by Mo Costandi
19 August 2012
Bacteria in your gut may be
influencing your thoughts and moods,
raising the possibility that probiotics
could be used to treat psychiatric illnesses
in the July/ August
issue of Scientific American MIND
"The thought of parasites preying on
your body or brain very likely sends shivers down your spine.
Perhaps you imagine insectoid
creatures bursting from stomachs or a malevolent force
controlling your actions. These visions are not just the night
terrors of science-fiction writers - the natural world is
replete with such examples.
"Take Toxoplasma gondii, the
single-celled parasite. When mice are infected by it, they
suffer the grave misfortune of becoming attracted to cats.
Once a cat inevitably consumes the
doomed creature, the parasite can complete its life cycle inside
its new host. Or consider
Cordyceps, the parasitic fungus that
can grow into the brain of an insect.
The fungus can force an ant to climb
a plant before consuming its brain entirely. After the insect
dies, a mushroom sprouts from its head, allowing the fungus to
disperse its spores as widely as possible."
That's the introduction to my feature
article about how the microbes in your gut might influence your
brain and behavior, which is out now in the July/August issue of
Scientific American MIND.
The article focuses mainly on the work
Jane Foster and
John Bienenstock of McMaster
University in Ontario and
John Cryan of University College
Cork, who have been collaborating on experiments designed to test
how certain species of gut bacteria influence the activity of genes
in the brain.
Below is a story I wrote last year about
some of the work from Foster's group, updated to include quotes and
new research that has been published since I wrote the feature.
may influence thoughts and behavior
The human gut contains a diverse community of bacteria that colonize
the large intestine in the days following birth and vastly outnumber
our own cells.
These so-called gut microbiota
virtual organ within an organ, and influence many
bodily functions. Among other things, they aid in the uptake and
metabolism of nutrients, modulate the inflammatory response to
infection, and protect the gut from other, harmful micro-organisms.
study by researchers at McMaster
University in Hamilton, Ontario now suggests that gut bacteria may
also influence behavior and cognitive processes such as memory by
exerting an effect on gene activity during brain development.
Jane Foster and her colleagues compared the performance of germ-free
mice, which lack gut bacteria, with normal animals on the elevated
plus maze, which is used to test anxiety-like behaviors. This
consists of a plus-shaped apparatus with two open and two closed
arms, with an open roof and raised up off the floor.
Ordinarily, mice will avoid open spaces
to minimize the risk of being seen by predators, and spend far more
time in the closed than in the open arms when placed in the elevated
This is exactly what the researchers found when they placed the
normal mice into the apparatus. The animals spent far more time in
the closed arms of the maze and rarely ventured into the open ones.
The germ-free mice, on the other hand,
behaved quite differently - they entered the open arms more often,
and continued to explore them throughout the duration of the test,
spending significantly more time there than in the closed arms.
The researchers then examined the animals' brains, and found that
these differences in behavior were accompanied by alterations in the
expression levels of several genes in the germ-free mice.
Brain-derived neurotrophic factor (BDNF) was significantly
up-regulated, and the 5HT1A serotonin receptor sub-type
down-regulated, in the dentate gyrus of the hippocampus.
The gene encoding the NR2B subunit of
the NMDA receptor was also down-regulated in the amygdala.
All three genes have previously been implicated in emotion and
anxiety-like behaviors. BDNF is a growth factor that is essential
for proper brain development, and a recent study showed that
deleting the BDNF receptor TrkB alters the way in which newborn
neurons integrate into hippocampal circuitry and increases
anxiety-like behaviors in mice.
Serotonin receptors, which are
distributed widely throughout the brain, are well known to be
involved in mood, and
compounds that activate the 5HT1A subtype also
produce anxiety-like behaviors.
The finding that the NR2B subunit of the NMDA receptor
down-regulated in the amygdala is particularly interesting. NMDA
receptors are composed of multiple subunits, but those made up of
only NR2B subunits are known to be critical for the development and
function of the amygdala, which has a well established role in fear
and other emotions, and in
learning and memory.
Drugs that block these receptors have
been shown to
block the formation of fearful memories and to reduce
the anxiety associated with alcohol withdrawal in rodents.
The idea of cross-talk between the brain and the gut is not new.
For example, irritable bowel syndrome
(IBS) is associated with psychiatric illness, and also involves
changes in the composition of the bacterial population in the gut.
But this is the first study to show that the absence of gut bacteria
is associated with altered behavior.
Bacteria colonize the gut in the days
following birth, during a sensitive period of brain development, and
apparently influence behavior by inducing changes in the expression
of certain genes.
"One of the things our data point to
is that gut microbiota are very important in the first four
weeks of a mouse's life, and I think the processes are
translatable [to humans]," says Foster.
"I'm getting a lot of attention from
pediatricians who want to collaborate to test some of these
connections in kids with early onset IBS. Their microbiota
profile is wrong, and our results suggest that we have a window
up until puberty, during which we can potentially fix this."
Exactly how gut bacteria influence gene
expression in the brain is unclear, but one possible line of
communication is the autonomic branch of the peripheral nervous
system, which controls functions such as digestion, breathing and
A better understanding of cross-talk
within this so-called 'brain-gut axis' could lead to new approaches
for dealing with the psychiatric symptoms that sometimes accompany
gastrointestinal disorders such as IBS, and may also show that gut
bacteria affect function of the mature brain.
More evidence that gut bacteria can influence neuronal signaling has
emerged in the past few months. In June, Cryan's group reported that
germ-free mice have significantly
elevated levels of serotonin in
the hippocampus compared to animals reared normally.
This was also associated with reduced
anxiety, but was reversed when the gut bacteria were restored.
And at the General Meeting of the
American Society for Microbiology, also in June, researchers from
the Baylor College of Medicine in Texas described experiments
showing that one bacterial species found in the gut, Bifidobacteria
synthesizes large amounts of the inhibitory
SSRIs, the class of antidepressants that includes Prozac, prevent
neurons from mopping up serotonin once it has been released, thus
maintaining high levels of the transmitter at synapses. And
benzodiazepines, a class of anti-anxiety drugs that includes
diazepam, mimic the effects of GABA by binding to a distinct site on
the GABA-A receptor.
All of this suggests that probiotic formulations that are enriched
in specific strains of gut bacteria could one day be used to treat
"There's definitely potential on
numerous levels, but I do think studies need to be done in a
proper, robust manner in representative samples," says Cryan.
"Even as an adjunctive therapy for anti-depressants, this could
be really important, but first we'll have to figure out which
species are going to be beneficial, and how they're doing it."
of the University of Colorado, Boulder, agrees that probiotics could
potentially be useful.
"I find the mouse data convincing
but there's not yet direct evidence in humans," he says.
"What's needed is longitudinal
studies of at-risk individuals to determine whether there are
systematic changes in the microbiota that correlate with
psychiatric conditions, and double-blind randomized clinical
Research-supported, FDA-approved and
effective products are likely at minimum 5-10 years off, but
given the lax regulation of probiotics, I'm sure that products
could be on the shelf tomorrow."