The tantalizing links between gut microbes and the brain

Neuroscientists are probing the idea that intestinal microbiota might influence brain development and behaviour.

Nearly a year has passed since Rebecca Knickmeyer first met the participants in her latest study on brain development. Knickmeyer, a neuroscientist at the University of North Carolina School of Medicine in Chapel Hill, expects to see how 30 newborns have grown into crawling, inquisitive one-year-olds, using a battery of behavioural and temperament tests. In one test, a child’s mother might disappear from the testing suite and then reappear with a stranger. Another ratchets up the weirdness with some Halloween masks. Then, if all goes well, the kids should nap peacefully as a noisy magnetic resonance imaging machine scans their brains.

“We try to be prepared for everything,” Knickmeyer says. “We know exactly what to do if kids make a break for the door.”

Knickmeyer is excited to see something else from the children — their faecal microbiota, the array of bacteria, viruses and other microbes that inhabit their guts. Her project (affectionately known as ‘the poop study’) is part of a small but growing effort by neuroscientists to see whether the microbes that colonize the gut in infancy can alter brain development.

The project comes at a crucial juncture. A growing body of data, mostly from animals raised in sterile, germ-free conditions, shows that microbes in the gut influence behaviour and can alter brain physiology and neurochemistry.

In humans, the data are more limited. Researchers have drawn links between gastrointestinal pathology and psychiatric neurological conditions such as anxiety, depression, autism, schizophrenia and neurodegenerative disorders — but they are just links.

“In general, the problem of causality in microbiome studies is substantial,” says Rob Knight, a microbiologist at the University of California, San Diego. “It’s very difficult to tell if microbial differences you see associated with diseases are causes or consequences.” There are many outstanding questions. Clues about the mechanisms by which gut bacteria might interact with the brain are starting to emerge, but no one knows how important these processes are in human development and health.

That has not prevented some companies in the supplements industry from claiming that probiotics — bacteria that purportedly aid with digestive issues — can support emotional well-being. Pharmaceutical firms, hungry for new leads in treating neurological disorders, are beginning to invest in research related to gut microbes and the molecules that they produce.

Scientists and funders are looking for clarity. Over the past two years, the US National Institute of Mental Health (NIMH) in Bethesda, Maryland, has funded seven pilot studies with up to US$1 million each to examine what it calls the ‘microbiome–gut–brain axis’ (Knickmeyer’s research is one of these studies). This year, the US Office of Naval Research in Arlington, Virginia, agreed to pump around US$14.5 million over the next 6–7 years into work examining the gut’s role in cognitive function and stress responses. And the European Union has put €9 million (US$10.1 million) towards a five-year project called MyNewGut, two main objectives of which target brain development and disorders.

The latest efforts aim to move beyond basic observations and correlations — but preliminary results hint at complex answers. Researchers are starting to uncover a vast, varied system in which gut microbes influence the brain through hormones, immune molecules and the specialized metabolites that they produce.

“There’s probably more speculation than hard data now,” Knickmeyer says. “So there’s a lot of open questions about the gold standard for methods you should be applying. It’s very exploratory.”

Microbes and the brain have rarely been thought to interact except in instances when pathogens penetrate the blood–brain barrier — the cellular fortress protecting the brain against infection and inflammation. When they do, they can have strong effects: the virus that causes rabies elicits aggression, agitation and even a fear of water. But for decades, the vast majority of the body’s natural array of microbes was largely uncharacterized, and the idea that it could influence neurobiology was hardly considered mainstream. That is slowly changing.

Studies on community outbreaks were one key to illuminating the possible connections. In 2000, a flood in the Canadian town of Walkerton contaminated the town’s drinking water with pathogens such as Escherichia coli and Campylobacter jejuni. About 2,300 people suffered from severe gastrointestinal infection, and many of them developed chronic irritable bowel syndrome (IBS) as a direct result.

During an eight-year study of Walkerton residents, led by gastroenterologist Stephen Collins at McMaster University in Hamilton, Canada, researchers noticed that psychological issues such as depression and anxiety seemed to be a risk factor for persistent IBS. Premysl Bercik, another McMaster gastroenterologist, says that this interplay triggered intriguing questions. Could psychiatric symptoms be driven by lingering inflammation, or perhaps by a microbiome thrown out of whack by infection?

The McMaster group began to look for answers in mice. In a 2011 study, the team transplanted gut microbiota between different strains of mice and showed that behavioural traits specific to one strain transmitted along with the microbiota. Bercik says, for example, that “relatively shy” mice would exhibit more exploratory behaviour when carrying the microbiota of more-adventurous mice. “I think it is surprising. The microbiota is really driving the behavioural phenotype of host. There’s a marked difference,” Bercik says. Unpublished research suggests that taking faecal bacteria from humans with both IBS and anxiety and transplanting it into mice induces anxiety-like behaviour, whereas transplanting bacteria from healthy control humans does not.

Such results can be met with scepticism. As the field has developed, Knight says, microbiologists have had to learn from behavioural scientists that how animals are handled and caged can affect things such as social hierarchy, stress and even the microbiome.

There is much more to unravel, she says. “I’m always surprised. It’s very open. It’s a little like a Wild West out there.” Read more:

Nature 526, 312–314 (15 October 2015) doi:10.1038/526312a  Nature Original web page at Nature