Introduction
Major depressive disorder (MDD) manifests by persistent depressed mood, anhedonia, changes in sleep and appetite, fatigue, guilt as well as hopelessness and suicidality.1 MDD is quite prevalent and remains a leading cause of disease burden worldwide.2 Antidepressants in combination with psychotherapies are helpful but do not work for all persons with MDD. In fact, 30%–50% of depressed patients exhibit only a partial response to antidepressants with significant residual symptoms.3 Conversely, about 10%–30% of patients with MDD are resistant to the therapeutic effects of antidepressants and are classified as treatment non-responders.3 This variability in treatment response among these patients may reflect diverse pathogenesis of yet undetermined subgroups of MDD.4 Biological markers have implicated multiple mechanisms including neuroinflammation, neuroendocrine changes and gut microbiome abnormalities.2 4 While there is no clear pathway unifying these theories, the mapping of the human microbiota offers new avenues of exploration.5–7
The gut microbiota is an ecosystem containing some 100 trillion microorganisms that enjoy a symbiotic relationship with the host in times of good health.5 Firmicutes and Bacteroidetes are the two dominant bacterial phyla that constitute 90% of the total ecosystem.5 Genes, age, sex, diet, life experiences, the environment and stress levels can all impact the development of the gut microbiota.5 The microbiota influences digestion, vitamin production, the permeability of the intestinal barrier and immunity. The gut microbiome also has a bidirectional effect on the brain through the gut-brain axis.2 5 The gut-brain axis refers to the bidirectional crosstalk between the gut and the brain and is implicated in hormonal, immunological and neural homoeostasis. This means that changes in the gut microbes can affect the central nervous system (CNS), including response to stress, mood and anxiety states.2 5 Similarly, persistent stress may alter the composition of the microbiota resulting in the so-called stress-related dysbiosis (ie, a relative abundance of proinflammatory gut microbes). Persistent stress can also affect the intestinal barrier, causing a ‘leaky gut’, which allows toxic microbial products into the systemic circulation and ultimately the brain.5 This intricate relationship remains largely uninvestigated in human samples but shows promise in providing different approaches through which to view and treat MDD.2 6 8