Most of us are familiar with Hippocrates’s four humors. According to the humoral theory, our bodies consist of four essential bodily fluids or humors: blood, phlegm, yellow bile and black bile. Hippocratic medicine considered illness to be the result of physical excesses or deficiencies of different humors. For instance, melancholia (depression) was considered to be a consequence of excess black bile and its treatment consisted of restoring humoral equilibrium by bloodletting, purging, exercise and dietary changes. The Hippocratic emphasis on rectifying humoral imbalance gave way to the Cartesian separation of mind and body. This need for a localized, tangible cause of pathology rendered the humoral theory as little more than an artifact of pre-scientific western medicine. However, recent research suggests that Hippocrates may have been onto something.
The Cartesian dominance in western medicine is also evident in mental healthcare. Despite inadequate evidence, the etiology of mental health disorders has largely been confined to the head, giving rise to ‘top-down’ explanatory models. In recent years, the ‘gut-brain axis’ has been gaining a lot of attention in scientific and medical communities. An exploration into the bi-directional connections between our brain and our gut has given rise to the possibility that our gut may be influencing our mental well-being and playing a major role in disorders like anxiety and depression, thereby affecting our quality of life. Thus, this bottom-up influence of the gut may provide a potential new treatment approach for these disorders.
The evidence of a bi-directional communication between our brain and gut can be found in the gastrointestinal co-morbidities involved in psychiatric illnesses. For instance, people suffering from major depression commonly suffer from comorbid irritable bowel syndrome. Conversely, administration of antibiotics has been associated with psychiatric side effects like anxiety and delirium, even in patients without a history of psychiatric illnesses. The Gut-Brain Axis (GBA) comprises of the central nervous system (the brain and the spinal cord), the autonomic nervous system (the sympathetic, parasympathetic and enteric nervous systems) as well as the Hypothalamic-Pituitary-Adrenal axis (HPA axis). A major component of the GBA is the gut microbiome. The human intestine is host to a plethora of microorganisms such as bacteria, collectively known as the gut microbiome. These microbes play a role in digestion, absorption of nutrients and healthy development of the immune system, thereby engaging in a mutually beneficial relationship with the host. They are also responsible for the synthesis of a substantial amount of the body’s serotonin and maintaining the integrity of the gut wall, both of which have important implications in depressive disorders.
Major Depressive Disorder is a mood disorder characterized by persistent feelings of sadness, hopelessness, loss of appetite and several other physical and psychological symptoms, including suicidal ideation. Our knowledge of this debilitating condition remains incomplete and the existing treatments are falling short in the efficient management of these symptoms, as evidenced in its estimated global prevalence of over 300 million. One of the primary biological causal factors underlying depressive episodes is the dysregulation of the HPA axis. The HPA axis, consisting of the hypothalamus, the pituitary glands and the adrenal glands, is responsible for our body’s response to stress and maintenance of homeostasis.
Stress can be defined as a physical or psychological threat to an organism’s homeostasis. Exposure to stressors, thus initiates a chain of physiological changes in the body, aimed at restoring this disrupted homeostasis. Stress changes the composition of the gut microbiota and affects the permeability of the intestine wall. This “leaky gut” in turn induces the release of pro-inflammatory cytokines, proteins that regulate our body's inflammatory and immune responses to fight off infections. Certain proinflammatory cytokines activate the HPA axis. The hypothalamus, located in the brain, responds by secreting the corticotropin-releasing hormone (CRH). The CRH further acts on the anterior pituitary gland located at the base of the hypothalamus and triggers the release of the adrenocorticotropic hormone (ACTH) which travels to the adrenal glands through blood circulation. Upon reaching the adrenal glands, ACTH stimulates the release of cortisol which aids in our body’s survival and adaptation to the stressor. However, after reaching a certain blood concentration, the cortisol exerts a negative feedback on the HPA axis to return to basal homeostasis. The failure of this negative feedback leads to sustained elevation of blood cortisol levels (a hallmark of depression) which is harmful to the body. This failure may occur as a result of consistent activation of the HPA axis in response to chronic stress.
In 2004, Nobuyuki Sudo and his colleagues at the Kyushu University, Japan, reported an undeveloped immune system and exaggerated stress reactivity in mice without intestinal microbiota (germ-free mice). They also found that it was possible to reverse this stress response by introducing a strain of bacteria called Bifidobacterium Infantis in the germ-free mice. Following this landmark study, a growing number of animal studies have consistently demonstrated the influence of gut microbiota on anxiety and depression as well as the beneficial effects of probiotic treatment on these symptoms. Though the literature on human participants is lacking, evidence from existing clinical trials suggests that gut microbiota is a promising therapeutic target for anxiety and depression.
Isha Puntambekar
