From Our 2015 Archives
'Gut Feelings': More Than Heartburn, Indigestion?
By Rita Rubin
Reviewed by Brunilda Nazario, MD
June 5, 2015 -- If promising but early studies pan out, psychiatrists of the future could make a most unusual request of their patients: a sample of their stool.
Yes, the bodily specimen used to help diagnose digestive diseases might also offer clues as to what's happening at the other end of someone's anatomy.
Intriguing research, done mainly in rats and mice so far, suggests that bacteria that live in the gut influence brain development, mood, and behavior. Someday, doctors might be able to treat mood disorders with probiotics, supplements containing good gut bacteria; prebiotics, which promote the growth of good bacteria in the gut; or highly specific antibiotics that kill bad gut bacteria.
Depression "clearly isn't all about Prozac and serotonin," says Roger McIntyre, MD, who directs the Mood Disorders Psychopharmacology Unit at the University of Toronto. "We need to look at alternative explanations, alternative treatments."
And at least for some people with a mental illness, a major contributing factor might be the 100 trillion bacteria -- "aliens," as Dartmouth microbiologist and immunologist Lloyd Kasper, MD, calls them -- that live in the gut.
Scientists call this two-way street the gut-brain axis, and they're just beginning to learn how the two organs talk with each other. "We're so far at the tip of the iceberg on this that we don't know where it's going to go," Kasper says.
Babies are born with sterile guts, but bacteria begin moving in within hours. The bacteria population remains relatively stable from age 3 onward, but things like environment, diet, drug exposure, and genetics can influence which ones thrive, McIntyre says.
Healthy people tend to have similar types and proportions of gut bacteria. Changes in the gut bacteria have been linked not only to digestive disorders but also to metabolic and brain disorders, says Jane Foster, PhD, an associate professor of psychiatry and behavioral neurosciences at McMaster University.
In an interview, Foster described several possible ways that gut bacteria and the brain communicate.
One is via the enteric nervous system, the part of the nervous system that governs the digestive tract. Also, gut bacteria can alter how the immune system works, which can affect the brain. The gut bacteria are involved in digestion, too, and the substances they make when they break down food can affect the brain.
And under certain conditions, such as stress or infection, potentially disease-causing gut bacteria, or bad bugs, can leak through the bowel wall and enter the bloodstream, enabling them and the chemicals they make to talk with the brain through cells in blood vessel walls. Bacteria could also communicate directly with cells in certain regions of the brain, including those located near areas involved in stress and mood, Foster says. It's unclear, though, how that might affect your mood.
Of Mice and Humans
So far, much of what's known about the relationship between gut microbes and the brain has come from studying rodents. "Germ-free" mice, which have no gut bacteria, have provided clues about the impact of the loss of normal microbes on mood and behavior. In other research, scientists have looked at how probiotics affect mouse behavior and mood. One study found that feeding mice a particular probiotic led to higher concentrations of beneficial fatty acids in the brain, suggesting that taking probiotics might help achieve optimal brain health.
Researchers have done small tests looking at what happens when healthy adults eat either probiotics or prebiotics -- soluble fiber that promotes the growth of good bacteria already present in the gut -- or a placebo for 3 or 4 weeks.
In one study, scientists in England randomly divided volunteers into three groups: One group took one prebiotic, a second group took a different prebiotic, and the third group took a sugar pill. The researchers measured levels of cortisol, the "stress" hormone that's related to depression and anxiety, in the volunteers' saliva. Over the 3-week study, cortisol levels dropped significantly in the group taking one prebiotic but not in the other two groups, the scientists reported recently in the journal Psychopharmacology.
The researchers also gave several computer tests to see if the prebiotics made any difference in how the volunteers viewed emotional information. The prebiotic group with the lowered cortisol levels paid less attention to negative information and more attention to positive info than the other two groups did. But there were no differences among the three groups as far as how anxious or stressed they felt.
"Perhaps we would have seen some behavioral changes after a longer period of supplementation," says coauthor Philip Burnet, PhD, a neurobiologist. "Also, we tested in healthy volunteers, so any changes may be subtle." Burnet says he now plans to study the effect of prebiotics in schoolchildren with mild anxiety.
In another study, UCLA scientists randomly assigned 36 healthy women to one of three groups. One group ate plain yogurt containing probiotics, another ate yogurt that looked and tasted exactly the same but did not have probiotics, and the third group wasn't given any yogurt. The yogurt was made at a Danone Research facility in France. Danone, the parent company of Dannon, funded the study, and three of the coauthors were employees.
Participants got MRIs of their brains at the beginning and at the end of the study. The researchers found that the yogurt containing probiotics affected activity in brain regions that control processing of emotion and sensation.
Gastroenterologist Kirsten Tillisch, MD, a coauthor of the yogurt study, is now collecting stool samples from people with anxiety to see how different their gut bugs look compared to those in people who aren't anxious or depressed. Tillisch, who's on the faculty of UCLA's Oppenheimer Family Center for Neurobiology of Stress, says she expects to see differences among the anxious people as well.
But genetics and environment might play greater roles than gut bacteria in some cases, which is one reason it's too soon to recommend that anxious or depressed people turn to probiotics, Tillisch says.
"The issue becomes if you start taking probiotics, which probiotics are you going to take? And under what conditions? And how much do you need to take?" Kasper says. Until more specifics are known, he says, taking probiotics for mood disorders "is a crapshoot."
Another promising approach, Kasper says, is "magic bullet" antibiotics, highly specific drugs that could get rid of bad gut bacteria without tampering with the good bugs. And maybe someday, he says, doctors might be able to achieve a healthy balance of gut bacteria with fecal transplants.
SOURCES: Roger McIntyre, MD, director of the Mood Disorders Psychopharmacology Unit at the University of Toronto. Lloyd Kasper, MD, professor of microbiology and immunology, Geisel School of Medicine at Dartmouth. Jane Foster, PhD, associate professor of psychiatry and behavioral neurosciences at McMaster University. Philip Burnet, PhD, psychiatry department researcher, Oxford University. Kirsten Tillisch, MD, Oppenheimer Family Center for Neurobiology of Stress at UCLA. Schmidt, K. Psychopharmacology, May 2015. Tillisch, K. Gastroenterology, June 2013. Zhou, L. Neuropsychiatric Disease and Treatment, March 2015. Slyepchenko, A. CNS & Neurological Disorders—Drug Targets, November 2014. Wang, Y. Brain, Behavior, and Immunology, May 2014. Wall, R. The American Journal of Clinical Nutrition, May 2012. Borre, Y.E. Trends in Molecular Medicine, September 2014.