Can gut bacteria meddle with the brain?

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Links between the microbiota and psychological disorders such as depression and anxiety have, for the most part, only been shown in rodents.
Credit: Richard Wareham Fotografie / Getty Images

The microbes in your gut may be tiny, but their influence appears to extend as far as the brain, affecting mental health, stress levels, memory and cognitive abilities. Yet many of the most compelling results illustrating the microbiota-gut-brain axis, as it has become known, have only been seen in animals. 

The potential for gut microbes to affect mood is probably best illustrated by an experiment conducted at McMaster University in Canada. Mice devoid of a microbiota were effectively given ‘personality make-overs’ via poo transplants. Timid mice became more brazen, and once daring mice retreated into shyness, taking on the anxiety profiles of their donors.

Human-to-rodent poo transplants also work. When researchers at University College Cork in Ireland fed rats poo from people with depression, the rats became depressed and anxious.

In humans, a handful of studies link changes in the gut microbial ecosystem to our mental health. Anxiety levels in patients with inflammatory bowel disease, for instance, track with the level of disruption to their gut microbial communities. Altered gut microbes, as well as gastrointestinal symptoms – such as constipation, diarrhoea and inflammation – are also common in autism spectrum disorders.

Scientists are still nutting out the possible mechanisms behind these long-ranging effects, and have found several possible communication channels between the gut and brain.

The first is via neurotransmitters – chemicals that relay messages between nerve cells. Many of these chemical messengers are made by the brain and other neural tissue. But some, including serotonin (and its precursor tryptophan), norepinephrine and dopamine are also synthesised by gut microbes. 

When the University College Cork team treated mice with the probiotic Lactobacillus rhamnosus, they saw levels of a lock-and-key partner of one neurotransmitter – GABA – rise in some brain areas and drop in others. The mice were also less depressed, less anxious and less prone to stress.

But whether tinkering with the gut ecosystem in humans translates into changes in neurotransmitter signalling in the brain – much less the behaviours they affect – is still largely a mystery.

Another communication highway between gut and brain is the vagus nerve. The vagus nerve connects the base of the brain (the brainstem) to the gut – as well as the heart and lungs – and controls a bunch of unconscious tasks, such as regulating heart rate, squeezing food through the gastrointestinal tract, and sweating. It also relays stress response signals back to the brain.

Research in mice suggests that when the vagus nerve is severed, a crucial line of communication between gut and brain is taken down. In the study of mice fed the probiotic Lactobacillus rhamnosus, the beneficial effects of the bacteria – lower levels anxiety, depression and stress – disappeared when the vagus nerve was cut. But it’s still a mystery how the vagus nerve works to relay messages from the gut to the brain.

The leaky gut phenomenon also makes an appearance in the microbiota-gut-brain axis. When there are fewer beneficial microbes to spit out short chain fatty acids, the lining of the intestine – usually firmly glued together and protected by a thick layer of mucous – becomes permeable to bacteria and other by-products of digestion that wouldn’t normally leave the confines of the gut.

This leakage can ramp up inflammatory signals around the body, including in the brain, and could be one source of the chronic, low-level inflammation seen in people with depression.

A leaky blood brain barrier may also be part of the picture. The short chain fatty acids that help to maintain the gut barrier play a similar role maintaining the highly selective membrane that protects the brain from bits and pieces in the bloodstream.

Germ-free mice have a leakier blood brain barrier than conventional mice. But a Swedish team at the Karolinska Institute found that when fed poo from conventionally raised mice, or a selection of microbes known to churn out short chain fatty acids, the blood brain barrier becomes less leaky.

Fast food diets have been linked to leaky gut and depressive symptoms. Unsurprisingly, diets rich in fruits, vegetables and fish tend to decrease depressive symptoms.

These dietary studies raise the question of whether behaviours seen in mice – and perhaps in humans, too – could be the result of what’s happening in the gut, rather than just the brain. They also beg the question of whether rectifying disturbances in the gut ecosystem could improve symptoms.

In mice, the evidence is promising but mixed. Bacteroides fragilis – a microbe known to protect against gut inflammation – plugged the leaky gut, restored microbiota to normal and reduced autistic-like behaviours in mice with an experimental form of autism, even those fully grown.

But a study of a different mouse model of autism using a different beneficial microbe found that adding back the depleted microbe could restore some, but not all, of the behavioural deficits.

There are hopeful signs that probiotic microbes could alleviate depression. Bacteroides infantis and Lactobacillus rhamnosus decrease depressive symptoms in rodents, and a French team showed that a Lactobacillus helveticus/ Bifidobacterium longum cocktail does the same in non-depressed human volunteers.

It is enticing to think probiotic supplements to treat psychological disorders – dubbed “psychobiotics” – could one day hit the shelves. But much more work needs to be done – especially in populations of people with mental health disorders – before this happens.

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