Unraveling the Influence of Gut Microbes on the Mind

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JAMA

May 5, 2015, Vol 313, No. 17 

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

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?

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).

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