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JAMA
Within the last decade, the phrase “gut feelings” has taken on a whole new meaning. Traditionally, scientists have focused on the role of the central nervous system in regulating our moods and behaviors, but a paradigm shift is afoot, with new research revealing a unique role of our gut microbiota in influencing emotion.
A seminal study published in 2004 provided some of the first evidence of bidirectional interaction between gut bacteria and the brain, demonstrating that germ-free (GF) mice without commensal microorganisms have an exaggerated response to stress, accompanied by altered brain chemistry and elevated stress hormones, which could be normalized by administration of a single type of bacterium, Bifidobacterium infantis (Sudo N et al. J Physiol. 2004;558[pt 1]:263-275).
M. J. Friedrich
MOOD-MODIFYING BUGS
Several years later, gastroenterologist Stephen Collins, MD, and his colleagues at McMaster University, Hamilton, Ontario, Canada, discovered that Bifidobacterium longum NCC3001 administered as a probiotic could reverse anxiety-like behavior associated with chronic colitis in a mouse model of inflammatory bowel disease (Bercik P et al. Gastroenterology. 2010;139[6]:2102-2112).
The change in the behavior of the mice was so dramatic that it prompted Collins and his colleagues to perform a systematic investigation of the ability of intestinal bacteria to influence the brain and behavior.
Subsequent animal experiments in Collins’ laboratory bore out the researchers’ initial observations by demonstrating through both antibiotic perturbation and fecal transplants that intestinal microbiota can influence anxiety-like behaviors (Bercik P et al. Gastroenterology. 2011;141[2]:599-609). Mice treated with oral antibiotics showed a reduction in anxiety-like behavior. What’s more, swapping intestinal microbiota of mice also switched their behavioral phenotypes, where a once anxious mouse adopted the less anxious behavioral phenotype of the donor mouse and vice versa.
A growing amount of preclinical evidence from other laboratories continues to underscore the relationship between the gut microbiota, stress, and anxiety-related behaviors, such as the recent study showing that stress-sensitive rats that lacked gut microbiota showed an increase in anxiety-like behavior compared with rats with pathogen-free gut microbiota (Crumeyrolle-Arias et al. Psychoneuroendocrinology. 2014;42:207-217).
Although these findings clearly suggest that modulation of the gut microbiome can affect behavior, making mice more or less anxious, the exact nature of this relationship and the mechanisms whereby the microbiome influences the brain remain to be fully elucidated.
NEURAL MECHANISMS OF MIND-ALTERING MICROBES
Microbes in the gut appear to rely on several strategies to communicate with the brain and nervous system.
In a preclinical placebo-controlled study, investigators from University College Cork in Ireland found that feeding healthy rats a strain of the bacterium Lactobacillus rhamnosus reduced anxiety and depression-related behaviors and also altered expression of GABA receptors, which are implicated in anxiety and depression (Bravo JA et al. PNAS. 2011;108[38]:16050-16055). Furthermore, they found that the neurochemical and behavioral effects required an intact vagus nerve, implicating this nerve as important in communicating changes in the gastrointestinal tract to the brain, noted Timothy Dinan, MD, a psychiatrist on the Cork research team that carried out the study.
“We gained some mechanistic understanding of how this probiotic was communicating with the brain, but that isn’t to suggest that all bacteria act through this mechanism,” said Dinan.
In exploring other bacterial communication strategies, researchers have investigated the effects gut flora have on central signaling systems, such as the neurotransmitter serotonin and brain-derived neurotrophic factor (BDNF), both of which have been implicated in the regulation of mood and emotion.
In an exemplary study comparing gene expression and behavior of GF mice to “normal” healthy mice with pathogen-free gut microbiota, an international team of investigators found that GF mice were not only more active and less anxious than the adult mice with gut microbiota, but they also had reduced BDNF messenger RNA and altered expression of genes involved in synaptic signaling in brain regions associated with motor control and anxiety (Diaz Heijtz et al. PNAS. 2011;108[7]:3047-3052). Interestingly, when GF mice were exposed to gut microbiota early in life, they developed the same behavioral characteristics and gene expression profile seen in adult mice exposed to microorganisms from birth. However, waiting until the mice were adults to colonize GF mice with bacteria did not alter their behavior.
Dinan and his colleagues demonstrated that the absence of bacteria in GF mice in early life increased brain serotonin concentrations in adulthood in a sex-dependent manner, with the effects being more marked in male animals than in females. When mice are colonized with bacteria after weaning, they found that many of the changes in serotonin levels could not be reversed (Clarke G et al. Mol Psychiatry. 2013;18[6]:666-673).
What’s more, adult GF mice also displayed increased formation of new neurons in the hippocampus and colonizing the mice after weaning did not prevent these changes in neurogenesis. (Ogbonnaya ES et al. Biol Psychiatry. doi:10.1016/j.biopsych.2014.12.023 [published online February 17, 2015]). It is interesting to note that increased neurogenesis was found primarily in the dorsal hippocampus, which has been proposed to play a role in the ability to discriminate between similar experiences (a process referred to as pattern separation) that when dysregulated may contribute to anxiety phenotypes (Kheirbek et al. Nat Neurosci. 2012;15[12]:1613-1620).
Importantly, these studies suggest that there is a critical window in early life during which microbial colonization shapes adult neural circuitry and signaling and in this case normalizes adult behavior.
Other avenues of gut microbe–brain communication involve metabolites produced by bacteria, such as short-chain fatty acids, that can get into the body and the bloodstream and affect brain function. Dinan’s group recently completed a study in which they analyzed the gut microbiota from fecal material of patients with depression and found a reduction in bacteria associated with butyrate production in those patients compared with healthy controls.
“This is an intriguing finding, because a number of recent papers suggest that sodium butyrate has antidepressant properties,” added Dinan.
OF MICE AND MEN?
Despite studies showing that certain bacteria, particularly selective strains ofBifidobacteria and Lactobacilli, are capable of modifying the brain and behavior in rodent models, only a few studies have looked at their effect in any kind of systematic way in humans.
It is important to note that although GF mice are useful tools for answering specific “yes-no” questions, such as whether the gut microbiome is involved in the stress response, the clinical relevance of GF rodent studies is limited because these animals show abnormalities in brain, immune, and gastrointestinal function, thus emphasizing the need for human studies (Mayer et al. J Neurosci. 2014;34[46]:15490-15496).
One clinical study recently looked at the potential effect of probiotics on the human brain. Gastroenterologist Emeran Mayer, MD, who has worked to understand signaling between the gut and the brain, and his team at the University of California, Los Angeles, found that giving a probiotic cocktail in a fermented dairy drink to healthy female participants could bring about changes in brain activity as measured by functional MRI (fMRI) compared with control participants (Tillisch K et al.Gastroenterology. 2013;144[7]:1394-1401).
The women carried out a face-matching attention task while they underwent fMRI before and after the 4-week intervention. They were shown pictures of human faces displaying fear or anger that normally trigger increased activity in areas of the brain involved in processing emotion. Brain activity was monitored during a resting state and while participants identified the emotions associated with human facial expressions. While executing this task, the group taking the probiotic showed less activity in brain regions involved in anxiety relative to control groups, suggesting that the brain’s reaction to negative emotional stimuli had changed.
“This was a positive proof of concept that shows if you manipulate the gut microbiota in a very subtle way, you can pick up a fairly robust brain signal that affects multiple brain regions,” said Mayer.
Mayer said that while studies in humans so far seem to indicate that gut microbes do affect the brain, these effects are likely going to turn out to be much less robust than what is seen in animal studies.
The magnitude of these effects may be developmentally dictated, as studies suggest there are specific critical windows in which microbiota play a key role in sculpting behavior. Collins noted that “anything that interferes with the microbial colonization process early on can set the scene for trouble down the road, and the declining robustness of the microbiome as one ages is likely to be a major determinant of healthy aging.”
In particular, investigators are finding that maternal stress, infections, or antibiotic administration can cause microbial perturbations during critical prenatal and neonatal periods, when the gut is first colonized by the mother’s microbiome, that disrupt normal neurodevelopment and may even increase the risk of neuropsychiatric disorders later in life (Borre YE et al. Trends Mol Med. 2014;20[9]:509-518).
Dinan pointed out that mode of delivery—cesarean vs vaginal—can also affect an infant’s microbiome. A baby born by cesarean delivery does not pick up its mother’s microbes through the vagina but instead picks up its microbiome from the surrounding environment. The health implications of cesarean delivery on the developing brain are not well understood, but given that the rate of cesarean deliveries has increased by more than 50% in areas around the world, including China and Brazil, this question begs investigation, he said. Dinan and colleagues are investigating the long-term effects of cesarean delivery, relative to vaginal birth, on mental health status in ongoing prospective studies in humans.
Efforts are currently under way to substantiate the clinical efficacy of probiotics, including a placebo-controlled study by the McMaster group in patients with irritable bowel syndrome who have significant scores for depression, said Collins. The researchers examined whether the administration of a Bifidobacterium strain can attenuate depression and improve gut function. Using fMRI, they looked for an objective measurement in terms of brain activity in the amygdala, hippocampus, and parts of the frontal cortex that would correspond with improvement in depression, said Collins.
Dinan’s group also has been working on a number of clinical studies involving probiotics. They completed a placebo-controlled study of a Bifidobacterium in healthy participants, looking at stress responses and cognition in the subjects as well as doing an in-depth electroencephalography analysis. And they are about to embark on 2 studies of L rhamnosus—the strain used in the earlier rodent study in which they determined the vagus nerve to be the communication route to the brain. One study is being carried out in healthy participants and the other in patients with treatment-resistant depression to see if augmentation with L rhamnosus can improve the therapeutic benefits of antidepressant drug treatment.
Collins’ group has also recently carried out a yet-to-be published clinical study examining the microbiota of individuals newly diagnosed with depression or anxiety who have never been prescribed drug therapy for their condition, focusing in particular on the metabolites produced by the bacteria as well as the composition of the microbiome.
“In this way, if we do start to identify profiles or bacteria of interest, we can culture them and study what metabolites they produce that might have effects on the host brain,” said Collins. Such microbiome profiling studies may be particularly informative as it is currently unknown what microbial composition constitutes a “healthy” gut (Dash S et al. Curr Opin Psychiatry. 2015;28:1-6).
In the meantime, with human fecal transplants proposed as a treatment for intractable Clostridium difficile infections (Youngster I et al. JAMA. 2014;312[17]:1772-1778), findings from microbial transplants in rodent models raise the question of whether human fecal donors should be screened not only for pathogens but for a history of psychiatric illness, said Collins.
While the evidence is mounting that the gut microbiome is important in mental health and development, the field is still in its infancy, and there remains healthy skepticism as to whether recent work may have translational potential for treating anxiety and depression in humans.
Dinan pointed out that we need to better understand issues such as which communication routes between gut microbes and the brain are most important in humans, whether a psychiatric phenotype can be transferred with a fecal microbiota transplant, and if probiotics that produce an anxiolytic/antidepressant effects in rodents have the same effect in humans. In particular, experts have noted that there is a clear need for high-quality randomized clinical trials in humans to fully investigate the efficacy of microbiome modulation in improving mental health (Dash S et al. Curr Opin Psychiatry. 2015;28:1-6).
