Everyone has had a “gut feeling”—some liken it to “butterflies” in the stomach before a stressful event, while others deem it a type of intuition—and scientists are bringing this age-old phenomenon into the present-day lab in order to better understand how mental health disorders arise and how they might be treated better.
Studies borne out of the Human Microbiome Project (HMP) have begun to tease out the role the human gut microbiome plays in the development of a host of diseases, including mental health disorders like anxiety and depression, autism spectrum disorders, and schizophrenia. While millions of Americans live with a mental health disorder, treatment is often partial at best, ineffective at worst. Understanding what causes these diseases in order to find more effective treatments is a top priority for researchers, doctors, and patients alike.
Begun in 2008, the HMP is a United States NIH-sponsored, nationwide endeavor to categorize the trillions of microbes that live on and in the human body. Made possible by advances in next-generation sequencing technologies, metagenomics has allowed researchers to sequence the bacterial strains that make their home in our mouths, noses, skin, guts, and private parts. It turns out that bacterial cells are 10 times more prevalent than our own bodily cells, and that there are 100 times more bacterial genes than human genes.1,2,3
Gastroenterologists have known for decades that the gut microbiome plays a large role in maintaining our bodily functions through its secretions and metabolites, mainly via immune signaling, endocrine signaling, and the enteric nervous system— neurotransmitters produced by gut bacteria.4 This cross-talk between gut and brain takes place through the vagus nerve, a cranial nerve that conducts a long and winding path from the brain to many different organs, including the gut. This system enables the parasympathetic nervous system to maintain homeostasis.
In the past 10 years, a growing number of preclinical (mice) studies have demonstrated that “bidirectional signaling” between the brain and the gut microbiome can actually affect the brain’s neurochemistry and subsequently, our emotions and behavior. To be sure, it’s a paradigm shift in neuroscience, and some believe it will change the way psychiatrists ultimately treat mental health disorders, says Dr. John Cryan, a leading researcher in the field. Disorders once believed to be conditions of the brain might actually be linked to—maybe even exacerbated by—an imbalance in the microbial community of the gut.
“We’ve known for a long time that the gut-brain axis is very important for regulating homeostasis,” Cryan, a neuroscientist at the University College Cork in Ireland, says. So, why wouldn’t it be possible for the gut microbiome to influence neurochemistry? While “psychobiotics,” a term coined by Cryan and Dr. Ted Dinan,5 “is still very much [in] its infancy,” Cryan believes it will have an impact on how psychiatrists treat these diseases in the future. Psychobiotics harness the idea that when administered in the right amount, certain bacteria that normally colonize the gut will have a positive effect on mental health, he says. “You look at the last time you had food poisoning, you felt malaise. All of the symptoms apply in mood disorders like depression, all the same physical symptoms are analogous—and that’s driven by bacteria.”
The blood–brain barrier (BBB) separates the blood circulating throughout the body from the brain, allowing only certain molecules to cross. While more studies are showing a link between the presence of certain bacteria and altered gene expression in the brain, the mechanisms are still unknown. In other words, we don’t know yet how gut bacteria communicate with the brain. Is it directly through metabolites that cross the BBB? Through downstream signaling? Both?
Bidirectional signaling, says Dr. Christopher Lowry, an associate professor in the Department of Integrative Physiology at the University of Colorado Boulder, means that the “brain can influence the gut microbiota, and that, conversely, the gut microbiota can influence the brain.” Gut microbiota secrete neuroactive metabolites, including the neurotransmitters dopamine, serotonin, and gamma-aminobutyric acid, or GABA. These microbes also release molecules that can change neurochemistry. Additionally, they can cause localized inflammation, whereby immune cells release immune signaling molecules—another way to alter downstream signaling and host immunity. “These immune signaling molecules can then alter brain function, either through influence on sensory nerves, or through accessing the brain directly,” Lowry says.
Mental health and gut microbes
Up until recently, the vagus nerve was known only as the “parasympathetic highway.” However, more studies are showing a link between an altered microbial community and changes in mental health, like anxiety and depression. While it has been known for a long time that a large proportion of our neurotransmitters like dopamine and serotonin are created in the intestines, neuroscientists are just beginning to learn how our microbiota actually use these molecules to communicate with the brain.
Cryan’s groundbreaking paper appearing in PNAS in 2011 showed that indeed, there was bidirectional signaling between the gut and the brain via the vagus nerve that could lead to changes in mental health. 6 In the animal study, he and his collaborators showed that chronic treatment with Lactobacillus rhamnosus (bacteria normally found in the gut) caused changes in GABA expression in the brain compared to control mice. GABA acts as a major inhibitory, or calming, neurotransmitter. L. rhamnosus, they found, “reduced stress-induced corticosterone and anxiety- and depression-related behavior” in the mice. Importantly, the behavioral effects were absent in mice whose vagus nerve had been cut.
The four main types of bacteria found in the gut are Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. While we can survive without these species, they all play an important role in metabolizing our food, establishing and promoting immunity, protecting against harmful, or pathogenic microbes, and producing numerous molecules, including vitamins and hormones. L. rhamnosus is one of several strains of bacteria normally found in the gut and being tested as a probiotic—a bacterial strain that might help promote healing by rebalancing the gut bacterial community.
Accumulating evidence is showing that stress changes the microbiome.4 “A well-replicated effect is that stress exposure decreases the diversity of the gut microbiota,” Lowry says. This decreased diversity allows pathogenic microorganisms “an opportunity to get a foothold in the gut and potentially cause disease.”
A seminal paper from 2004 observed that germ-free mice—those bred to not have a natural microbiome—showed an exaggerated hypothalamic-pituitary-adrenal stress response, and that this could be reversed by colonizing their guts with Bifidobacterium infantis (normally found in the gut).7 Recent work has shown reductions in anxiety-like behavior when germ-free mice are re-colonized with a normal microbiota. However, the mice had to be colonized early in life—what would equate to early life through adolescence in humans—for it to work.8
Child development; Autism
Early life events can have a major impact on the developing gut. These events can include exposure to antibiotics, whether a baby is born vaginally or by cesarean section, and if a baby is breastfed. However, stress might be the biggest factor of all, Cryan says. In 2009 Cryan showed that early life stress in male rats led to a host of changes, including those of the fecal microbiota,9 which, in his words, could have an impact on future stress-related disorders like depression and irritable bowel syndrome. Dr. Tracy Bale, a neuroscientist at of the University of Pennsylvania, published a recent study in the journal Endocrinology implicating a mother’s stress level on an altered microbiome in her offspring.10 Bale used mice to find that when mothers were exposed to stress during pregnancy, their pups’ levels of Lactobacillus bacteria were lowered. Male pups showed an increase in the anaerobic bacteria Clostridium and Bacteroidesin.
“The bacteria interact with the very immature gut environment—it’s not that they just reside, they are participating in how that gut is developing,” Bale says. “As an adult, if you have an unhealthy gut microbiome—nutrient metabolism, absorption, immunity, vagal feedback—all those things can affect the brain.”
The gut microbiome may also play a role in autism spectrum disorders. A recent study out of microbiologist Dr. Sarkis Mazmanian’s lab at Caltech showed that a strain of bacteria given early in life could reverse autism-like symptoms and behavior in mice.11 In trying to understand how the microbiome affects mouse models of autism, his lab used mice that had been infected with a virus to activate their immune system. In this maternal immune activation (MIA) model, MIA offspring showed different metabolites in their blood as well as autism-like features and behaviors, and, by giving the pups Bacteroides fragilis, these behaviors could be changed. “We suspect this outcome may be due to the bidirectional cross-talk between the gut and the brain,” Mazmanain, whose work focuses on the role that microbial metabolites play, says. “Further, we have discovered, among other things, that gut bacteria produce molecules that “leak” out of the intestine and into the circulation, and that specific microbial molecules affect higher order neurological functions such as complex behaviors, including anxiety.”
Treatment of psychiatric diseases and future focus
While “easily translatable” to humans, Penn’s Bale says, current research in rodents shouldn’t be interpreted beyond improving our understanding of the mechanism behind gut-brain communication. Still, there is much excitement about leveraging this cross-talk to our benefit—especially toward improving treatments for a variety of diseases.
“We can expect that, in the future, we may be able to manage the gut microbiota to optimize health outcomes, not only in adults, but [in] developing fetuses and children,” Lowry says. The American Gut Project, for instance, is a current population-based study that is “increasing our knowledge of what a “healthy” gut microbiome looks like.”12
Bifidobacterium and Lactobacillus are the main bacteria that show beneficial effects on anxiety- and depression-like behavior.5 However, only a few strains have any positive effect at all. “The core point is, we need to understand why some bacteria are having a positive effect and some are not, and the vast majority will have no effect at all,” Cryan says. Being able to “selectively modify mood by targeting the microbiome” is a lofty goal, especially since mental health diseases are a “whole body disorder,” he says. “Where it might fit in is understanding how the body responds to stress,” which plays an essential role in anxiety, depression, chronic pain, and immune-related diseases, like inflammatory bowel disease, multiple sclerosis, and even Parkinson’s disease and Alzheimer’s disease.
Some studies have shown improved cognition and mood using antibiotics and probiotics to treat specific conditions,4 but much more work needs to be done to elucidate the extent of their action on the gut-brain axis in human subjects. “There’s a lot that has to be done before we can say your bacteria are the solution to mental health,” Bale says.
- 1. NIH Human Microbiome Project http://hmpdacc.org/overview/highlights.php
- 2. The Human Microbiome Project Consortium (2012) Structure, function and diversity of the healthy human microbiome. Nature 486(7402):207-214. doi: 10.1038/nature11234
- 3. The Human Microbiome Project Consortium (2012) A framework for human microbiome research. Nature 486(7402):215-221. doi: 10.1038/nature11209
- 4. Tillisch K et al. (2014) Gut Microbes and the Brain: Paradigm Shift in Neuroscience. Journal of Neuroscience 34(46):15490-15496. doi: 10.1523/JNEUROSCI.3299-14.2014
- 5. Dinan TG, Stanton C, Cryan JF (2013) Psychobiotics: a novel class of psychotropic. Biological Psychiatry 74(10):720-726. doi: 10.1016/j.biopsych.2013.05.001
- 6. Cryan JF et al. (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences 108(38):16050-16055. doi: 10.1073/pnas.1102999108
- 7. Koga Y et al. (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. Journal of Physiology 558(Pt 1):263-275. doi: 10.1113/jphysiol.2004.063388
- 8. Cryan JF et al. (2013) The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Molecular Psychiatry 18(6):666-673. doi: 10.1038/mp.2012.77
- 9. Dinan TG et al. (2009) Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biological Psychiatry 65(3):263-267. doi: 10.1016/j.biopsych.2008.06.026
- 10. Bale TL et al. (2015) Alterations in the Vaginal Microbiome by Maternal Stress Are Associated With Metabolic Reprogramming of the Offspring Gut and Brain. Endocrinology 156(9):3265-3276. doi: 10.1210/en.2015-1177
- 11. Mazmanian SK et al. (2013) Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155(7):1451-1463. doi: 10.1016/j.cell.2013.11.024
- 12. Human Food Project http://humanfoodproject.com/americangut/