It is the year 2036. A patient struggling with depression and anxiety is referred to her local psychobiotics clinic where the consultant prescribes a course of personalised pills to improve her symptoms. But rather than acting on her own cells, let alone those in her brain, the pills work by administering specific strains of microbes in her gut.

This future vision of doctors tweaking the contents of your digestive tract to improve complex and hard-to-treat psychological disorders might seem far-fetched. But research over the past couple of decades has revealed the far-reaching impact of the ecosystem of bacteria, fungi, viruses and other microbes that lives within us. Perhaps most surprising has been the associations scientists have discovered between the gut microbiome and our mental health. Now they are exploring whether harnessing this intricate ecosystem could help people feel better.

Growing evidence

The notion that your 鈥済ut feeling鈥� connects with your psychological experience of the world is well established in popular imagination. But until recently, scientists were deeply sceptical鈥攑articularly of the notion that the multitude of microbial cells inside us could have an impact on mental health. 鈥淔ifteen years ago, there was sniggering at the back of the seminar room when people presented their research,鈥� says Professor Phil Burnet, a neuroscientist at the University of Oxford, UK.

But the field of microbial neuroscience has accelerated rapidly over the past decade, thanks to an explosion of lab studies and trials in humans that involve microbiota. Some explore live beneficial microbes known as probiotics, others formulations of microbe food, or prebiotics, to fertilise specific bacterial strains. Meanwhile, heat-treated microbes, or postbiotics, are also being developed.

Together, these studies paint a picture of deep and important connections between the 鈥� from as many as 5000 different species 鈥� in your digestive tract and your physical and mental health. 鈥淗ow can we use this to maintain wellbeing or treat brain disorders?鈥� asks Burnet. 鈥淲ithin the gut-brain circuit, the gut microbiome is the most accessible component.鈥�

What happens in vagus

The neurons that operate the gut are sometimes referred to as our 鈥渟econd brain鈥�. Known as the enteric nervous system, in humans it contains an estimated 500 million neurons, more than . It operates autonomously to control digestion but is also in constant bidirectional communication with the brain via the vagus nerve.

This second brain and its connection with the one inside your skull is one way that gut microbes can affect mental health. There are others too:聽via metabolites they produce passing into the blood and crossing the blood-brain barrier, by impacting gut hormones and by stimulating the immune system.

鈥淭he microbiome is endlessly complicated, and what I suspect is that there is more than one mechanism for the clinical effects that we see,鈥� says Dr Richard Day, V.P. Medical Affairs and Clinical Development within R&D at ADM, a company that researches and markets pre-, pro-, and postbiotics. 鈥淲e鈥檙e still on that journey to unpick the mechanisms of action.鈥�

The fact that the gut microbiome is capable of impacting the brain is, however, clear.

Some of the strongest evidence comes from research into mood disorders, with studies showing associations with gut microbiome composition. Now, scientists are moving beyond these observational studies to experimental interventions to find out more.

A mechanistic study led by the University of Oxford, for example, found that giving participants a probiotic had measurable effects on their cognitive and emotional processing.聽 Other studies are exploring the gut-brain axis in clinical populations. In 2023, for example, researchers at King鈥檚 College London and ADM published a study in JAMA Psychiatry, exploring the effects of a probiotic in people with major depression. 鈥淭ogether, these studies paint an increasingly compelling picture of the gut-brain connection,鈥� says Dr Malwina Naghibi, Head of Clinical Development at ADM.

A two-way street

This connection works both ways: mental health can affect digestive health and vice versa. Irritable bowel syndrome (IBS), for example, has an established relationship with anxiety, and this link is being actively explored. In , ADM鈥檚 researchers gave adults with IBS either a live or a heat-treated strain of gut bacteria. Both produced similar results in patients, providing researchers with vital clues on how bacteria鈥攁live or dead鈥攊nteract with the gut and nervous system (see Box, right).

scientists are relishing the challenge of exploring this new frontier

These studies are typical of a proliferation of mostly small, but rigorous clinical trials testing the impact of the gut microbiome on , (ADHD) and . There is even into whether it plays a role in Alzheimer鈥檚 disease.

What鈥檚 needed now are larger studies over longer periods that can show how robust any impacts really are. 鈥淭here is just this explosion of research at the moment,鈥� says Naghibi.

The sniggering at the back of seminar rooms has gone quiet, but there is still a long way to go. Microbial neuroscience is a field in its infancy, psychobiotics even more so. Yet scientists are relishing the challenge of exploring this new frontier. 鈥淚 think this is the most exciting part,鈥� says Naghibi.

MICROBIAL AFTERLIVES鈥擳HE SCIENCE OF POSTBIOTICS

The new kid on the block in microbiome research is postbiotics. Unlike probiotics (live microbes) or prebiotics (microbe nutrients), these are preparations of microbes inactivated by heat or other methods, sometimes also together with the soup of cell fragments and metabolites they produce (see graphic). Even though the microbes are no longer alive, they can still exert biological effects. ADM scientists, for example, have shown that heat-treated bacteria produce to live ones in people who have IBS.

These effects can be rapid. A of postbiotics and the gut-brain axis noted physiological changes within an hour of administration. And findings from other trials suggest that the effects of postbiotics wear off when participants stop taking them. This suggests a direct effect rather than a permanent change to the microbiota, though much more research on mechanisms is needed.

Meanwhile, postbiotics are being investigated in a wide range of conditions. The ADM team, for example, has conducted a trial of 72 people exploring whether postbiotics can reduce the symptoms of allergic rhinitis.
The advantage of postbiotics over probiotics is that they don鈥檛 need to be kept alive, meaning they can be added to foods or drinks. Why swallow a pill if you could take postbiotics in the milk on your cereal?聽

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Discarded sex hormones can be returned to the bloodstream by bacteria in the gut 鈥� and now, a study has found that there are far more of these sex-hormone-recycling bacteria in the guts of people in industrialised societies than in those of hunter-gatherers and non-industrial farmers. This might mean that, as a result of urban living, some people have higher blood levels of certain sex hormones, which would have profound health effects.

鈥淲e don鈥檛 how the body would respond to this increased input,鈥� says Rebecca Brittain at Jagiellonian University Medical College in Poland. 鈥淏ut the implications could be quite large.鈥�

Sex hormones, such as oestrogens, circulate in the blood. When levels are too high, cells in the liver add a chemical tag that results in a hormone being excreted, often via the gut. But that tag happens to be a sugar molecule that certain bacteria feed on. So, some bacteria in the gut cut off the tags, using enzymes called beta-glucuronidases.

Once a tag is removed, a hormone can be reabsorbed by the body and end up back in the bloodstream. Studies suggest that substantial proportions of excreted sex hormones are recycled by gut bacteria in this way.

In 2011, to describe all the gut bacteria that can alter oestrogens, and thus potentially affect blood levels in both sexes. Earlier this year, it was proposed that be used to describe the gut bacteria that can affect testosterone levels.

The latest study from Brittain鈥檚 team has compared the oestrobolomes of hundreds of people from 24 populations around the world, using data from previous studies in which their gut microbiomes were sequenced. These populations included, for example, hunter-gatherers in Botswana and Nepal, rural farmers in Venezuela and Nepal, and city dwellers in Philadelphia and Colorado.

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Specifically, Brittain鈥檚 team looked for genetic sequences coding for beta-glucuronidase enzymes, measuring the overall proportion of these sequences and their diversity. The results suggest that the oestrogen-recycling capacity of gut microbes in industrialised populations is up to seven times greater than in the hunter-gathering and rural farming populations, with twice the diversity too.

The team also found that there is up to three times the recycling capacity in babies who are fed formula than in those who are breastfed, with up to 11 times the diversity. People鈥檚 age, sex and BMI, however, made no difference to their oestrobolomes.

Brittain鈥檚 team and others are now trying to establish if the higher recycling capacity suggested by the gene sequences really does correspond with higher levels of oestrogen recycling and, most crucially, if this results in higher blood levels of the hormones. It could be, for instance, that people鈥檚 bodies can adjust hormone levels to partially or completely compensate for higher recycling.

But if some individuals do have higher blood levels of oestrogens throughout their lives because of their microbiomes, it could have a big impact on their fertility and health, increasing the risk of certain cancers, for instance. But in some cases, these effects could be beneficial. 鈥淭he assumption is usually that higher oestrogen recycling is harmful,鈥� says Brittain. 鈥淚 don鈥檛 think that鈥檚 a fair assumption. For some people with really low oestrogen levels this could be a good thing.鈥�

A better understanding of our hormones and sleep could improve both

The hormonal changes of puberty, the menstrual cycle and menopause can all affect our sleep, but there are also subtler ways that hormones and sleep interact

鈥淚t is an interesting study that adds to the growing evidence of the importance of the gut microbiome function in human health and development,鈥� says at Wake Forest University School of Medicine in North Carolina, who is investigating the possible links between the microbiome and the risk of breast cancer.

But it does have limitations, she says, including the fact that all the industrialised populations were in the US. 鈥淎dditional cohorts, perhaps from Europe, could have strengthened the industrial associations,鈥� says Cook.

Brittain says that she and her colleagues will try to identify the lifestyle factors responsible for the differences they found. 鈥淲e would love to know so much more about these individuals, but the data didn鈥檛 exist, so we鈥檒l do our own study,鈥� she says.