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When Gut Bacteria Changes Brain Function
Some researchers believe that the microbiome may play a role in regulating how people think and feel.
By now, the idea that gut bacteria
affects a person’s health is not revolutionary. Many people know that these
microbes influence digestion, allergies, and metabolism. The trend has become
almost commonplace: New books appear regularly detailing precisely which diet
will lead to optimum bacterial health.
But these microbes’ reach may extend
much further, into the human brains. A growing group of researchers around the
world are investigating how the microbiome, as this bacterial ecosystem is
known, regulates how people think and feel. Scientists have found evidence that
this assemblage—about a thousand different species of bacteria, trillions of
cells that together weigh between one and three pounds—could play a crucial
role in autism, anxiety, depression, and other disorders.
“There’s been an explosion of
interest in the connections between the microbiome and the brain,” says Emeran
Mayer, a gastroenterologist at the University of California, Los Angeles, who
has been studying the topic for the past five years.
Some of the most intriguing work has
been done on autism. For decades, doctors, parents, and researchers have noted
that about three-quarters of people with autism also have some gastrointestinal
abnormality, like digestive issues, food allergies, or gluten sensitivity. This
recognition led scientists to examine potential connections between gut
microbes and autism; several recent studies have found that autistic people’s
microbiome differs significantly from control groups. The California Institute
of Technology microbiologist Sarkis Mazmanian has focused on a common species
called Bacteroides fragilis, which is seen in smaller quantities in some
children with autism. In a paper published two years ago in the journal Cell,
Mazmanian and several colleagues fed B. fragilis from humans to mice
with symptoms similar to autism. The treatment altered the makeup of the
animals’ microbiome, and more importantly, improved their behavior: They became
less anxious, communicated more with other mice, and showed less repetitive
behavior.
Exactly how the microbes interact
with the illness—whether as a trigger or as a shield—remains mostly a mystery.
But Mazmanian and his colleagues have identified one possible link: a chemical
called 4-ethylphenylsulphate, or 4EPS, which seems to be produced by gut
bacteria. They’ve found that mice with symptoms of autism have blood levels of
4EPS more than 40 times higher than other mice. The link between 4EPS levels
and the brain isn’t clear, but when the animals were injected with the
compound, they developed autism-like symptoms.
“We may be able to reverse these ailments. If you turn off
the faucet that produces this compound, then the symptoms disappear.”
Mazmanian, who in 2012 was awarded a
MacArthur grant for his microbiome work, sees this as a “potential
breakthrough” in understanding how microbes contribute to autism and other
neurodevelopmental disorders. He says the results so far suggest that adjusting
gut bacteria could be a viable treatment for the disease, at least in some
patients. “We may be able to reverse these ailments,” he says. “If you turn off
the faucet that produces this compound, then the symptoms disappear. That’s
what we see in the mouse model.”
Scientists have also gathered
evidence that gut bacteria can influence anxiety and depression. Stephen
Collins, a gastroenterology researcher at McMaster University in Hamilton,
Ontario, has found that strains of two bacteria, lactobacillus and bifidobacterium,
reduce anxiety-like behavior in mice (scientists don’t call it “anxiety”
because you can’t ask a mouse how it’s feeling). Humans also carry strains of
these bacteria in their guts. In one study, he and his colleague collected gut
bacteria from a strain of mice prone to anxious behavior, and then transplanted
these microbes into another strain inclined to be calm. The result: The
tranquil animals appeared to become anxious.
Overall, both of these microbes seem
to be major players in the gut-brain axis. John Cryan, a neuroscientist at the
University College of Cork in Ireland, has examined the effects of both of them
on depression in animals. In a 2010 paper
published in Neuroscience, he gave mice either bifidobacterium or
the antidepressant Lexapro; he then subjected them to a series of stressful
situations, including a test which measured how long they continued to swim in
a tank of water with no way out. (They were pulled out after a short period of
time, before they drowned.) The microbe and the drug were both effective at
increasing the animals’ perseverance, and reducing levels of hormones linked to
stress. Another experiment, this time using lactobacillus,
had similar results. Cryan is launching a study with humans (using measurements
other than the forced swim test to gauge subjects’ response).
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In Autism, the Importance of the Gut
So far, most microbiome-based brain
research has been in mice. But there have already been a few studies involving
humans. Last year, for example, Collins transferred gut bacteria from anxious
humans into “germ-free” mice—animals that had been raised (very carefully) so
their guts contained no bacteria at all. After the transplant, these animals
also behaved more anxiously.
Other research has examined entire
humans, not just their bugs. A paper published in the May 2015 issue of Psychopharmacology
by the Oxford University neurobiologist Phil Burnet looked at whether a
prebiotic—a group of carbohydrates that provide sustenance for gut
bacteria—affected stress levels among a group of 45 healthy volunteers. Some
subjects were fed 5.5 grams of a powdered carbohydrate known as
galactooligosaccharide, or GOS, while others were given a placebo. Previous
studies in mice by the same scientists had shown that this carb fostered growth
of Lactobacillus and Bifidobacteria; the mice with more of these
microbes also had increased levels of several neurotransmitters that affect
anxiety, including one called brain-derived neurotrophic factor.
In this experiment, subjects who
ingested GOS showed lower levels of a key stress hormone, cortisol, and in a
test involving a series of words flashed quickly on a screen, the GOS group
also focused more on positive information and less on negative. This test is
often used to measure levels of anxiety and depression, since in these
conditions anxious and depressed patients often focus inordinately on the
threatening or negative stimuli. Burnet and his colleagues note that the
results are similar to those seen when subjects take anti-depressants or
anti-anxiety medications.
Perhaps the most well-known human study was done by Mayer, the UCLA researcher. He
recruited 25 subjects, all healthy women; for four weeks, 12 of them ate a cup
of commercially available yogurt twice a day, while the rest didn’t. Yogurt is
a probiotic, meaning it contains live bacteria, in this case strains of four
species, bifidobacterium, streptococcus, lactococcus, and lactobacillus.
Before and after the study, subjects were given brain scans to gauge their
response to a series of images of facial expressions—happiness, sadness, anger,
and so on.
“This was not what we expected, that eating yogurt twice a
day for a few weeks would do something to your brain.”
To Mayer’s surprise, the results,
which were published in 2013 in the journal Gastroenterology, showed
significant differences between the two groups; the yogurt eaters reacted more
calmly to the images than the control group. “The contrast was clear,” says
Mayer. “This was not what we expected, that eating a yogurt twice a day for a
few weeks would do something to your brain.” He thinks the bacteria in the
yogurt changed the makeup of the subjects’ gut microbes, and that this led to
the production of compounds that modified brain chemistry.
It’s not yet clear how the
microbiome alters the brain. Most researchers agree that microbes probably
influence the brain via multiple mechanisms. Scientists have found
that gut bacteria produce neurotransmitters such as
serotonin, dopamine and GABA, all of which play a key role in mood (many
antidepressants increase levels of these same compounds). Certain organisms
also affect how people metabolize these compounds,
effectively regulating the amount that circulates in the blood and brain. Gut
bacteria may also generate other neuroactive chemicals, including
one called butyrate, that have been linked to reduced anxiety and depression.
Cryan and others have also shown that some microbes can activate
the vagus nerve, the main line of communication between the gut and
the brain. In addition, the microbiome is intertwined with the immune system,
which itself influences mood and behavior.
This interconnection of bugs and
brain seems credible, too, from an evolutionary perspective. After all,
bacteria have lived inside humans for millions of years. Cryan suggests that
over time, at least a few microbes have developed ways to shape their hosts’
behavior for their own ends. Modifying mood is a plausible microbial survival
strategy, he argues that “happy people tend to be more social. And the more
social we are, the more chances the microbes have to exchange and spread.”
As scientists learn more about how
the gut-brain microbial network operates, Cryan thinks it could be hacked to
treat psychiatric disorders. “These bacteria could eventually be used the way
we now use Prozac or Valium,” he says. And because these microbes have eons of
experience modifying our brains, they are likely to be more precise and subtle
than current pharmacological approaches, which could mean fewer side effects.
“I think these microbes will have a real effect on how we treat these
disorders,” Cryan says. “This is a whole new way to modulate brain function.”
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