
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Collectively, these microbial legions are known as the "microbiota" –
and they play a well-established role in maintaining our physical
health, from digestion and metabolism to immunity. They also produce
vital compounds the human body is incapable of manufacturing on its own.
But what if they also had a hotline to our minds? In our new book, Are
You Thinking Clearly? 29 Reasons You Aren't And What To Do About It, we
explore the dozens of internal and external factors that affect and
manipulate the way we think, from genetics, personality and bias to
technology, advertising and language. And it turns out the microbes that
call our bodies their home can have a surprising amount of control over
our brains.
Over the last few decades, researchers have started to uncover curious,
compelling – and sometimes controversial – evidence to suggest that the
gut microbiota doesn't just help to keep our brains in prime working
order by helping to free up nutrients for it from our food, but may also
help to shape our very thoughts and behaviour. Their findings may even
potentially bolster how we understand and lead to new treatments for a
range of mental health conditions, from depression and anxiety to
schizophrenia.
The picture is still very far from complete, but in the wake of the
Covid-19 pandemic, which has had a deleterious impact on people's mental
health in many parts of the world, unpicking this puzzle could be more
important than ever.
One of the research field's key origin stories took place in the North
American wilderness – and, be warned, it makes for some stomach-churning
reading. The year was 1822 and a young trader named Alexis St Martin was
loitering outside a trading post on what is now called Mackinac Island,
in what is now Michigan, when a musket accidentally went off next to
him, firing a shot into his side from less than a yard (91cm) away. His
injuries were so bad that part of his lungs, part of his stomach and a
good portion of his breakfast that day spilled out through the wound in
his left side. Death seemed certain, but an army surgeon named William
Beaumont rode to the rescue and saved St Martin's life, although it took
the best part of a year and multiple rounds of surgery.
What Beaumont couldn't repair, however, was the hole in his patient's
stomach. This persistent fistula would remain a grim and lasting legacy
of the accident, but Beaumont wasn't one to pass up a good opportunity –
however unpleasant. Realising that the hole provided a unique window
into the human gut, he spent years investigating the intricacies of St
Martin's digestion. Exactly how willing a volunteer St Martin was is
open to debate as Beaumont employed him as a servant while conducting
research on him – the murky arrangement almost certainly wouldn't be
considered ethical today. Among the findings Beaumont uncovered during
his studies of St Martin's guts, however, included how they were
affected by its owner's emotions, such as anger.
Through this finding, Beaumont, who would go on to be lauded as the
"father of gastric physiology", had hit upon the idea of a "gut-brain
axis" – that the gut and the brain aren't entirely independent of one
another but instead interact, with one influencing the other and vice
versa. And now we know that the microorganisms within our gut make this
process even more complex and remarkable.
"More and more research is revealing that the gut microbiome can
influence the brain and behaviour across a variety of different
animals," says Elaine Hsiao, associate professor in integrative biology
and physiology, at the University of California, Los Angeles (UCLA).
It's important to remember that the microbes were here before humans
existed, so we have evolved with these 'friends with benefits' – John
Cryan
How exactly our microbiota might be influencing our mind is a growing,
pioneering and still relatively novel field. But there have been
advances over the last 20 years or so, particularly in animals. And,
slowly, a case is being built to suggest that these microorganisms
aren't just a vital part of our physical selves, but also our mental and
emotional selves, too.
"In medicine, we tend to compartmentalise the body," says Cryan. "So,
when we talk about issues with the brain, we tend to think about the
neck upwards. But we need to frame things evolutionarily. It's important
to remember that the microbes were here before humans existed, so we
have evolved with these 'friends with benefits'. There has never been a
time when the brain existed without the signals coming from the
microbes.
"What if these signals are actually really important in determining how
we feel, how we behave and how we act? And could we modulate these
microbes therapeutically to improve thinking, behaviour and brain
health?"
Hsiao is one of the researchers leading the way in this field and her
lab at UCLA has explored the part these microorganisms might play in
everything from foetal brain development to cognition and neurological
conditions such as epilepsy and depression. She has also investigated
how these microbes might be influencing our brains and thinking.
"Specific gut microbes can modulate the immune system in ways that
impact the brain and also produce molecules that signal directly to
neurons to regulate their activity," she says. "We find that gut
microbes can regulate the early development of neurons in ways that lead
to lasting impacts on brain circuits and behaviours. We also find that
under shorter timescales, gut microbes can regulate the production of
biochemicals, like serotonin, that actively stimulate neuronal
activity."
Indeed, research suggests our microbes may be communicating with our
brains through numerous pathways, from immunity to biochemicals. Another
candidate is the vagus nerve, which acts as the superfast "internet
connection" between our brain and internal organs, including the gut.
The bacteria Lactobacillus rhamnosus JB1, for example, appears to
improve the mood of anxious and depressed mice. This beneficial effect
is removed, however, when the signals travelling along the vagus nerve
are blocked, suggesting it could be being used as a communication
pathway by the bacteria.
Much of the research in this field is conducted in mice (and other small
animals). And mice, of course, aren't humans. But given the mindboggling
complexities of establishing causality between microbial signals and
changes in human thought and behaviour, animal studies have provided
some intriguing insights into the strange interactions between bacteria
and brain. Research, for example, shows that "germ-free" rats and mice
(those without any microbiota after being reared in sterile conditions)
are more prone to anxiousness, and less sociable than those with an
intact microbiota. Germ-free mice, and those given antibiotics have also
been found to be more hyperactive, prone to risky behaviour and less
able to learn or remember. Antibiotics, which can reduce the microbiota
in an animal, also reduce shoaling behaviour in zebrafish, while
probiotics boost it.
Again, the human brain is vastly more complex than that of a rodent or
fish, but they do share some similarities and can offer clues. It makes
sense that bacteria, wherever they live, might benefit from helping
their hosts to be more sociable and less anxious. By interacting with
other people, for example, we help our bacteria spread. And whether or
not they're really pulling our strings, it's in our microbes'
evolutionary interests to make their environment as conducive to
survival as possible.
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But do communicative microbes, congregating zebrafish or friendly mice
really matter? Hopefully, yes, say the researchers. Ultimately, a better
understanding of these processes could lead us towards ground-breaking
new treatments for a range of mental health conditions.
Psychobiotics might one day be used to nurture populations of "good"
bacteria and treat a variety of mental health conditions
"We've coined the term 'psychobiotics' for [microbiota-based]
interventions that have a beneficial effect on the human brain," says
Cryan. "And there are more and more of these psychobiotic approaches
coming."
There are caveats, of course. While some strains of bacteria appear to
have a positive effect on the human mind, many others don't and
researchers have yet definitively to establish why – and how. Humans are
also unfathomably complex, and when it comes to thinking and mental
health, there are countless other factors at play, from genetics and
personality to the environment around us.
"We need many more large-scale human studies to take into account these
individual differences," says Cryan. "And maybe not everyone will
respond to a single bacteria in the same way because everyone will have
a slightly different baseline microbiota anyway."
Disclaimers aside, however, more research could bring fresh hope. "The
good news is that you can change your microbiota, while there's not a
whole lot you can do to change your genetics – except blame your parents
and your grandparents," Cryan adds. "The fact that you can modify your
microbiota potentially gives you agency over your own health outcomes."
Indeed, pro- and prebiotic supplements, simple dietary changes, such as
eating more fermented foods and fibre – and even, perhaps, meditation –
can help alter our microbiota in ways that benefit our minds.
Philip Burnet, an associate professor in the University of Oxford's
department of psychiatry, notes that many mental health conditions have
been associated with changes in the microbiota. Often, this imbalance or
"dysbiosis" is characterised by a reduced amount of certain bacteria,
particularly those that produce short-chain fatty acids (such as
butyrate, which is widely believed to improve brain function) when they
break down fibre in the gut.
Indeed, a 2019 study by Mireia Valles-Colomer, a microbiologist at KU
Leuven University of Leuven in Belgium at the time, and her colleagues
found a correlation between the amount of these butyrate-producing
bacteria and wellbeing. Specifically, the researchers noted in the study
that: "Butyrate-producing Faecalibacterium and Coprococcus bacteria were
consistently associated with higher quality of life indicators. Together
with Dialister, Coprococcus spp. were also depleted in depression, even
after correcting for the confounding effects of antidepressants."
Human studies on the communication between the gut, the brain and the
microbiota are still relatively few and far between. And Burnet urges
caution: "It is not known whether these altered levels in gut bacteria
cause low mood or whether microbial numbers change because people who
are depressed might modify their eating habits or eat less."
Nevertheless, he has been exploring how prebiotics (which encourage
bacteria to grow) and probiotics (live bacteria) might one day be used
as psychobiotics to nurture populations of "good" bacteria – and treat a
variety of mental health conditions.
For example, one 2019 study by Burnet, Rita Baião, a psychologist also
at the University of Oxford, and their colleagues uncovered some
particularly interesting findings. Although the study was funded by a
company that manufactures probiotic bacteria, it used a randomised,
double-blind, placebo-controlled trial – considered to be a gold
standard study design during which neither participants nor researchers
are aware whether they are receiving the treatment or not. The
researchers investigated the effect a multispecies probiotic might have
on emotional processing and cognition in people with mild to moderate
depression. But the study also monitored their mood before and after the
experiment using the Patient Health Questionnaire-9 (PHQ-9), which
measures depression severity.
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The participants, who weren't taking any other medication, were either
given a placebo or a commercially available probiotic – which contained
14 species of bacteria, including Bacillus subtilis, Bifidobacterium
bifidum, Bifidobacterium breve and Bifidobacterium infantis for four
weeks.
The results were fascinating, not least that the participants on the
probiotic experienced a significant subjective improvement in mood
compared with the group on placebo, essentially becoming less depressed
according to the PHQ-9. Changes in the participants' levels of anxiety,
which were also measured, were not observed.
This was a small (71 participants), brief study and more research is
needed to prove causality. But it's an early indication that "psychobiotics"
may one day be a helpful treatment for those with depression –
particularly those who are reluctant to seek medical help or take
traditional antidepressants, says Burnet. Indeed, psychobiotics won't
replace existing medications – but may eventually provide a helpful
adjunct.
"They won't make everyone happier," says Burnet, but probiotics could
one day complement more established mental health treatments. "Only time
will tell whether we will have psychobiotics," he adds. "But the field
is really moving forward... This area of research is dominated by animal
studies, however, so we do need more human studies using larger numbers
of participants."
But the potential of psychobiotics has captured imaginations.
Those who had used antibiotics for long periods of time scored lower on
cognitive tests such as learning, working memory and attention tasks
"We also attracted a lot of interest from the public," adds Burnet.
"People are extremely interested in maintaining their health and
wellbeing with natural supplements and encouraging the growth of good
bacteria to support mental health has captured the imagination of the
general public. Especially now, when people are more anxious and
depressed as a result of the pandemic."
With Amy Chia-Ching Kao and others, Burnet has also explored the role
these microorganisms might play in psychosis – and whether prebiotics
(which help to promote the growth of bacteria in the gut) might help
people with the condition think more clearly.
Many people are aware that psychosis can cause hallucinations, delusions
and a detachment from reality. But people with psychosis also often
encounter difficulties with cognitive functions such as attention,
memory and problem-solving, which can impact their ability to hold down
jobs and relationships. While medication can be used to treat the
hallucinations and delusions, improving sufferers' cognitive impairments
has proved more difficult.
A double-blind, placebo-controlled crossover study by Burnet and
Chia-Ching Kao, however, suggests a possible way forward. "We found that
giving a prebiotic to people with psychosis did improve cognitive
function according to the clinical scales," says Burnet.
At the start of the study, the participants were on medication and free
of psychotic symptoms – but were still experiencing the cognitive
impairment typical of psychosis. Over 12 weeks, they were given a
prebiotic or a placebo while their metabolism, immunity and level of
cognitive impairment was measured over time. At the end of the 12 weeks,
they were then switched, so both groups had an equal amount of time on
the prebiotic and the placebo.
And the effect was small but significant. The prebiotic improved overall
cognitive function, particularly attention and problem solving, leading
the researchers to conclude that the improvement was sufficient to boost
social and mental wellbeing. There was no evidence of the participants'
immunity or metabolism changing so it wasn't clear how the prebiotic may
have triggered this effect. But it's another small step towards
understanding the relationship between our microbiota and our mental
health and the potential development of new treatments for disorders
that affect our thinking.
There are hints that the gut microbiota may affect cognitive skills more
broadly, too. It is well known that antibiotics disrupt the gut
microbiota, but do they affect our cognition? One recent study, which
monitored the health and wellbeing of 14,542 female nurses for several
years while they worked for the NHS in the UK, found that those who had
used antibiotics for long periods of time (more than two months) scored
lower on cognitive tests such as learning, working memory and attention
tasks than those who hadn't taken such medication. Importantly, the
cognition of the women who had taken antibiotics was slightly poorer
when they were followed up seven years later. Although this is only a
correlation, the researchers think it could be due to
antibiotics-induced changes in the gut.
There's still a very long way to go, though, to understand this
properly. This is a fascinating but highly complex field, and research
requires funding. The rewards, however, could be profound. "There are
only a handful of specific microbes that have been studied so far," says
Hsiao. "Not necessarily because they are the most significant, but
because we as scientists have much more to do to really understand the
enormous diversity of microbes in the gut and how they function
individually and as communities.
"I'm most excited about the opportunity to uncover new mechanistic
understanding of how we and our microbial symbionts can work together to
promote health and thwart disease."
In the meantime, perhaps we should all pay a bit more attention to our
microbiota. A Mediterranean diet that's high in fibre, particularly from
vegetables, is likely a good place to start. And fermented foods, such
as kimchi and kefir (a fermented milk drink) may also be beneficial. In
a small study with 45 participants, for example, Cryan and colleagues
showed that those who were put on a diet that included a lot of fibre,
prebiotics and fermented food (such as onions, yoghurt, kefir and
sauerkraut), reported feeling less stressed than a control group which
was on a different diet.
"What I like about fermented foods is that they democratise the
science," says Cryan. "They don't really cost much and you don't have to
get them from some fancy store. You can do it yourself. In this field,
we want to provide mental health solutions to people from all
socioeconomic areas."
The relationship we have with our microbiota is "a bit like a
federation", adds Cryan. "These microbes are our fellow travellers."
We'd do well to remember that – for the sake of both our physical and,
quite possibly, mental health.
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