The Gut-Brain Axis: Can Your Belly Heal Your Brain?
Hannah Daley
Illustrations by: Amelia Zeh
Have you ever felt “butterflies in your stomach?” Had a “gut-wrenching” experience? Went with your “gut feeling?” These expressions are used for a reason: the gut and the brain are intimately connected. Though a gut-brain link was suspected as early as the eighteenth century, research on the subject has exploded within the past decade. In fact, recent studies have shown that mental health and gut health affect each other. This information suggests that a novel approach may be possible for treating mental illness and gastrointestinal disorders by focusing on the disconnect between the systems. Probiotics, lifestyle changes, and psychological therapy are a few methods that have exciting potential to revolutionize clinical treatments for both types of disorders.
The connection between the gut and the brain, termed the “gut-brain axis” (GBA), is defined as the link between the central and enteric nervous systems [1]. The central nervous system (CNS) refers to the brain and spinal cord, while the enteric nervous system (ENS) refers to the neurons that govern intestinal function. Therefore, the emotional, behavioral, and cognitive centers of the brain communicate bidirectionally with the stomach. The ENS is often forgotten about during discussion of important branches of the nervous system, but it is vitally important in maintaining proper human functioning. Notably, the ENS is the largest division of the peripheral nervous system, containing all of the neurons outside of the central nervous system and 100 million neurons in the small intestine alone [2]. ENS neurons function largely in detecting the physiological condition of the gut and determining a remedial response. Due to its enormous number of neurons and autonomy, the ENS has been nicknamed the “second brain.”
The GBA not only incorporates the gut and the brain, but it also receives input from the endocrine system, immune system, and perhaps, most importantly, the gut microbiota [3]. The endocrine system is a chemical messenger network, using hormones to send messages to different organs throughout the body. One of the main networks of the endocrine system is called the HPA axis (hypothalamus-pituitary-adrenal gland). The HPA axis contains the main brain structures that are responsible for the body’s response to environmental stress. When organisms are exposed to environmental stimuli, the HPA axis evaluates if a stress response is necessary [4]. The adrenal gland is responsible for the famous “fight-or-flight” response through its release of the body’s principal stress hormone: cortisol. Hence, depressive episodes are associated with a dysregulated HPA axis and high cortisol levels, while the resolution of depressive symptoms is associated with a normalized HPA axis [5]. Additionally, depressed individuals lack chemical regulators to suppress the abnormally high HPA response [6]. In other words, those with depression experience an exaggerated response to everyday stressors and have problems mitigating this response.
The HPA axis is also closely connected to gut microbiota, the naturally occurring bacteria that colonizes the intestines, revealing another way that the two systems interact. Studies show that germ-free mice (mice lacking any gut bacteria) have an exaggerated response to stress compared to specific-pathogen-free mice, suggesting that microbes have an observable effect on the stress response. Additionally, microbiota produce metabolites (products produced through its natural metabolic processes) that have been shown to alter nutrient availability, thus affecting the release of biologically significant proteins in the gut. One of the most important metabolites involved in the gut-brain axis, short-chain fatty acids (SCFAs), are fatty acids that have less than six carbon atoms. Gut microbes produce them by digesting dietary carbohydrates and fibers. SCFAs maintain stomach lining integrity, regulate mucus production, and protect against inflammation [3]. Additionally, SCFAs are able to cross the blood-brain-barrier (BBB) and impact the biological processes within the brain itself. The BBB is a highly selective, semipermeable membrane that prevents solutes in the blood from entering the brain. The BBB protects brain tissue by blocking potentially toxic molecules from entering the brain. Once SCFAs cross this barrier, they are involved in regulating the brain’s waste management system. The cells responsible for this process, called microglia, are important for proper brain development, the health of the brain tissue, and behavioral modulation. Microglia are like the immune system cells of the brain, protecting it against pathogens and other dangers, further supporting their importance.
Interestingly, disruptions in short chain fatty acid metabolism have been linked to the development of autism spectrum disorder due to the improper functioning of microglia [7]. This metabolism is important because it provides energy and nutrients for cells in the gastrointestinal tract. The administration of excess propionic acid (PPA) in the brain has been shown to produce autism-like symptoms in adult rats. PPA is a short chain fatty acid that is used as a food preservative in refined wheat and dairy products. PPA is also known to cause many of the gastrointestinal distress symptoms experienced by autism patients, such as decreased efficiency of digestion, intestinal muscle pain, and increased concentration of certain neurotransmitters responsible for pain. Thus, it is possible that PPA is an environmental risk factor for the development of autism. Several studies have shown that eliminating certain dietary components, such as gluten and casein (a protein found in dairy products), can relieve symptoms of autism, further indicating that the gut may be involved in its onset [8]. Though there is clear evidence of a strong genetic basis of autism, this research suggests a possible environmental, diet-based component as well.
The GBA is also highly connected to the immune system. The immune system is important because it is the body’s way of protecting itself from harmful pathogens that could cause disease. When a foreign particle enters the body, the immune system is supposed to activate in order to destroy it. Gut microbiota modulate the release of cytokine, which is the primary signaling molecule of the immune system [9]. Abnormal gut microbiota populations can activate an immune response in the stomach, altering the permeability of the intestinal lining [3]. The contents of the stomach are very acidic, and can have damaging effects if they are released into the bloodstream and spread throughout the body. This phenomenon, known as the “leaky gut,” causes low level chronic inflammation that is present in a variety of health problems [10, 11].
Not only is the gut microbiome a part of many gut-brain axis mechanisms, but it also is necessary for proper development and maturation of the CNS and ENS [1]. In fact, the absence of gut bacteria in animal models is associated with chemical changes in the brain and problems in gut motor function in digestion. Additionally, the absence of gut microbes is associated with a dysregulated HPA axis, decreased serotonin (one of the main mood regulating neurotransmitters) production, and memory deficits. The decrease in serotonin production is especially important, because the gut is responsible for the production of approximately 95% of it in the body [12]. In other words, without bacterial colonization in the gut early in life, the brain will have problems communicating with the rest of the body, potentially resulting in intestinal distress and/or mental illness.
How do these biological connections relate to specific illnesses and diseases? Irritable bowel syndrome (IBS), a prevalent yet misunderstood GI disease, is now beginning to be recognized as a gut-brain axis disconnection. IBS is an intestinal disorder that causes stomach pain, gas, diarrhea, and constipation, among other symptoms. It is so common that approximately 50% of GI complaints to general practitioners are because of IBS [13]. As there is no treatment or cure for IBS, the current solution is limited to alleviating symptoms. However, multiple studies have shown that IBS patients have abnormal gut microbiome profiles, indicating that gut bacteria plays a role in the development of the disease. Furthermore, IBS, depression, and anxiety have high rates of co-occurrence, suggesting bidirectional communication between the brain and the gut [13]. Due to this comorbidity, current research is focusing on treating depression, anxiety, and IBS simultaneously. For example, it has been shown that using cognitive behavioral therapy, a common psychotherapy technique for depression, can help eliminate symptoms of IBS [14].
One study used germ-free and control group rats to test the differences in HPA axis responses to stressful situations [15]. Researchers found that the germ-free rats displayed more anxiety-like behaviors and had higher concentrations of cortisol, the primary stress hormone, in their blood serum following the stress test. Additionally, germ-free rats had less dopaminergic turnover in certain areas of the brain, meaning that the neurotransmitter dopamine could not be utilized by the neurons. Dopamine is the main mood regulating neurotransmitter, so its unavailability can cause anxiety-like behaviors. This study suggests a direct correlation between the presence of gut microbes and anxiety by showing that animals lacking gut bacteria have a more active HPA axis during stressful situations.
Another mental disorder that has GBA implications is bipolar disorder. Bipolar disorder (BD) is characterized by episodes of mood swings, ranging from depressive lows to manic highs. BD is also associated with severe cognitive dysfunction and social impairment [16]. One study aimed to characterize gut microbiota in depressed BD patients before and after BD treatment, and to study microbiota’s association with depressive severity. The study found that although quetiapine treatment did not affect gut microbiota, BD patients had very different gut microbiota species and less SCFA producing bacteria than controls. This study shows that BD patients can potentially be distinguished from healthy individuals by gut microbiota, introducing a potential diagnostic tool.
To return to the importance of the GBA in the development of autism, one study aimed to transplant gut bacteria from autism patients into germ-free mice to observe if more autism-like behavior occurred compared to a control group that received bacteria from typically developing children. When researchers examined the contents of the gut samples before the transplant, they found that the samples from autistic patients differed in their diversity and the type of metabolites being produced. After the transplant, they found that the mice with donations from autistic patients developed autism-like behaviors compared to the control group. The authors propose that gut microbiota regulate ASD behaviors via the production of chemicals that alter behavior [17]. These findings suggest that there is potential for new treatments of ASD that include diet and supplement interventions with the goal of repopulating the gut with normal species.
Since recent studies have shown that those with various mental health disorders have different makeups of their gut bacteria, it may be possible to implement new treatment methods that target these differences. Research has begun to investigate how specific diets and supplementation can alleviate symptoms of mental health disorders. For example, consuming a Western diet with high levels of fats, salt, sugar, and processed foods has a clear association with decreased gut microbiota diversity [18]. Western diets are also associated with an abundance of a specific species of bacteria that is often seen in obesity, further showing a direct relationship between diet, gut microbiota, and overall health. A healthier alternative to a Western diet is a Mediterranean diet, which consists of whole grains, nuts, fruits, vegetables, fish, poultry, and low amounts of other meats. The Mediterranean diet is a potential treatment for several mental health disorders, as it has been shown to reduce incidence of clinical depression and usage of antidepressant medication [18]. Mediterranean diets are also high in omega-3, which has an anti-inflammatory effect on the body. As previously mentioned, anxiety and depression are associated with chronic low-grade inflammation, so taking additional omega-3 supplements has also been shown to help with these disorders [18].
Another potential therapy method for treating GBA dysfunction is the consumption of probiotics. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit to the host. Probiotics, usually taken in pill form, are known to have enormous GI benefits. Multiple studies have shown that taking probiotics decreases anxiety and depression-like behavior in mice. One study cites that anxiety-like behavior induced by a high fat diet can actually be prevented by probiotic treatment [19]. Administration of probiotics can also prevent the intestinal permeability of gut lining that is caused by stress, and also decrease plasma levels of cortisol. These findings suggest that probiotic treatment is able to dampen the HPA axis response to chronic stress, and in the process lessen anxiety and depression-like behaviors [19]. The results of these studies suggest that simply taking a probiotic pill can improve gut microbiota composition and thus alleviate symptoms of anxiety and depression.
In addition to taking supplements, other lifestyle changes can improve the health of the GBA. For example, eating fermented foods such as yogurt, sauerkraut, kimchi, cured meats, and kombucha. Fermented foods are made through controlled microbial growth and enzymatic conversions of different food components. Eating fermented food is beneficial because they contain live microorganisms which can act similarly to probiotics [20]. High fiber foods with prebiotics such as onions, leeks, asparagus, and bananas can also induce the growth of beneficial microbes in the gut [21]. Other methods that improve the health of the GBA that do not involve medication include lowering stress levels, getting enough sleep, eating slowly, staying hydrated, and getting tested for any food intolerances.
Understanding how the central and enteric nervous systems are connected and exactly how they interact has vast implications for the future treatment of both GI and mental health disorders. There are numerous ways in which one can try to improve their GBA health, many not even requiring a prescription. The explosion of research in this field in the past decade has opened many doors for novel treatment ideas for those who have not found relief with traditional methods. At the very least, this new information sheds a light on how important taking care of gut health is to promote holistic health and overall well being.
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