REMEMBER the last time you had a stomach bug and just wanted to crawl into bed and pull up the covers? That is called “sickness behaviour” and it is a kind of short-term depression. The bacteria infecting you aren’t just making you feel nauseous, they are controlling your mood too. It sounds absurd: they are in your gut and your feelings are generated in your brain. In fact, this is just an inkling of the power that microbes have over our emotions.
In recent years, such organisms in the gut have been implicated in a range of conditions that affect mood, especially depression and anxiety. The good news is that bacteria don’t just make you feel low; the right ones can also improve your mood. That has an intriguing implication: one day we may be able to manipulate the microbes living within our gut to change our mood and feelings.
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It is early days, but the promise is astounding. The World Health Organization rates depression and anxiety as the number one cause of disability, affecting at least 300 million people worldwide. The new findings challenge the whole paradigm of mental illness being caused by a chemical imbalance in the brain, and offer an alternative to drug treatment. You’ve probably heard of probiotics, but these are their new incarnation – psychobiotics. They could be about to change the mood of the planet.
Bacteria have been associated with sickness almost since they were discovered 350 years ago by Dutch biologist and microscope pioneer Antonie van Leeuwenhoek. Only recently have we begun to understand that microbes also contribute to our health. They produce vitamins and help us eke out extra energy from otherwise indigestible food, for example. Most importantly, by outcompeting and directly battling pathogens, our home-grown microbes protect us from disease.
It wasn’t until the 21st century that we got the first hint that microbes might also influence how we feel. It started with very clean mice. In 2004, Nobuyuki Sudo at Kyushu University, Japan, found that mice lacking microbes had . These so-called germ-free mice are born through antiseptic caesarean sections and raised in a sterile environment. Such animals don’t exist in nature because microbes are inescapable: they coat the skin and are especially fond of the mucous lining of the gut. They accumulate in the colon, which has the right conditions to support a dense population of bacteria, fungi and viruses. Without a protective set of microbes, germ-free mice are particularly vulnerable to pathogens. A normal mouse isn’t finicky about food, and can consume millions of pathogens without a hiccup, but a germ-free mouse can die from eating a mere dozen or so harmful bacteria.
Sudo and his team expected physical disease in their mice, but they weren’t prepared for the behavioural differences they observed. Compared with their more germy cousins, the germ-free mice devoted more time to inanimate objects than to other mice and had an exaggerated response to stress. They also had less developed brains. It is hard to know what is going on in the mind of a mouse, but they acted like they were depressed. Tellingly, when Sudo fed them a pathogen-free microbial concoction, they developed a normal stress response within days.
This surprising connection between microbes and mood was dubbed the gut-brain axis. Sudo’s discovery fascinated researchers across a wide range of fields and launched a spate of studies. Some of these uncovered differences in the brain chemistry of germ-free mice compared with normal ones, including a dramatic reduction in serotonin, a neurotransmitter linked to depression. Others showed that mice bred to model depression in humans appeared to benefit from being fed certain types of bacteria. A study by John Cryan and Ted Dinan, both at University College Cork in Ireland, found that the bacterium Lactobacillus rhamnosus, which is in some live yogurt, has . “They became a lot more chilled out and relaxed. They behaved as if they were on Valium or Prozac,” says Cryan. “We looked at their brains and found widespread changes.”
“Microbes can produce almost every neuro-transmitter found in the human brain”
It isn’t possible to do germ-free research in humans. However, Cryan and Dinan also found that . This convinced them that the findings in mice have relevance to people.
The pair also realised that if gut bacteria influence our emotions this would have huge implications for how we understand and treat a variety of mental health issues. In 2013, together with their colleague Catherine Stanton, – a new class of probiotics that could improve people’s mood. Not least, the new line of research suggested ways in which we could use our diet to positively influence our mood (see “Healthy gut, happy mind: What to eat to boost how you feel”).
It was an audacious idea, not least because, at that point, nobody was sure how the gut-brain axis might work. “The question is, how can bacteria in your gut communicate with your brain?” says Cryan.
A clue seemed to lie in the astonishing discovery, in the early 2000s, that found in the human brain, including serotonin and dopamine, which is involved in motivation and reward. But there was a problem: the brain is designed to insulate itself from most outside influences with a “blood-brain barrier” that prevents cells, particles and certain molecules – including neurotransmitters – from getting in. How could these chemicals produced by microbes in the gut affect the brain?
Hotline to the brain
A breakthrough came in 2017 with the . These enterochromaffin cells can detect neurotransmitters produced by microbes, resulting in a pulse being triggered in the vagus nerve, which connects the gut to the brain. What’s more, experiments in mice show that cutting this nerve terminates many psychobiotic actions. For example, Dinan and Cryan found that L. rhamnosus didn’t alleviate stress in mice when the vagus nerve was severed. More evidence suggests that gut microbes and the molecules they produce can directly too.
This apparent communication between gut microbes and the brain may even affect the organ’s development. The brain is full of structures with specialised functions. Those involved with stress and mood include the amygdala, prefrontal cortex, hippocampus and hypothalamus. They are connected by spaghetti-like axons running helter-skelter throughout the brain, in a complex wiring pattern that is unique for each of us. That wiring starts getting laid down in the uterus and continues in earnest during the first three years of a baby’s life. Amazingly, . Germ-free mice show abnormal development in their amygdala, hippocampus and prefrontal cortex.
How gut microbes do this, and influence the brain thereafter, is less clear, but we do know that these structures aren’t static. For example, depression can cause your amygdala – which is responsible for the crucial fight-or-flight response in life-threatening situations – to become more active and swell up. The condition can also cause the hippocampus to shrink, potentially affecting your memory. These physical changes explain why you can’t simply “think yourself happy”.
The exact extent to which microbes are involved is unknown, but . In 2017, Kirsten Tillisch and Emeran Mayer, both at the University of California, Los Angeles, examined the gut microbes of 40 women and found the volunteers could be divided into two groups: those with lots of bacteria from the genus Prevotella and those with lots from the genus Bacteroides. The researchers then used functional MRI scans to look at activity in specific parts of the women’s brains while they viewed emotionally disturbing images. Each group had distinct brain activity, which was different enough to indicate which an individual belonged to with an accuracy of 87 per cent. In particular, the group with plenty of Prevotella bacteria, which was much smaller, had less activity in the hippocampus. This is also found in people with depression.
Tillisch and Mayer have also found that they can influence the way people’s brains process emotions by using probiotics. They gave 36 healthy women probiotic yogurt containing four types of bacteria twice daily for four weeks. Brain scans revealed that this affected the , producing changes associated with healthier emotional processing.
Ingesting microbes may even help people at risk of depression and anxiety. Several studies focus on pregnant women because severe depression affects around 15 per cent of women during and after pregnancy, and can interfere with their ability to bond with their babies. In a 2017 study, more than 200 women were given L. rhamnosus from early pregnancy to six months after delivery. It found they . The finding is particularly welcome because many women are reluctant to take antidepressants during pregnancy or while breastfeeding. Likewise, healthy college students who took off-the-shelf probiotics for a month showed , including panic, worry and negative mood. Students with the highest stress levels, who took the most probiotics, showed the biggest improvement.
“I do believe the data supports a role for microbes modulating how we feel,” says Tillisch. However, she cautions that the studies in people show correlation, not causation, so it is possible that mood is affecting the microbes rather than the other way around.
“Ingesting microbes may even help people at risk of depression and anxiety”
This is all very exciting, but there is still another hurdle before psychobiotics can become mainstream treatments. Currently, we have only the vaguest notion of which bacteria might have a good influence on moods. In fact, we don’t even know exactly which microbes are in our gut, because many can’t be cultured.
Thousands of gut microbes have been identified by analysing samples for a small sequence of genetic material called 16S rRNA. But this can only reliably distinguish bacteria down to the genus level. However, a new technique is revolutionising microbial research. Called whole-genome shotgun sequencing, it can find species and even subspecies by looking at every gene in a sample taken from any environment.
Using this technique, Jeroen Raes and colleagues at KU Leuven in Belgium were able to get a fine-grain view of the . In April, they reported that people diagnosed with depression had reduced numbers of bacteria in two genera, Coprococcus and Dialister. These, then, are potential human psychobiotics.
The subjects also completed questionnaires about their quality of life. This revealed that people with a better quality of life tended to have more microbes that produce butyrate, a short-chain fatty acid that nourishes and heals the gut. Their gut microbes also produced more of a precursor to the neurotransmitter dopamine. One of the team, Mireia Valles-Colomer, subsequently identified a bacterium called Butyricicoccus pullicaecorum 25-3T as .
This large-scale human study was possible because Belgium keeps extensive electronic medical records that are available for scientific analysis. Several northern European countries have similar data sets and, with whole-genome shotgun analysis, they are likely to reveal the identity of more possible psychobiotics. However, we may be able to do more than simply finding “good bacteria”. Dinan and Cryan suspect that just as pathogenic bacteria share certain genes, there may also be genes connected with mental health benefits. If so, then the ideal psychobiotic might be a genetically modified organism containing genes from several different bacteria, they say.
That is for the future. There are things we can all do now to boost the psychobiotics we already possess. This is such a hot topic it can surely only be a matter of time before psychobiotics offer an alternative treatment for people diagnosed with a variety of mood disorders. Instead of targeting the head, we could go for the gut. “This new way of looking at brain health is literally turning things upside down,” says Cryan.
