C&B Notes

Psychobiotics (The Good Kind)

Scientists continue to expand their understanding of how microbiomes, the systems of microorganisms that are found in and around our bodies, impact human health.  To date, this focus has been primarily on physical health, but more attention is being paid to how the constitution of and changes in microbiomes may impact moods and overall mental health.

Since 2007, when scientists announced plans for a Human Microbiome Project to catalog the micro-organisms living in our body, the profound appreciation for the influence of such organisms has grown rapidly with each passing year.  Bacteria in the gut produce vitamins and break down our food; their presence or absence has been linked to obesity, inflammatory bowel disease and the toxic side effects of prescription drugs.  Biologists now believe that much of what makes us human depends on microbial activity.  The two million unique bacterial genes found in each human microbiome can make the 23,000 genes in our cells seem paltry, almost negligible, by comparison…

Given the extent to which bacteria are now understood to influence human physiology, it is hardly surprising that scientists have turned their attention to how bacteria might affect the brain.  Micro-organisms in our gut secrete a profound number of chemicals, and researchers like Lyte have found that among those chemicals are the same substances used by our neurons to communicate and regulate mood, like dopamine, serotonin and gamma-aminobutyric acid (GABA).  These, in turn, appear to play a function in intestinal disorders, which coincide with high levels of major depression and anxiety.  Last year, for example, a group in Norway examined feces from 55 people and found certain bacteria were more likely to be associated with depressive patients.

At the time of my visit to Lyte’s lab, he was nearly six months into an experiment that he hoped would better establish how certain gut microbes influenced the brain, functioning, in effect, as psychiatric drugs.  He was currently compiling a list of the psychoactive compounds found in the feces of infant monkeys.  Once that was established, he planned to transfer the microbes found in one newborn monkey’s feces into another’s intestine, so that the recipient would end up with a completely new set of microbes — and, if all went as predicted, change their neurodevelopment.  The experiment reflected an intriguing hypothesis.  Anxiety, depression and several pediatric disorders, including autism and hyperactivity, have been linked with gastrointestinal abnormalities.  Microbial transplants were not invasive brain surgery, and that was the point: Changing a patient’s bacteria might be difficult but it still seemed more straightforward than altering his genes.

* * * * *

‘‘There are certain fields that just don’t seem to interact well,’’ he said.  ‘‘Microbiology and neuroscience, as whole disciplines, don’t tend to have had much interaction, largely because the brain is somewhat protected.’’  He was referring to the fact that the brain is anatomically isolated, guarded by a blood-brain barrier that allows nutrients in but keeps out pathogens and inflammation, the immune system’s typical response to germs.  Cryan’s study added to the growing evidence that signals from beneficial bacteria nonetheless find a way through the barrier.  Somehow — though his 2011 paper could not pinpoint exactly how — micro-organisms in the gut tickle a sensory nerve ending in the fingerlike protrusion lining the intestine and carry that electrical impulse up the vagus nerve and into the deep-brain structures thought to be responsible for elemental emotions like anxiety.  Soon after that, Cryan and a co-author, Ted Dinan, published a theory paper in Biological Psychiatry calling these potentially mind-altering microbes ‘‘psychobiotics.’’

It has long been known that much of our supply of neurochemicals  — an estimated 50 percent of the dopamine, for example, and a vast majority of the serotonin — originate in the intestine, where these chemical signals regulate appetite, feelings of fullness and digestion.  But only in recent years has mainstream psychiatric research given serious consideration to the role microbes might play in creating those chemicals.  Lyte’s own interest in the question dates back to his time as a postdoctoral fellow at the University of Pittsburgh in 1985, when he found himself immersed in an emerging field with an unwieldy name: psychoneuroimmunology, or PNI, for short.  The central theory, quite controversial at the time, suggested that stress worsened disease by suppressing our immune system.

By 1990, at a lab in Mankato, Minn., Lyte distilled the theory into three words, which he wrote on a chalkboard in his office: Stress->Immune->Disease.  In the course of several experiments, he homed in on a paradox.  When he dropped an intruder mouse in the cage of an animal that lived alone, the intruder ramped up its immune system — a boost, he suspected, intended to fight off germ-ridden bites or scratches.  Surprisingly, though, this did not stop infections.  It instead had the opposite effect: Stressed animals got sick.  Lyte walked up to the board and scratched a line through the word ‘‘Immune.’’  Stress, he suspected, directly affected the bacterial bugs that caused infections.

To test how micro-organisms reacted to stress, he filled petri plates with a bovine-serum-based medium and laced the dishes with a strain of bacterium.  In some, he dropped norepinephrine, a neurochemical that mammals produce when stressed.  The next day, he snapped a Polaroid.  The results were visible and obvious: The control plates were nearly barren, but those with the norepinephrine bloomed with bacteria that filigreed in frostlike patterns.  Bacteria clearly responded to stress.

Then, to see if bacteria could induce stress, Lyte fed white mice a liquid solution of Campylobacter jejuni, a bacterium that can cause food poisoning in humans but generally doesn’t prompt an immune response in mice.  To the trained eye, his treated mice were as healthy as the controls.  But when he ran them through a plexiglass maze raised several feet above the lab floor, the bacteria-fed mice were less likely to venture out on the high, unprotected ledges of the maze.  In human terms, they seemed anxious.  Without the bacteria, they walked the narrow, elevated planks.

Each of these results was fascinating, but Lyte had a difficult time finding microbiology journals that would publish either.  ‘‘It was so anathema to them,’’ he told me.  When the mouse study finally appeared in the journal Physiology & Behavior in 1998, it garnered little attention.  And yet as Stephen Collins, a gastroenterologist at McMaster University, told me, those first papers contained the seeds of an entire new field of research.  ‘‘Mark showed, quite clearly, in elegant studies that are not often cited, that introducing a pathological bacterium into the gut will cause a change in behavior.’’

* * * * *

The list of potential treatments incubating in labs around the world is startling.  Several international groups have found that psychobiotics had subtle yet perceptible effects in healthy volunteers in a battery of brain-scanning and psychological tests.  Another team in Arizona recently finished an open trial on fecal transplants in children with autism. (Simultaneously, at least two offshore clinics, in Australia and England, began offering fecal microbiota treatments to treat neurological disorders, like multiple sclerosis.)  Mazmanian, however, cautions that this research is still in its infancy.  ‘‘We’ve reached the stage where there’s a lot of, you know, ‘The microbiome is the cure for everything,’’’ he said.  ‘‘I have a vested interest if it does.  But I’d be shocked if it did.’’