You've probably heard the phrases "go with your gut" when advised on how to make a decision, or felt "sick to your stomach" when nervous about something. Ever wonder why brain processes like decision making and anxiety are linguistically represented in our stomach? My guess is you probably haven't dwelled much on this question, BUT for those who have, read on. The brain and the gut are connected well beyond language.
Bacteria is Boss
"Gut" is another word for the gastrointestinal tract starting with your mouth, winding through your esophagus, stomach, intestines, and colon, and ending with your anus. It's about 30 feet long! When we think about what the gut does, we think of digestion. But the gut (specifically the bacteria in the gut) plays a critical role in many other bodily functions such as immunity, metabolic processes, removal of poisons and toxins, and even gene expression.
It is estimated that the gut has about 100 trillion microbiota...that's approximately 10 times the amount of cells in the entire human body (1).
Gut bacteria is known as microbiota. It's not only comprised of bacteria, but also fungus, viruses, and other cells. Microbiota are found all along the digestive tract. It is estimated that the gut has about 100 trillion microbiota...that's approximately 10 times the amount of cells in the entire human body (1). The composition of this microbiota is established early in life and is unique to each individual. It is influenced by how you were born, the ease or stress of your birth, the environment in which you were raised, and of course, your nutrition (1, 2). However, because it is established early on, does not mean it stays this way for the rest of your life. It is a dynamic environment that can change dramatically with diet, stress, disease, and illness.
The Microbiota Microphone
There is not only one line of communication from the gut to the brain, there are multiple lines of communication. This bacteria boss wants to be heard! The microbiota of the gut communicate to the brain via neural pathways, hormonal signaling, and immune responses.
The microbiota of the gut communicate to the brain neurally primarily via two pathways: the vagus nerve (a cranial nerve) and the autonomic nervous system (our fight or flight and rest & digest system). Both of these pathways are bi-directional, meaning the gut can send signals to the brain, and the brain can send signals to the gut. These lines communicate both directly (gut neurons to brain neurons) and indirectly by synthesizing neurotransmitters such as dopamine (pleasure/reward), GABA (controller of neuronal activity), and serotonin (mood stabilizer), to name a few. In fact, 90-95% of our serotonin is produced in the gut (2). Because of this, a lot of psychology research is looking at the effect of diet and nutrition on mood disorders.
The gut and the brain also communicate with each other via the hypothalamic-pituitary-adrenal (HPA) axis originating in the brain. The HPA axis is responsible for our body's management of stress. When stress, or a disruption to homeostasis, is sensed anywhere in the body, the HPA axis is activated and cortisol is released. The point at which one's HPA axis is activated is termed the set point. It is the threshold for when your fight-flight stress alarm goes off. This set point is unique to each person and depends on multiple physical and psychological factors, such as history of chronic pain, depression/anxiety, and... gut health. Animal models have shown that germ free mice, or mice without microbiota, have a lower HPA axis set point, meaning their stress response is activated more easily. When probiotics are introduced to these same mice, their HPA axis set point, and thus their body's response to stress, is normalized (1, 3).
The gut has the largest concentration of immune cells in the body that are in constant communication with microbiota, both directly through physical contact, and indirectly through secretion of molecules through the gut lining (3). A key purpose of this communication is for the gut microbiota to signal to immune cells when a harmful pathogen is present and to launch an immune response. Microglia cells in the brain are responsible for launching this immune response when there is infection (like meningitis) or trauma (as in a concussion). Animal studies have show that these brain microglia fail to properly develop and diversify in germ free or antibiotic-treated mice (or mice without diverse microbiota), and even more interestingly, show that these effects can be reversed after 6-weeks of recolonization of gut microbiota (3).
It's a 2-way street
Research has shown multiple genetic, environmental, and situational factors that influence the gut-brain axis (in blue) (3). In turn, the gut-brain axis influences many physical, cognitive, social, and emotional aspects of our lives (in red) (3). Expand each topic below to learn more.
How behavior and environment affect our gut-brain axis
Diet seems like the most obvious impact on the gut-brain axis and that's because it is one of the most influential factors on gut microbiota. Western diets rich in sugar, salt, and fat have been shown to contribute to metabolic disorders (i.e. diabetes), obesity, and systemic inflammation (3). Animal studies have shown that even artificial sweeteners negatively impact gut microbiota (2). A mediterranean diet is considered rich in anti-inflammatories and research has shown it to reduce the incidence of neurological disease, cardiovascular disease, depression, and cancer (3). Ketogenic diets have been show to not only reduce the progression of neurological diseases, but also have a neuroprotective function, reducing symptoms of neurological conditions such as Alzheimer's and Parkinson's (3). It is also noted that consuming 4-6 servings of fermented foods like kimchi, kefir, or sauerkraut, throughout your day significantly increases gut microbiota diversity (2).
Genetics and Epigenetics
While research in this area is still growing, a number of animal studies have shown the diversity of gut microbiota to have an effect on micro-RNAs (miRNAs), a branch of non-coding RNA responsible for gene expression. Mice without diverse microbiota have shown decreased levels of miRNA in the amygdala (our brain's emotional center), the pre-frontal cortex (our brain's cognitive center), and the hippocampus (our brain's memory and learning center). Once again, when these mice were recolonized with diverse microbiota, their miRNA levels returned to normal (3).
Mode of delivery
Our initial microbiota is established as we pass through the vaginal canal and come into contact with our mother's vaginal microbiota. Babies born cesarian who miss this exposure get their initial exposure through skin-to-skin contact; however, there is decreased microbiota diversity (2, 3).
Environmental exposures to heavy metals, BPA found in plastics, and increased concentrations of antibiotics in rivers, lakes, soils...and thus food, produce a significant disruption on gut microbiota.
If diet has such a profound affect on our gut microbiota, it is not surprising that drugs we ingest would also impact our gut. The most obvious of these are antibiotics, and in fact, many animal studies use antibiotics to study the impact of poor microbiota diversity on health. But other drugs have also shown to impact microbiota diversity, including: laxatives, medication treating Irritable Bowel Disease, female hormones, benzodiazepines (used to treat anxiety), anti-depressants, anti-histamines (an example is Meclizine, commonly used to treat vertigo), proton-pump inhibitors to treat acid reflux, metformin (treating diabetes), and statins for cholesterol.
Routine exercises had been shown to have numerous health benefits, but specific to this topic, is particularly beneficial to brain health. Exercise has been shown to reduce the rate of hippocampal neuro-degeneration responsible for Alzheimer's, reduce stress (think HPA axis), and build immunity (3). While we are just beginning to understand the effects of exercise on the gut, it is reasonable to think there is some impact as exercise influences not only the brain directly, but two key communication pathways (HPA axis and immune response) between the brain and the gut.
How our gut-brain axis affects our behavior
Two mechanisms by which gut microbiota influence food intake are cravings and sensitivity to taste. One proposition is that the more microbiota diversity in your gut, the more competition among microbes. Because of this competitive environment, your gut signals to your brain to seek out, or crave, nutrients which support a particular microbe, thereby maintaining healthy gut microbiota diversity. The less microbiota diversity, the less competition, and thus less craving for nutritionally rich foods. In addition to this, multiple studies have shown that microbiota influence one's sensitivity to taste. Obesity, for example, has been associated with decreased sensitivity to sweet and fatty tastes, thus requiring more intensely sweet or fatty foods in order to perceive that taste (3).
Animal studies have consistently shown the effects of gut microbiota on the hippocampus, influencing memory and learning. After a short bout of antibiotics, mice have impaired object recognition memory and working memory. After long-term use of antibiotics, mice have impaired spatial memory. Conversely, various pre- and pro-biotic treatments aimed at increasing microbiota diversity in mice have shown to improve object recognition, spatial memory, and cognitive flexibility (3).
Given the aforementioned effect gut microbiota have on the HPA axis (our body's stress management system), current research is investigating how alterations in the gut microbiome affect one's resilience to stress. Evidence in both animal and human studies have shown administration of various probiotics to to assist with cognitive function during stressful periods, reduced stress-related anxiety and depression, prevention of a hyperactive HPA axis during acute stress, decreased cortisol levels, and decreased stress-induced GI issues and head colds (3).
Multiple animal studies have shown germ-free mice to be less likely to interact with unfamiliar mice, tending to interact only with familiar mice. Mice with diverse microbiota, on the other hand, interact more frequently with non-familiar mice. The mechanism of this is not clearly understood; however, studies suggest this is due to increased neuronal activity in the amygdala (our brain's fear center) in germ-free mice (3).
Our fear response is largely regulated by the amygdala and hippocampus, and an exaggerated fear response is a core feature of anxiety. Emerging evidence in human studies has shown increased microbiota diversity was associated with a reduced fear response and reaction to negative emotional images (3). In animal studies, mice learned to pair a conditioned stimulus (a tone) with an unconditioned stimulus (an electric shock). When the unconditioned stimulus was removed, mice with poor microbiota diversity had a harder time learning that the conditioned stimulus would not result in a shock, and continued to demonstrate an exaggerated fear response. In contrast, mice with healthy microbiota diversity were able to learn that the conditioned stimulus (the tone) would not produce an electric shock, and therefore did not demonstrate an exaggerated fear response (3).
"You are what you eat."
It's no wonder our language has developed multiple idioms and expressions linking the gut to our brain and behavior. And while research has made huge strides in verifying this connection, we still have a lot to learn about the intricacies of the gut-brain relationship. While I am not a nutritionist or dietician, I always ask my patients about their diet. I often encourage many of my patients with chronic post-concussive symptoms, to consult their doctors, naturopaths, or dietitians for recommendations on anti-inflammatory diets that can assist in managing their symptoms. Sometimes, the smallest changes in diet can have huge impacts on brain health and healing.
Wang HX, Wang YP. Gut Microbiota-brain Axis. Chin Med J (Engl). 2016;129(19):2373-2380.
Huberman A. Huberman Lab. How to Enhance Your Gut Microbiome for Brain & Overall Health. 2022. Accessed April 23, 2022. https://hubermanlab.com/how-to-enhance-your-gut-microbiome-for-brain-and-overall-health/.
Cryan JF, O’Riordan KJ, Cowan CSM, et al. The Microbiota-Gut-Brain Axis. Physiological Reviews. 2019;99(4):1877-2013.