We tend to think of neurons exclusively as the constituents of our brain. Neurons inside our skulls are part of the Central Nervous System (CNS), which is made up of our brains and spinal cords. But communication occurs between the CNS and the rest of our bodies via the Peripheral Nervous System (PNS). There are an enormous amount of neurons and their projections – axons, packed in bunches called nerves – that perform their works outside of our skulls.
In contrast, the Autonomic Nervous System (ANS), an involuntary division of our PNS, regulates the function of the rest of our vital organs, such as our heart, lungs, and gastrointestinal tracts. Within the ANS lies the enteric plexus, a whole set of neurons dispersed along the entire length of the gut. The enteric neurons secrete neurotransmitters – chemical messengers produced by neurons – to control motility and function of our gastrointestinal tract. In defiance of the image we have of our intestines as something remote and radically different from our brains, it is a fact that we have around five hundred million neurons nested between the layers of our gut, which is why some scientists actually call it “our second brain.”
Our brain talks to our gut
One of the reasons why studying the relationship between the brain and the digestive system became so popular and important is that it represented a paradigm shift in allopathic medicine’s (a type of medicine in which the symptoms produced by the treatment are the opposite of that produced by the disease) dualistic approach of disease. In this view, mind and body are considered independently, and “physical” disorders are considered more real and worthy of medical attention than ‘psychological’ issues. In terms of the gut, this means that digestion problems and abdominal pain are taken care of by a gastroenterologist while anxiety or depression are treated by a psychiatrist or psychotherapist, without any necessary dialogue between these two lines of medical care. Digestive diseases were among the first medical problems to fit into a biopsychosocial model of disease, which considers the complex interrelation between a person’s social environment, their ‘psychological life’ – emotions and thoughts – and their bodies.
When we face a stressful situation, such as being confronted with potential danger, our body reacts by increasing our heartrate, making us sweat, dilating our pupils and pumping more blood into our muscles. This evolutionarily conserved response – sometimes referred to as “fight or flight” response – is orchestrated in the brain and manifested through the “sympathetic” division of the ANS; stressful situations trigger the release of stress hormones and adrenaline, which in turn activate our muscles and other organs to get us ready to react to danger. The counterpart of this “sympathetic” response is not often spoken about: the “parasympathetic” division of the ANS, fundamental for many of the functions of the gastrointestinal system. When a stress response is activated, the balance between sympathetic and parasympathetic function is altered. The enteric system is sensitive to this change, affecting gut sensation, motility, and secretion.
Under these concepts, conditions such as Irritable Bowel Syndrome and some kinds of abdominal pain were recognized as dysregulations of the ‘brain-gut axis.’ The brain-gut axis falls under the control of the ANS, and is a great example of the stress activation response, and its effects on other organs. Therefore, the communication between the brain and the neurons of the enteric plexus – the ‘second brain’ – became one of the first scientifically accepted explanations on how emotional states may affect our digestive system.
Does our gut talk back to our brain?
Acknowledging that our brain communicates with our gut may seem logical now, but it is still a little counterintuitive to accept that the opposite is true: digestive system activity has an effect on mood and cognition. However, in our everyday lives, we use expressions such as “having butterflies in our stomach” to describe what we feel when we are nervous, or a ‘gut feeling’ to speak about instinct or intuition. These expressions are not coincidental. We have all felt the abdominal sensations that accompany certain strong emotional states, as if we could truly feel things with our gut.
The form of communication between two neural structures is often circular, which is why we use the term “neural circuits.” In a neural circuit, information does not flow in only one direction; most nervous structures that send “forward” signals receive feedback information from its target, and the brain-gut axis is no exception. It then makes perfect sense that our enteric plexus can also play a role in ‘higher order’ functions that we thought were exclusive of the CNS, such as cognition and emotion.
In recent years, the focus on the relationship between the brain and the guts has been reversed. There has been a huge spike in research exploring the way the former influences the latter. Local connections between the enteric neurons can function somewhat independently from the CNS, processing information of what is going on inside the gut and responding with reflex activity. But enteric neurons will also send information about the state of the gastrointestinal tract back to the brain, where some of it will reach our consciousness. Interestingly, the focus of this new rise in research is not so much about the neurons in our second brain or the functioning of our intestines themselves, but about a third pivotal angle to understand this interaction: the ecosystem of the bacteria that inhabit our guts.
The Microbiome project
Our bodies are home to trillions of microbes, fundamental for the biological equilibrium of the tissues they inhabit. Throughout our life, every organ in contact with the external environment – our skin, mouth, nose, vagina and respiratory and gastrointestinal tracts – is colonized by different microbes: a few fungi and protists, but mainly numerous bacterial species. Since 2007, the National Institutes of Health (NIH) launched a project to characterize and catalog the microbes in our organisms, leading to a growing body of experiments showing the important roles of these microscopic beings in our overall health.
Understanding the gut as a complex microbial ecosystem is of crucial importance to study the gut-brain axis. Approximately a hundred trillion bacteria live in its distal part. Although some of these bacteria are implicated in pathological processes, the great majority provides health benefits. Besides supplying gut cells with some essential nutrients, gut microbes help us digest and defend against infection, caused by other types of bacteria. The communication between these various bacteria in our gut and the cells of our immune system has also proven essential for maintaining an equilibrium in immunity. The fundamental role of microbiota in our guts and the importance of the gut-brain axis has given biological credibility in an idea that would have been considered absurd in older views of human physiology: that microbes in our guts can influence our mental states.
The evidence for this interaction comes from different lines of animal research. Some researchers have focused on altering the intestinal microbes to observe the impact on the development of the CNS. For example: a research group from the University of Freiburg in Germany studying mice that had been genetically modified, observed a role of intestinal microbes in the maturation of cells in the CNS. Germ-free mice had a bigger amount of microglia, a non-neuronal cell that is responsible for the brain’s immune response. Interestingly, the activity of microglial cells has also been recently linked to mood symptoms in inflammatory diseases such as Multiple Sclerosis (which includes symptoms such as anxiety, irritability, and mood changes). Parallel to this series of studies, other researchers focused on the impact of mice gut microbes on anxiety and depression-like symptoms. A recent review by Jane Foster, a researcher in the Psychiatry Department at McMaster University, summarizes a series of studies in which mice that had been genetically altered to change their microbial flora showed important changes in behaviour. A third approach has been to give probiotics – substances that improve the gut microbes development – to mice with lab-induced models of anxiety and depression, leading to an improvement of symptoms.
However, as interesting as these results are, studies in humans have not been as consistent. Genetic modifications to alter the gut microbiota are not feasible in humans, thus experimental evidence has been limited to the administration of probiotics and the measurement of anxiety and depression symptoms. A 2014 study done by Kristin Schmidt and other researchers in Oxford showed that the administration of probiotics reduced the release of cortisol, a hormone related to stress, but to date few studies have looked at the impact of probiotics on behaviour. Given the scarcity of articles, and the diverse methods of research, we still lack a systematic review of the literature with a sound conclusion on the effect of probiotics on mood symptoms.
We are still far from understanding the whole functioning of the microbiome-gut-brain axis, and therefore it is premature to jump to conclusions of its role in mental health and disease. In circular interactions such as the brain-gut axis, it is hard to distinguish correlation from causation. But the recent increase in evidence from different lines of research on the microbiome-gut-brain axis tells us that it is time to start accepting that our gastrointestinal system function is not merely digesting food. In the same way that we acknowledged that our brain affects the functioning of our gut, it’s time to change another paradigm, and begin to more seriously consider research suggesting that our gut and its microbes can also play a role in the functioning of our brain.