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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A toxin produced by bacteria found in dirty water kills off immune cells in the lining of the colon, meaning people whose guts are colonised by these bacteria are much more likely to develop a condition known as ulcerative colitis.

That is the conclusion of a series of studies in people and animals conducted by at Nanjing University in China and her colleagues. If this finding is confirmed, it could lead to new treatments for the condition.

Ulcerative colitis is one of the two main kinds of inflammatory bowel disease, or IBD. It is characterised by inflammation of the lining of the colon and rectum. People typically have periods of no symptoms that alternate with flare-ups. The most serious cases can require the removal of the colon.

The causes of ulcerative colitis have been uncertain, but it is usually regarded as an autoimmune disease with complex environmental and genetic causes. Zhang and her team suspected that immune cells known as macrophages might play a role.

Macrophages are found in most tissues in the body, where they mop up any debris or bacteria and also help regulate local immune responses. They can sound the alarm to call in more immune cells, causing inflammation, but 鈥� crucially 鈥� they can also sound the all-clear, reducing inflammation.

In colon tissue taken from people with ulcerative colitis, the researchers found lower levels of resident macrophage cells than in people without the condition. They then showed that killing macrophages in the colons of mice made them more susceptible to colitis. The researchers think the loss of the protection usually provided by the macrophages results in the lining of the colon becoming damaged and inflamed.

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But why were macrophage levels lower in people with ulcerative colitis? By testing samples of faecal bacteria from people with the condition, the team found a toxin called aerolysin, which turns out to be highly damaging to macrophages but has little effect on other cells in the gut.

Aerolysin is produced by some strains of bacteria in the genus Aeromonas, which are commonly found in fresh and brackish waters. The researchers call the strains that produce aerolysin MTB (macrophage-toxic bacteria).

When the team deliberately infected mice with MTB, this made them more susceptible to colitis. But if the gene for aerolysin was deleted from the bacteria, or if the toxin was neutralised by antibodies, the mice didn鈥檛 become more susceptible to colitis.

Finally, the researchers looked for Aeromonas bacteria in stool samples. They found them in 72 per cent of 79 people with ulcerative colitis, but only 12 per cent of 480 people without the condition. This test couldn鈥檛 reveal whether these bacteria were MTB and therefore if they produced aerolysin.

Overall, the studies point to a complex picture. Not every case of ulcerative colitis may involve MTB, and people can also have MTB in their guts without developing colitis.

鈥淲e cannot conclude that MTB is the sole cause of ulcerative colitis,鈥� says Zhang. 鈥淧ersistent MTB infection can induce a hypersensitive state in the colon, but this does not mean that every infected individual will develop colitis.

鈥淭he occurrence of colitis in this context is undoubtedly influenced by environmental and genetic factors,鈥� she says.

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There are at least three potential approaches for developing new treatments, says Zhang. One would be to develop drugs that neutralise the toxin. Another would be to develop vaccines targeting either the toxin or the bacteria that produce it. The third would be to use viruses that kill specific bacteria, known as phage therapy, to eliminate the toxin-producing bacteria.

鈥淭he case is strong for the MTB toxin disrupting gut immunity by depleting special macrophages in the gut tissue,鈥� says at University Hospital M眉nster in Germany.

He points out that when the team killed off all gut bacteria in mice, then infected them with MTB, the animals didn鈥檛 become more susceptible to colitis. This suggests other, as-yet-unidentified bacteria also play a role.

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鈥淣evertheless, it may represent an important, missing factor in the multi-step pathogenesis of ulcerative colitis, at least in China,鈥� says Kriegel.

Zhang and her team now plan to do wider epidemiological studies to try to confirm the link between MTB and ulcerative colitis. If MTB infections do play a role and are becoming more common, it might help explain why the incidence of IBD is rising.

Therapies that alter the behaviour of people with irritable bowel syndrome (IBS) may be more effective than the existing go-to treatments. If offered digitally, these could also help speed up their relief.

IBS commonly results in bloating, diarrhoea, constipation and abdominal pain. While its causes are unclear, is thought to play a major role. Gut infections or certain foods may trigger the gastrointestinal tract to send alarm signals to the brain, while psychological stress can send them the other way, hence why .

Dietary advice and drugs like laxatives can help, but for some, symptoms persist, leading researchers to explore novel approaches such as faecal transplants. As somewhat of a last resort, doctors often turn to behavioural therapies, which a 2020 review suggested

These can include cognitive behavioural therapy (CBT), which helps people change how they think and act to manage and accept their symptoms, and gut-directed hypnotherapy, where people are put into a trance-like state before receiving suggestions that their symptoms are improving.

With more studies published since then, at the University of Leeds in the UK and his colleagues 鈥� some of whom were involved in the earlier review 鈥� have now sifted through 67 randomised-controlled trials, involving more than 7000 participants. These compared behavioural therapies that lasted between four and 12 weeks with various control groups who received standard interventions like dietary advice or laxatives, or who were on a waiting list for therapy.

鈥淚t鈥檚 the largest review of behavioural IBS treatments in terms of number of studies and participants [to my knowledge],鈥� says at the Karolinska Institute in Sweden.

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The researchers found that CBT and gut-directed hypnotherapy 鈥� delivered either in-person or via an app or the internet 鈥� were more effective than standard treatments, based on the participants comparing their symptoms before and after.

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Rather than being offered only after standard interventions haven鈥檛 sufficiently helped, and then usually solely in-person, the findings suggest that behavioural therapies should be rolled out much earlier, with digital approaches helping to deliver at speed, says Ford. 鈥淭hey could give you a way of scaling up behavioural therapy to be delivered on a mass scale,鈥� he says. But more trials that directly compare digital therapies to standard ones are needed before guidelines can be updated, says Ford, who thinks this could take another five years.

In addition, most of the participants in the studies couldn鈥檛 be blinded to which group they were in, so some of the benefits may be down to the placebo effect, says Lindfors. Trials where participants receive either a complete form of a therapy or only parts of it could help to assess the scale of this effect, if they were all under the impression they were getting the actual behavioural treatment, says Lindfors.