Accumulating evidence suggest that there exits a bi-directional communication system between the gastrointestinal tract and the brain. Changes in gut microbiota can influence cognitive and emotional stress processes through interactions with the brain and altered emotional states and dysfunction of the gut microbiome-brain axis has been implicated in stress-related disorders such as depression. Brain-gut interactions could occur in various ways: 1) microbial compounds communicate via the vagus nerve, which connects the brain and the digestive tract, and 2) microbially derived metabolites interact with the immune system, which maintains its own communication with the brain. Although the pathways linking gut bacteria with the brain are incompletely understood, one of the principal mechanisms proposed to underlie stress-induced alterations is the "leaky gut" phenomenon. Specifically, increased translocation of bacterial products, due to a compromised gut barrier has been linked to activation of the immune system and HPA axis. In line with these findings, human studies have demonstrated a stress-induced increase in bacterial translocation in depression. The stress-induced interactions between the gut microbiome and the brain are further mediated via central processes such as neurotransmission and neurogenesis. For instance, there is substantial evidence to demonstrate a role for the gut commensals in the regulation and development of the 5-HT system and the expression of BDNF. Virtually all corticolimbic brain structures that are involved in mood regulation and stress response express 5-HT receptors. These include the prefrontal cortex, amygdala, hippocampus and nucleus accumbens. A recent meta-analyses of fMRI studies support hyperactivation of several of these regions in response to fearful faces in MDD, which extent correlated positively with the severity of depressive symptoms. Furthermore, during resting state fMRI, MDD patients showed lower connectivity between the amydgala, hippocampus, parahippocampus, and brainstem, while the connectivity strength was inversely correlated with general depression. The hippocampus, and its connection to other limbic, striatal and PFC regions, seems to play a key role in stress regulation, given that hippocampal neurogenesis mediates antidepressant effects via the ventral hippocampus' influence on the HPA axis, and mechanisms by which antidepressants may reverse chronic stress-induced 5-HT and neurogenic changes. Notably, BDNF may contribute to the modulation of neurogenesis in response to both stress and antidepressants, as hippocampal BDNF levels decrease in response to chronic stress and increase in response to antidepressant treatments.