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SRI Magazine 2016

SRI Magazine 2016

Gut bacteria and the brain

Ultra-high-resolution imaging suggests bacteria produce a calming effect

What weighs around three pounds and controls your behaviour?

The bacteria in your gut.

Surprised? You could be forgiven for thinking that the answer is your brain, but scientists are more and more recognizing the effects of gut bacteria on our thoughts and actions.

The human gut is home to a complex community of bacteria, known collectively as the gut microbiome. While researchers have known about the existence of these bacteria for a long time, they have only recently begun to understand the profound impact of these microbial dwellers on the body. The gut microbiome helps break down food into nutrients that would otherwise be inaccessible. It trains the immune system to recognize and defend against harmful pathogens. Now, a study by Dr. Greg Stanisz, a senior scientist at Sunnybrook Research Institute (SRI), has shown that the gut microbiome can alter brain chemistry to modify mood and behaviour. The preclinical study, published in the journal NeuroImage, is the first to use magnetic resonance spectroscopy (MRS) to measure changes in brain metabolites caused by gut bacteria.

In 2011, scientists at McMaster University in Canada and University College Cork in Ireland showed that mice fed a daily supplement of the bacterium Lactobacillus rhamnosus were less anxious and depressed than mice that did not receive the supplement. They had no way of looking into the brains of these mice, however, to see what was causing the changed behaviour. That’s when a family dinner saved the day.

“We never actually talk science at all,” says Stanisz about the relationship between he and his brother Andrew, a member of the McMaster group led by Dr. John Bienenstock who conducted the 2011 study. As it turned out, Stanisz’ expertise in MRI was exactly what the McMaster group needed. “They knew that probably the right approach is to use MRI or spectroscopy. They had been looking for a year or two [for someone who could help them do it], but my brother didn’t contact me. Finally during dinner we started talking, and here we are.”

An offshoot of MRI, MRS is a noninvasive technique that allows scientists to see directly into the metabolic factories of tissues and organs. An MRI scan provides structural information like the number and density of blood vessels leading to an organ. On the other hand, MRS offers snapshots of the biochemistry within an organ. It allows scientists to measure how different metabolite levels shift as nutrients are broken down and converted into useable compounds and waste.

In this case, Stanisz wanted to use MRS to look for chemical changes in the brains of mice fed the Lactobacillus bacteria. “I was a little bit skeptical about the whole project,” he says. “I had never done MRS in my entire life.” When he presented his idea to the lab, his PhD student Rafal Janik jumped at the chance to take on the challenging project.

Janik started by recreating the experimental setup of the 2011 study. He used the same breed of mice and fed them the same dose of L. rhamnosus for the same period. At various times during and after the four-week treatment, he put the mice in an ultra-high-resolution MRI scanner to measure the levels of different chemicals in their brains.

He found that concentrations of three chemicals—gamma amino butyric acid (GABA), glutamate and total N-acetyl aspartate (tNAA)—were higher in the brains of mice that received a bacterial supplement than those that did not receive it.

“The one we were most happy about was GABA, [because it is] the main inhibitory neurotransmitter in the brain and is implicated in the pathophysiology of depressive disorders,” says Janik. The primary role of GABA is to quiet overexcited neurons, thereby producing a calming effect. Benzodiazepines, a commonly prescribed class of drugs that includes Valium and Xanax, decrease anxiety in patients by enhancing GABA’s actions.

These results suggest that the alterations in neurotransmitters seen in animals with anxiety or depression are related to changes in their gut bacteria, says Stanisz, who is also a professor of medical biophysics at the University of Toronto. If that is true, then it might be possible to restore neurotransmitter levels and therefore normal behaviour by adding certain bacteria to their diet, he adds.

Stanisz and Janik’s study contribute to a growing body of work on the so-called microbiome-gut-brain axis, a bidirectional communication pathway linking the gut and brain. Specifically, it adds to research that seeks to understand why people with stress-related psychiatric disorders like anxiety and depression are far more likely to suffer from gastrointestinal ailments than are their healthy peers. Disorders like irritable bowel syndrome and inflammatory bowel disease often arise when the microbial community within the gut is thrown off balance by changes in diet, antibiotic exposure or stress. Based on these observations, groups like the one at McMaster University are now exploring the possibility that a disturbed gut microbiome may be contributing to an individual’s off-kilter state of mind.

Laboratory studies are increasingly pointing to a definitive link between the gut microbiome, mood and behaviour. In one experiment, scientists showed that feeding a normally calm mouse gut bacteria from a more high-strung mouse causes the calm mouse to exhibit more anxiety-like behaviours and vice versa. Studies of germ-free mice—those born and raised in completely sterile environments—found they were less anxious than mice whose guts were colonized by the normal spectrum of bacterial species.

Stanisz and Janik are now exploring the possibility of using MRS to find other bacteria that produce a calming effect on the brain. The metabolites they identified—GABA, glutamate and tNAA—will serve as biomarkers, helping them to predict which bacteria can reduce anxiety and depression. They will test different bacteria by first feeding them to mice. Then, instead of doing behavioural tests to measure anxiety and depression, they will put the mice in an MRI scanner to look for changes in neurotransmitter levels. This strategy is a faster and more objective way to test many different bacterial species. Promising candidates will then undergo behavioural tests to confirm whether the mice are less anxious and depressed.

“There are probably more bacteria that have a similar effect,” says Stanisz. “[L. rhamnosus] was a good start.”

Stanisz’ research is funded by the U.S. Office for Naval Research. Janik’s research is supported by a Frederick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institutes of Health Research. Infrastructure support comes from the Canada Foundation for Innovation.