Microbes and the mind: Who's pulling the strings?

There are many examples throughout nature of microorganisms like bacteria, viruses, and parasites influencing the neurobiology and behavior of their hosts. For example, the rabies virus enters the nervous system almost immediately after a bite or scratch and travels to the brain, where it influences neural activity to make aggressive behavior more likely. This, of course, is beneficial for the virus as it increases the probability its infected host will make contact with another susceptible host, in effect improving the likelihood the viral strain will be able to propagate. Another well-known example involves the parasite Toxoplasma gondii, which needs to live in its preferred environment of feline intestines to survive and reproduce. When T. gondii embryos are excreted in the feces of cats, they are consumed by rodents (who are wont to dig through cat feces looking for pieces of undigested food). It is thought that T. gondii then has a mechanism by which it can influence rodent behavior to make rats and mice less afraid of--and perhaps even attracted to--cat urine. The loss of inhibitions regarding the smell of their natural predator's urine causes rodents to be more likely to remain in the vicinity of cats, and thus be consumed by cats. This puts T. gondii right back in its preferred feline intestinal environment, giving the impression that the whole process may have been elegantly orchestrated by the microbial parasite.

Despite the existence of these natural cases of "microbial mind control," it is only very recently that neuroscientists have begun to take the idea seriously that microorganisms may also have an influence on human behavior. With recent advances in research technologies, however, we have learned more about the microorganism populations that inhabit our bodies, and their potential influence on our behavior--although not yet understood--is becoming difficult to dismiss. The gastrointestinal tract has received the most attention in this regard, as it has the most extensive bacterial colonization of any area in the human body. Thus, the gut has become a new target in attempts to understand behaviors ranging from eating, to stress, to disorders like autism.

The gut-brain axis

Researchers have long been aware of a powerful connection between the gut, or gastrointestinal tract, and the brain; it was already clear to 19th and early 20th century scientists like Charles Darwin, William James, and Walter Cannon that strong emotions influenced the functioning of the gastrointestinal system. Near the beginning of the 20th century, it became recognized that the gut is governed by a complex nervous system structure that we now know consists of hundreds of millions of neurons and can operate autonomously (without input from the central nervous system). This neuronal structure, dubbed the enteric nervous system, which can be found in the walls of the gastrointestinal tract from the esophagus to anus, is now considered another branch of the autonomic nervous system (although it is sometimes called our "second brain" due to its complexity and similarities with the brain of the central nervous system). The connections between the brain and the enteric nervous system are extensive; the two can communicate through neuronal, endocrine, and immune system signaling.

The gut microbiota

In addition to having its own nervous system, the gut is also home to up to 100 trillion microorganisms. This number includes over 1,000 different species of microbes, the vast majority of which are bacteria. Together, these microorganisms are thought to outnumber the cells in our body by more than 10 times (which has led writer Michael Pollan to describe us as only 10% human), and they possess about 150 times the number of genes found in our genome. As a whole, gut microorganisms make up the majority of our microbiota, the collection of microorganisms we share our bodies with.

Our resident microorganisms are not just passive roommates, either; they play significant roles in widespread physiological functions. For example, they are likely involved in nutrient absorption, fat storage, and the function and development of a healthy immune system. In fact, it seems like we have what is known as a mutualistic relationship with these microbes, wherein both species (us and the microbes) benefit from our proximity. The microorganisms in our gut are able to dwell in an environment where they can survive and reproduce, and in return they perform a number of functions that promote our own health and viability. 

On the other hand, one could argue that we are simply--as microbiologist Justin Sonnenburg puts it--"an elaborate vessel optimized for the growth and spread of our microbial inhabitants." According to this perspective, it is the microorganisms that are manipulating the evolution and behavior of their host in order to achieve their maximum level of fitness. For example, some researchers believe that, in order to obtain the nutrients they desire, microbes have developed ways of shaping our appetites to make us crave the types of food that will supply those nutrients. But this is just the tip of the iceberg, as the gut microbiota is now being explored as a potential driver of a wide array of human behavior and as an underlying cause in a number of mental disorders.

Gut microbiota and behavior

The range of mechanisms by which gut microbiota may be able to influence human behavior is likely very complex and not yet fully understood, but there are several aspects of gut-brain communication that have been identified as potential drivers of behavior. Some of these are fairly direct. For example, the vagus nerve travels down from the brainstem to innervate the internal organs of the body and provides extensive innervation to the gastrointestinal tract. It represents the most direct connection between the gut and the brain, and studies have found that stimulation of the vagus nerve by microorganisms is associated with changes in behavior, brain function, and neurotransmitter receptor levels in the brain.

Additionally, most of the neurotransmitters found in the brain are also found in the gut at equivalent or greater levels. These neurotransmitters are capable of stimulating the vagus nerve to affect central nervous system function, and the amount of neurotransmitter present in the gut is influenced by the activity of gut microbiota. For example, the vast majority of serotonin in the body is produced in the gut, and its production is regulated by microbial activity there. Additionally, gut microbes are involved in the production of neurotransmitter precursors, which can then cross the blood-brain barrier to affect neurotransmitter synthesis in the brain. Gut microbiota, for example, are involved in the synthesis of tryptophan, the precursor to serotonin. After it is produced, tryptophan can cross the blood-brain barrier to affect serotonin production in the brain.

The influence of gut microbiota on behavior can also be more indirect. For example, gut microbes can affect the activity of the immune system, and alterations in immune system function can impact behavior. A well-known example of the immune system's ability to influence behavior involves sickness behaviors. Sickness behaviors are thought to be an adaptive response to infection; they include things like decreased movement, loss of appetite, increased sleep, and decreased social interaction. A reduction in these otherwise common behaviors is thought to allow for energy conservation and a reduction in the risk of exposure to additional pathogens. One way these behaviors can be initiated is when microorganisms in the gut activate immune system cells, which then send signaling molecules called cytokines to the brain, leading to a modification of one's typical actions.

Clinical relevance of the gut microbiome

At this point, most of the investigative work on the relationship between the gut microbiota and behavior has involved experimental animals like rodents. Although the translation of results from animal models to humans is often problematic, the findings of these studies are intriguing and support the hypothesis that gut microbiota can affect more than just digestion. One approach to investigating this hypothesis has been to raise rodents in a sterile, germ-free environment, and then to compare their behavior with rodents raised in a typical environment. Because the microorganismic colonization of the gastrointestinal tract occurs after birth, rodents raised in germ-free environments never develop the diverse gut microbiota that normal animals do. Interestingly, their behavior is also very different. Germ-free animals display differences in cognition, responses to stress, and neurotransmitter levels, among other things.

The results of these studies are intriguing, but we cannot assume the same phenomena occur in humans until human experiments return similar findings. However, although the majority of the work in this area has been done with rodents, there are some findings with humans that suggest the gut microbiome is also influencing our behavior. One approach to exploring gut microbiota function in humans involves the administration of probiotics, which are microorganisms like certain bacterial strains that are thought to have a beneficial effect when ingested. Some believe particular probiotic formulations can be beneficial to the health of the gastrointestinal tract by replenishing levels of microorganisms that are important to normal gut function.

Because probiotics are capable of modifying the microbiotic composition of the gastrointestinal tract, several experiments have involved the administration of probiotics to humans followed by the monitoring of behavior. For example, in one placebo-controlled clinical trial, patients who received a multi-bacterial probiotic formulation had lower levels of self-reported depression and anxiety symptoms than patients who received placebos. Participants receiving probiotics also had lower urinary levels of the stress hormone cortisol, which supports a growing body of evidence linking the composition of the gut microbiota to stress reactivity and the function of the hypothalamic-pituitary-adrenal (HPA) axis. In another randomized controlled trial, participants who received a probiotic formulation displayed less depressive rumination, fewer aggressive thoughts, and reduced reactivity to sad moods. A 2012 study went a step further and used neuroimaging to explore how probiotics might be influencing brain activity to produce these types of results. The investigators found that participants who were given probiotics displayed less activity in the insula (an area of the brain involved in emotional responses) during an emotional reactivity test.

These findings that repeatedly link the gut microbiota to the central nervous system and behavior have sparked a great deal of interest in the hypothesis that gut microbiota may be involved in a variety of central nervous system-related conditions. One logical area of study, for example, is the role of the gut microbiome in obesity. As mentioned above, it is believed the gut microbiome is capable of manipulating eating behavior in order to obtain the nutrients its microorganisms desire. Interestingly, differences in the makeup of the gut microbiome exist between lean and obese individuals. Additionally, rodents raised in germ-free environments are more resistant to obesity, even when fed a high-fat diet. And, some studies have suggested that probiotic supplementation may aid in weight loss attempts and reduce abdominal fat deposition.

Research, however, has also begun to implicate the gut microbiota in disorders that are less clearly connected with the gastrointestinal tract. For example, due in part to the gastrointestinal symptoms often reported in children with autism spectrum disorders (ASDs), the makeup of the gut microbiome has been hypothesized to play a role in the disorder. Although the studies in this area are still preliminary, some have detected differences in the makeup of the gut microbiota in autistic versus control patients. Additionally, autistic-like behavior has been elicited in rodents after the administration of propionic acid, which is a byproduct of bacterial metabolism in the gut. These types of findings need to be explored further, but they raise intriguing questions about the development of a complex neurological disorder.

The gut microbiota is also being explored as a contributing factor in a number of other disorders ranging from multiple sclerosis to schizophrenia. Still, however, it seems as if we are just scratching the surface when it comes to explorations of the influence of microorganisms on human behavior. It would not be a surprise to many researchers in this area if, over the next couple of decades, we discover that the microorganismic residents of our body are exerting a powerful effect over many of the choices we believe we are making solely with our own free will. And perhaps that would strengthen the argument of the biological determinist--if not only is our behavior controlled by our genetics and our neurobiology, but also by the microscopic residents of our bodies.

Cryan, J., & Dinan, T. (2012). Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour Nature Reviews Neuroscience, 13 (10), 701-712 DOI: 10.1038/nrn3346